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    You are here : Home » MS Research News » Stem Cell Research & Treatment » General Stem Cell Research » Neural Stem Cells

    Neural Stem Cells

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    Important new findings with neural stem cells

    Stem CellsAs immature cells, neural stem cells must stick together in a protected environment called a niche in order to divide so they can make all of the cells that populate the nervous system. But when it's time to mature, or differentiate, the neural stem cells must stop dividing, detach from their neighbors and migrate to where they are needed to form the circuits necessary for humans to think, feel and interact with the world.

    Now, stem cell researchers at UCLA have identified new components of the genetic pathway that controls the adhesive properties and proliferation of neural stem cells and the formation of neurons in early development.

    The finding by scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA could be important because errors in this pathway can lead to a variety of birth defects that affect the structure of the nervous system, as well as more subtle changes that impair cognitive and motor functions associated with disorders such as autism.

    The results of the four-year study are published April 26, 2012 in the peer-reviewed journal Neuron.

    The UCLA team found that a delicate balance of gene expression enables the pool of neural stem and progenitor cells in early development to initially increase and then quickly stop dividing to form neurons at defined times.

    "One of the greatest mysteries in developmental biology is what constitutes the switch between stem cell proliferation and differentiation. In our studies of the formation of motor neurons, the cells that are essential for movement, we were able to uncover what controls the early expansion of neural stem and progenitor cells, and more importantly what stops their proliferation when there are enough precursors built up," said Bennett G. Novitch, an assistant professor of neurobiology, a Broad Stem Cell Research Center scientist and senior author of the study. "If the neurons don't form at the proper time, it could lead to deficits in their numbers and to catastrophic, potentially fatal neurological defects."

    During the first trimester of development, the neural stem and progenitor cells form a niche, or safe zone, within the nervous system. The neural stem and precursor cells adhere to each other in a way that allows them to expand their numbers and keep from differentiating. A protein called N-cadherin facilitates this adhesion, Novitch said.

    When it is time for the neural precursors to become motor neurons, two proteins that repress gene expression, called Foxp2 and Foxp4, become elevated and then silence N-cadherin expression, causing the clustered neural stem and precursor cells to break apart and begin differentiating.

    "We have these cells in a dividing state, making more of themselves, and to make neurons that process has to be stopped and those contacts between the cells disassembled," Novitch said. "Until now, it has not been clear how the cells are pulled apart."

    Novitch and his team showed that if you eliminate Foxp protein function, motor neurons and other mature cells in the nervous system are not properly formed because the N-cadherin gene is not silenced, confirming the delicate balancing act that must be achieved for normal development of both the stem and precursor cells and their neuronal progeny.

    "It's a fundamental discovery. Most studies have focused on defining what promotes the adhesiveness and self-renewal of neural stem cells, rather than what breaks these contacts," Novitch said. "We were also surprised to see how small changes in the degree of cell adhesion can markedly alter the development and structure of the nervous system. It's all about balance, if you have too many or too few stem and precursor cells, the result could be disastrous."

    Going forward, Novitch and his team will examine whether the functions of Foxp2 and Foxp4 in regulating cell adhesion may be important for the maintenance and differentiation of neural stem cells in the adult brain, and whether the loss of their activity may contribute to the formation and growth of brain tumors. In addition, Novitch's group plans to examine whether their findings are relevant for investigating the function of Foxp2 and Foxp4 in other aspects of neural development, as mutations in Foxp proteins have previously been associated with a range of intellectual disabilities and speech-language disorders.

    "It is tempting to speculate that these loss-of-function phenotypes might result from abnormal cell adhesion associated with dysregulated N-cadherin expression or function," the study states.

    "If true, these findings could provide a molecular explanation for the association of Foxp mutations with developmental human language and motor disorders, including autism."

    Source: Science Daily Copyright © 1995-2011 ScienceDaily LLC (26/04/12)

    'Housekeeping' mechanism for brain stem cells discovered

    StemcellsResearchers at Columbia University Medical Center (CUMC) have identified a molecular pathway that controls the retention and release of the brain’s stem cells. The discovery offers new insights into normal and abnormal neurologic development and could eventually lead to regenerative therapies for neurologic disease and injury.

    The findings, from a collaborative effort of the laboratories of Drs. Anna Lasorella and Antonio Iavarone, were published today in the online edition of Nature Cell Biology.

    The research builds on recent studies, which showed that stem cells reside in specialized niches, or microenvironments, that support and maintain them.

    “From this research, we knew that when stem cells detach from their niche, they lose their identity as stem cells and begin to differentiate into specific cell types,” said co-senior author Antonio Iavarone, MD, professor of Pathology and Neurology at CUMC.

    “However, the pathways that regulate the interaction of stem cells with their niche were obscure,” said co-senior author Anna Lasorella, MD, associate professor of Pathology and Pediatrics at CUMC and a member of the Columbia Stem Cell Initiative.

    In the brain, the stem cell niche is located in an area adjacent to the ventricles, the fluid-filled spaces within the brain. Neural stem cells (NSCs) within the niche are carefully regulated, so that enough cells are released to populate specific brain areas, while a sufficient supply is kept in reserve.

    In previous studies, Drs. Iavarone and Lasorella focused on molecules called Id (inhibitor of differentiation) proteins, which regulate various stem cell properties. They undertook the present study to determine how Id proteins maintain stem cell identity.

    The team developed a genetically altered strain of mice in which Id proteins were silenced, or knocked down, in NSCs. In the absence of Id proteins, mice died within 24 hours of birth. Their brains showed markedly lowered NSC proliferative capacity, and their stem cell populations were reduced.

    Studies of NSCs from this strain of mice revealed that Id proteins directly regulate the production of a protein called Rap1GAP, which in turn controls Rap1, one of the master regulators of cell adhesion. The researchers found that the Id-Rap1GAP-Rap1 pathway is critical for the adhesion of NSCs to their niche and for NSC maintenance.

    “There may be other pathways involved, but we believe this is the key pathway,” said Dr. Iavarone. “There is good reason to believe that it operates in other kinds of stem cells, and our labs are investigating this question now.”

    “This is a new idea,” added Dr. Lasorella. “Before this study, the prevailing wisdom was that NSCs are regulated by the niche components, conceivably through the release of chemical attractants such as cytokines. However, our findings suggest that stem cell identity relies on this mechanism.”

    More research needs to be done before the findings can be applied therapeutically, Dr. Iavarone said. “Multiple studies show that NSCs respond to insults such as ischemic stroke or neurodegenerative diseases. If we can understand how to manipulate the pathways that determine stem cell fate, in the future we may be able to control NSC properties for therapeutic purposes.”

    "Another aspect,” added Dr. Lasorella, “is to determine whether Id proteins also maintain stem cell properties in cancer stem cells in the brain. In fact, normal stem cells and cancer stem cells share properties and functions. Since cancer stem cells are difficult to treat, identifying these pathways may lead to more effective therapies for malignant brain tumors."

    Stephen G. Emerson, MD, PhD, director of the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital/Columbia University Medical Center, added that, "Understanding the pathway that allows stem cells to develop into mature cells could eventually lead to more effective, less toxic cancer treatments. This beautiful study opens up a wholly unanticipated way to think about treating brain tumors."

    The paper is titled “Id proteins synchronize stemness and anchorage to the niche of neural stem cells.”

    Other contributors are Francesco Niola (CUMC), Xudong Zhao (CUMC), Devendra Singh (CUMC), Angelica Castano (CUMC), Ryan Sullivan (CUMC), Mario Lauria (Telethon Institute of Genetics and Medicine, Naples, Italy), Hyung-song Nam (Memorial Sloan-Kettering Cancer Center, New York),, Yuan Zhuang (Duke University Medical Center, Durham, North Carolina), Robert Benezra (Memorial Sloan-Kettering), and Diego Di Bernardo (Telethon Institute of Genetics and Medicine).

    This research was supported by National Cancer Institute grants R01CA101644, R01CA131126, R01CA085628, and R01CA127643, and National Institute of Neurological Disorders and Stroke grant R01NS061776.

    The authors declare no financial or other conflicts of interest.

    Source: Newswise ©2012 Newswise, Inc (23/04/12)

    New stem cell found in brain: could help to heal and repair brain injury and disease

    Stem Cells Researchers at Lund University in Sweden have discovered a new stem cell in the adult brain. These cells can proliferate and form several different cell types -- most importantly, they can form new brain cells. Scientists hope to take advantage of the finding to develop methods to heal and repair disease and injury in the brain.

    Analyzing brain tissue from biopsies, the researchers for the first time found stem cells located around small blood vessels in the brain. The cell's specific function is still unclear, but its plastic properties suggest great potential.

    "A similar cell type has been identified in several other organs where it can promote regeneration of muscle, bone, cartilage and adipose tissue," said Patrik Brundin, M.D., Ph.D., Jay Van Andel Endowed Chair in Parkinson's Research at Van Andel Research Institute (VARI), Head of the Neuronal Survival Unit at Lund University and senior author of the study.

    In other organs, researchers have shown clear evidence that these types of cells contribute to repair and wound healing. Scientists suggest that the curative properties may also apply to the brain. The next step is to try to control and enhance stem cell self-healing properties with the aim of carrying out targeted therapies to a specific area of the brain.

    "Our findings show that the cell capacity is much larger than we originally thought, and that these cells are very versatile," said Gesine Paul-Visse, Ph.D., Associate Professor of Neuroscience at Lund University and the study's primary author. "Most interesting is their ability to form neuronal cells, but they can also be developed for other cell types. The results contribute to better understanding of how brain cell plasticity works and opens up new opportunities to exploit these very features."

    The study, published in the journal PLoS ONE, is of interest to a broad spectrum of brain research. Future possible therapeutic targets range from neurodegenerative diseases to stroke.

    "We hope that our findings may lead to a new and better understanding of the brain's own repair mechanisms," said Dr. Paul-Visse. "Ultimately the goal is to strengthen these mechanisms and develop new treatments that can repair the diseased brain."

    Source: Science Daily Copyright © 1995-2011 ScienceDaily LLC (23/04/12)

    Development of the glial cell revealed

    Glial CellsA vast majority of cells in the brain are glial, yet our understanding of how they are generated, a process called gliogenesis, has remained enigmatic. Researchers at Baylor College of Medicine have identified a novel transcripitonal cascade that controls these formative stages of gliogenesis and answered the longstanding question of how glial cells are generated from neural stem cells.

    The findings appear in the current edition of Neuron.

    "Most people are familiar with neurons, cells that process and transmit information in the brain. Glial cells, on the other hand, make-up about 80 percent of the cells in the brain and function by providing trophic support to neruons, participating in neurotransmission, myelin sheaths for axons, and comprise the blood brain barrier," said Dr. Benjamin Deneen, assistant professor of neuroscience at BCM. "Importantly, glia have been linked to numerous CNS pathologies, from brain tumors and spinal cord injury and several neurological disorders including, Retts Syndrome, ALS, and Multiple Sclerosis. Therefore deciphering how glial cells are generated is key to understanding brain function during health and disease."

    As researchers began investigating glial development in chicks they started by going backwards – examing what steps were needed before the glial cells matured. They discovered that glial cells are specified in neural stem cells when the transcription factor NFIA is induced.

    Taking another step back in the transcriptional cascade, they looked for what triggered NFIA induction.

    "By comparing mouse and chick regulatory sequences we were able to perform enhancer screening in the chick to identify regulatory elements with activity that resembled NFIA induction. This method allowed us to pinpoint Sox9," said Peng Kang, postdoctoral associate in the Center for Stem Cell and Regenerative Medicine at BCM. "Subsequently, we found that Sox9 doesn't just induce NFIA expression, it also associates with NFIA, forming a complex."

    Just after the initiation of gliogenesis this complex was discovered to co-regulate a subset of genes that play important roles in mitochondria energy metabolism and glial precursor migration.

    "Sox9 induces NFIA expression during glial initiation and then binds NFIA to drive lineage progression by cooperatively regulating a genetic program that controls cell migration and energy metabolism, two key processes associated with cellular differentiation," said Deneen. "We now need to ask what other proteins contribute to this process, and how does the nature of this complex evolve during astro-glial lineage progression."

    Additionally, these findings may also help researchers to understand how certain brain tumors might begin to form, as these same developmental processes and proteins are found in both adult and pediatric brain tumors. A more comprehensive understanding how this regulatory cascade operates during development, could eventually lead to better treatment targets for brain tumors.

    Others who took part in this study include Drs. Hyun Kyoung Lee (co-first author), Stacey Glasgow, Meggie Finely, Tataka Donti, Zachary B. Garber, Brett H. Graham, Aaron E. Foster, Bennett G. Novitch, and Richard M. Gronostajski.

    Research was supported by funding from the Musella Brain Tumor Foundation, V. Foundation for Cancer Research, and the National Institutes of Health.

    Source: Eureka Alert! Copyright ©2012 by AAAS, the science society (12/04/12)

    Neuroprotective effects seen in rats receiving placenta-derived stem cell transplant

    Stem CellsIn a study presented at the Society for Maternal-Fetal Medicine's annual meeting, The Pregnancy Meeting™, in Dallas, Texas, researchers reported that early transplantation of human placenta-derived mesenchymal stem cells into the lateral ventricles of neonatal rats with birth-related brain damage is possible, and that the donor cells can survive and migrate in the recipient's brain.

    The study was designed to have the rat's brain damage mimic brain injury in infants with very low birth weight.

    One of the major causes of neonatal brain damage is preterm delivery. Despite enormous efforts to prevent it, brain injury accounts for a major part of the clinical problems experienced by survivors of premature birth. The enormity of this problem is indicated by the occurrence of: cognitive, behavioral, attention related and/or socialization deficits in twenty-five to fifty percent of cases in this group; and major motor deficits in five to ten percent of cases in this group.

    The majority of neonatal encephalopathy cases are found in infants with a very low birth weight, and include both hypoxia-ischemia and inflammation, a double-hit. Approximately 63,000 infants are born in the United States with a very low birth weight (one to five percent of all live births). In order to understand the effect of such a double-hit insult in very premature infants, this study, Early Intracranial Mesenchymal Stem Cell Therapy After a Perinatal Rat Brain Damage, was undertaken to investigate the neuroprotective effects of mesenchymal stem cells therapy on postnatal rats, whose injury was designed to mimic brain injury in infants with a very low birth weight.

    "Stem cells are a promising source for transplant after a brain injury because they have the ability to divide throughout life and grow into any one of the body's more than 200 cell types, which can contribute to the ability to renew and repair tissues," said Martin Müller, MD, with the University of Bern, Obstetrics and Gynecology, Bern, Switzerland, and one of the study's authors. "In our study, the donor cells survived, homed and migrated in the recipient brains and neurologic improvement was detected."

    Assessment of the post-experiment brain damage indicated a neuroprotective effect of mesenchymal stem cell transplantation and a combination of mesenchymal stem cell and erythropoietin (a modulator substance the subjects received on postnatal days six, seven and eight) therapy.

    Source: Medical News Today © MediLexicon International Ltd 2004-2012 (13/02/12)

    Cloned brain cells could help MS, Parkinsons, depression patients

    NeuronsFrom the birthplace of Dolly the sheep comes another advancement in cloning, as scientists at Scotland’s University of Edinburgh have reportedly created brain tissue from patients suffering from mental illnesses.

    According to NewsCore reports, researchers at the university’s Centre for Regenerative Medicine (CRM) have developed a method of taking a patient’s skin sample, turning it into stem cells, and then directing them to grow into brain cells. They then study those man-made brain cells hoping to learn more about patients suffering from ailments such as bipolar depression and schizophrenia.

    “A patient’s neurons can tell us a great deal about the psychological conditions that affect them, but you cannot stick a needle in someone’s brain and take out its cells,” CRM Director Charles ffrench-Constant told Robin McKie of The Guardian on Saturday.

    “However, we have found a way round that,” he added. “Essentially, we are turning a person’s skin cells into brain. We are making cells that were previously inaccessible. And we could do that in future for the liver, the heart and other organs on which it is very difficult to carry out biopsies.”

    In addition to mental illnesses, the scientists are looking for ways to treat neurological conditions such as multiple sclerosis, Parkinson’s disease and motor neuron disease, McKie wrote. The former project is being led by Professor Andrew McIntosh of the Royal Edinburgh Hospital, while ffrench-Constant is heading up the latter.

    “We are making different types of brain cells out of skin samples from people with schizophrenia and bipolar depression,” McIntosh told the Guardian. “Once we have assembled these, we look at standard psychological medicines, such as lithium, to see how they affect these cells in the laboratory. After that, we can start to screen new medicines.”

    “Our lines of brain cells would become testing platforms for new drugs. We should be able to start that work in a couple of years,” he continued, adding that previously scientists could only obtain test samples from patients who had already passed on, and in many cases those samples were contaminated by whatever disorder killed them and whatever medication they had been taking to treat their condition(s).

    Meanwhile, ffrench-Constant will attempt to create brain cells from MS patients, hoping to determine why some patients can live many years with the ailment while others see their condition degenerate rapidly.

    “We will take skin samples from MS patients whose condition has progressed quickly and others in whom it is not changing very much,” he said, adding that if they “can find out the roots of the difference, we may be able to help patients.”

    Source: Red Orbit © 2002-2012 redOrbit.com. (31/01/12)

    Skin transformed into brain cells

    NeuronsSkin cells have been converted directly into cells which develop into the main components of the brain, by researchers studying mice in California.

    The experiment, reported in Proceedings of the National Academy of Sciences, skipped the middle "stem cell" stage in the process.

    The researchers said they were "thrilled" at the potential medical uses.

    Far more tests are needed before the technique could be used on human skin.

    Stem cells, which can become any other specialist type of cell from brain to bone, are thought to have huge promise in a range of treatments. Many trials are taking place, such as in stroke patients or specific forms of blindness.

    One of the big questions for the field is where to get the cells from. There are ethical concerns around embryonic stem cells and patients would need to take immunosuppressant drugs as any stem cell tissue would not match their own.

    An alternative method has been to take skin cells and reprogram them into "induced" stem cells. These could be made from a patient's own cells and then turned into the cell type required, however, the process results in cancer-causing genes being activated.

    Direct approach

    The research group, at the Stanford University School of Medicine in California, is looking at another option - converting a person's own skin cells into specialist cells, without creating "induced" stem cells. It has already transformed skin cells directly into neurons.

    This study created "neural precursor" cells, which can develop into three types of brain cell: neurons, astrocytes and oligodendrocytes.

    These precursor cells have the advantage that, once created, they can be grown in a laboratory into very large numbers. This could be critical if the cells were to be used in any therapy.

    Brain cells and skin cells contain the same genetic information, however, the genetic code is interpreted differently in each. This is controlled by "transcription factors".

    The scientists used a virus to infect skin cells with three transcription factors known to be at high levels in neural precursor cells.

    After three weeks about one in 10 of the cells became neural precursor cells.

    Lead researcher Prof Marius Wernig said: "We are thrilled about the prospects for potential medical use of these cells.

    "We've shown the cells can integrate into a mouse brain and produce a missing protein important for the conduction of electrical signal by the neurons.

    "More work needs to be done to generate similar cells from human skin cells and assess their safety and efficacy."

    Dr Deepak Srivastava, who has researched converting cells into heart muscle, said the study: "Opens the door to consider new ways to regenerate damaged neurons using cells surrounding the area of injury."

    Source: BBC News © British Broadcasting Corporation 2012 (31/01/12)

    Scientists grow neurons that integrate into brain

    StemcellsScientists at the University of Wisconsin-Madison have grown human embryonic stem cells into neurons that appear capable of adapting themselves to the brain's machinery by sending and receiving messages from other cells, raising hopes that medicine may one day use this tool to treat patients with such disorders as Multiple Sclerosis, Parkinson's and amyotrophic lateral sclerosis, commonly known as Lou Gehrig's disease.

    Researchers inserted the human cells into the brains of mice where they successfully integrated themselves into the wiring. Then the UW team applied a new technology, using light to stimulate the human cells and watching as they in turn activated mouse brain cells.

    In a lab dish, the brain cells or neurons began firing simultaneously "like a power surge lighting up a building," said Jason Weick, an assistant scientist at UW who worked on the study published online Monday in the journal Proceedings of the National Academy of Sciences.

    Weick said the use of light stimulation, called optogenetics, raises the possibility of modifying transplanted brain cells, in effect turning them up or down like the dimmer control on a light.

    "You can imagine that if the transplanted cells don't behave as they should, you could use this system to modulate them using light," said Su-Chun Zhang, a UW professor of neuroscience and one of the authors of the new study.

    For years, scientists have talked of the possibility of growing neurons in a dish to replace damaged cells in the brain, but there always have been questions about whether the transplanted cells could become fully functional.

    But the new work at UW suggests the idea may be poised to make the transition from theory to reality.

    'Function of neurons'

    "They have shown real function of neurons. This means they really can play a role in neural repair," said Arshak Alexanian, an associate professor in the department of neurosurgery at the Medical College of Wisconsin, who did not participate in the UW study.

    "We are getting similar results," Alexanian said, indicating that he has been working along similar lines, only using "neural-like cells" that had been reprogrammed from adult stem cells found in the bone marrow. The advantage to using the reprogrammed adult stem cells is that they would come from the patient, removing the risk of rejection.

    When scientists reprogram cells, they change them from one type to another, a trick that can be accomplished through a variety of methods. Alexanian used synthetic molecules to change the cells.

    Recent preliminary results from his lab have shown that the human neural-like cells, when grown in culture with human neurons, form connections and behave like the neurons we're born with.

    The Medical College researcher has been transplanting these lab-made human neurons into the injured spinal cords of rats. While the rats experience some regeneration of cells without any treatment at all, Alexanian said the transplanted cells spur significant improvement, allowing rats to move formerly immobile hind legs.

    Targeting hippocampus

    At UW, Weick said the new paper built on almost three years of lab work and was successful both in a lab dish and in a live mouse. The UW team did much of its work using embryonic stem cells rather than reprogrammed cells, which are believed to be very similar. Although the reprogrammed cells are less controversial, scientists say they have some disadvantages. Weick said the embryonic stem cells are more reliable than the reprogrammed equivalents and can be coaxed into neurons with greater success.

    Weick said the UW scientists have repeated some of the experiments using reprogrammed cells, "and it works just fine."

    In the experiments with live mice, the UW researchers anesthetized the animals, inserted a needle into precise areas of the brain and injected the human neurons. The scientists selected a target for the cells where the brain's architecture is well defined and the cells would have a good chance to integrate into the circuitry: the mouse hippocampus. The hippocampus is the part of the brain in which memories are formed, organized and stored.

    When the human neurons were cultured in a lab dish with mouse cortical neurons, the human cells adopted a behavior of the mouse cells called "bursting." For mouse cells, "bursting" is a kind of rhythmic firing. The cells are, in effect, talking to one another at the same time.

    The new study was co-written by Weick, Zhang and Yan Liu, a researcher at UW's Waisman Center.

    Source: JS Online © 2011, Journal Sentinel Inc. (22/11/11)

    New type of spinal cord stem cell discovered

    Stem CellsA group led by a University of British Columbia and Vancouver Coastal Health scientist has discovered a type of spinal cord cell that could function as a stem cell, with the ability to regenerate portions of the central nervous system in people with spinal cord injuries, multiple sclerosis or amyotrophic lateral sclerosis (Lou Gehrig's disease).

    The radial glial cells, which are marked by long projections that can forge through brain tissue, had never previously been found in an adult spinal cord. Radial glia, which are instrumental in building the brain and spinal cord during an organism's embryonic phase, vastly outnumber other potential stem cells in the spinal cord and are much more accessible. Their findings were published online in PLoS One.

    Stem cells have the capability of dividing into more specialized types of cells, either during the growth of an organism or to help replenish other cells. Scientists consider stem cells a promising way to replace injured or diseased organs and tissues.

    The search for spinal stem cells of the central nervous system has until now focused deep in the spinal cord. Jane Roskams, a professor in the UBC Dept. of Zoology, broadened the search by using genetic profiles of nervous system stem cells that were developed and made publicly accessible by the Allen Institute for Brain Science in Seattle.

    Roskams, collaborating with researchers at the Allen Institute, McGill University and Yale University, found cells with similar genes - radial glial cells - along the outside edge of spinal cords of mice.

    "That is exactly where you would want these cells to be if you want to activate them with drugs while minimizing secondary damage," says Roskams, a member ICORD (International Collaboration on Repair Discoveries) and the Brain Research Center, both partnerships of UBC and the Vancouver Coastal Health Research Institute.

    Roskams' team also found that radial glial cells in the spinal cord share a unique set of genes with other neural stem cells. Several of these - when mutated - can lead to human diseases, including some that target the nervous system. That discovery opens new possibilities for potential gene therapy treatments that would replace mutated, dysfunctional spinal cord cells with healthier ones produced by the radial glial cells.

    "These long strands of radial glial cells amount to a potentially promising repair network that is perfectly situated to help people recover from spinal cord injuries or spinal disorders," Roskams says. "For some reason, they aren't re-activated very effectively in adulthood. The key is to find a way of stimulating them so they reprise their role of generating new neural cells when needed."

    The research was supported by the Canadian Institutes of Health Research, the Michael Smith Foundation for Health Research, the Natural Sciences and Engineering Research Council of Canada and the Jack Brown and Family Alzheimer's Research Foundation.

    Source: Medical News Today © MediLexicon International Ltd 2004-2011 (19/09/11)

    Stem cell efforts to treat neurological diseases bolstered with $4.5 million

    Stem CellsThe endeavor to find better treatments or perhaps even one day a cure for a host of debilitating and fatal neurological diseases has been bolstered by an influx of funding from a mix of private and public sources.

    The laboratory headed by Steven Goldman, M.D., Ph.D., chair of the Department of Neurology at the University of Rochester Medical Center, has received $4.5 million in new funding to further its efforts to use stem cells and related molecules to treat several feared disorders for which there are currently no cures – including multiple sclerosis, Huntington’s disease, and fatal childhood diseases known as pediatric leukodystrophies.

    The new funding, which will support work in the laboratory for the next three to five years, comes from a mix of private and government sources, including the National Multiple Sclerosis Society, the CHDI Foundation for Huntington’s disease research, Biogen Idec, and the National Institutes of Health.

    Goldman’s research is at the forefront of attempts to harness the promise of stem cells to benefit patients who suffer from neurological diseases. To help patients by using stem cells and their close cousins, including progenitor cells and pluripotent cells, scientists like Goldman are learning about the molecular cues involved in directing the actions of those cells. Some signals, for instance, help prod stem cells to become brain cells called neurons, while others direct them to become glial cells. Understanding the elaborate labyrinth of signals involved is crucial for physicians who would like be able to put stem cells into patients and have the cells develop into just the types necessary to help those patients.

    Two newly funded projects focus on the molecular events involved in the repair of myelin, a critical substance in the brain that breaks down in conditions such as multiple sclerosis, as well as in a number of hereditary childhood diseases. In one project, Goldman’s team is working on ways to use stem cells derived from human skin cells as the source of cells to ultimately treat patients with multiple sclerosis. In MS patients, the myelin coating of nerve fibers breaks down, so that nerve cells stop signaling efficiently. Patients with MS then suffer symptoms such as weakness and a loss in sensation and coordination. Goldman’s lab has deciphered many of the molecular steps necessary to develop stem cells derived from skin cells into an oligodendrocyte, the type of brain cell that creates myelin in the brain. Now, the team has been awarded $770,000 from the National MS Society to better define how these cells respond to demyelination in the brain, as occurs in MS, so that scientists can better predict the effects of transplanting the cells into patients.

    In a second related project funded by a $1.7 million grant from the National Institutes of Health, Goldman’s team will establish mice whose brains contain some human oligodendrocytes and human myelin in order to recreate in these mice the type of damage that occurs in the brains of MS patients. By analyzing what happens to the cells at the molecular level, the team hopes to learn how to regenerate new myelin from progenitor cells that reside in the brain.

    A closely related project, for which the lab was granted $670,000 by Biogen Idec, focuses on using these mice with human myelin to study the progression of a rare brain disease, progressive multifocal leukoencephalopathy, which can affect people whose immune systems have been suppressed with medication. The virus is found only in the human brain, posing a problem for scientists who would like to study it thoroughly. But by seeding the brains of mice from birth with human myelin, Martha Windrem in the Goldman laboratory has established mice that can be infected by the virus that causes the illness, opening up new possibilities to learn about the disorder.

    In a fourth and related project, supported with a $1.34 million grant by the CHDI Foundation, the team will explore the use of brain cells known as astrocytes to improve the condition of mice with Huntington’s disease. The goal is to prevent the death of a type of cell, known as a medium spiny neuron, which degenerates and dies in patients with the disease. The new work focuses on using astrocytes derived from stem cells to change the local brain environment in patients with Huntington’s disease – a necessary step to stop the disease in people.

    The studies on myelin repair are closely linked to the lab’s research on a group of fatal children’s disorders known as pediatric leukodystrophies, in which myelin breaks down beginning in childhood. Many of those diseases kill young children only after they have endured a near lifetime of symptoms like seizures, falls, blindness, and diminishing cognitive abilities. Goldman’s laboratory has had unprecedented success using stem cells to extend the lifespan of mice with pediatric leukodystrophies, and the team hopes to begin clinical trials in children within the next few years, in part based on the findings to be obtained in these related projects.

    Source: University of Rochester Medical Center © 2011 University of Rochester Medical Center (08/09/11)

    MicroRNAs transform adult cells into neurons

    Stem CellsSmall bits of RNA called microRNAs, which can influence the way a cell’s genes are turned on and off, can single-handedly cause a connective tissue cell from human skin to transform into a nerve cell, new research shows.

    The study was conducted by Howard Hughes Medical Institute (HHMI) scientists who first showed two years ago that microRNAs help immature neural stem cells develop into mature neurons. The new work demonstrates that in developing neurons, microRNAs aren’t just handmaidens to change; they’re actually running the show.

    “This is the first time microRNAs have been shown to have this instructive role in mammalian or human cells,” said HHMI investigator Gerald R. Crabtree of Stanford University, whose work uncovering this premier role for two particular microRNAs was published July 13, 2011, in the journal Nature. “MicroRNAs were thought not to be capable of accomplishing fate transformation,” Crabtree said.

    The discovery introduces a new method of converting adult cells of one type into cells of another, without first dialing them back to the embryonic stage – which was previously the only way to change the identity of a fully differentiated cell. Although the late Hal Weintraub, who was an HHMI investigator at the Fred Hutchinson Cancer Research Center, showed in the early 1990s that fibroblasts -- connective tissue cells that secrete collagen and other molecules -- could be converted to muscle cells, this trick is new for neurons.

    The ability to change a cell’s identity offers promise for one day replacing damaged neurons in patients who have a neurodegenerative disease, such as Parkinson’s disease. More immediately, the ability to create neurons from adult cells could lead to new experimental models for diseases in which neuronal function is impaired, such as Down syndrome and Alzheimer’s, Crabtree said.

    “We’ve had to contend with mouse models of those diseases, which have been very helpful, but inadequate,” he said. “Those are diseases that affect cognition and intellectual characteristics. It’s quite clear the degree of learning impairment one sees in humans would probably never be noticed in a mouse. For example, Alzheimer’s disease affects learning and memory -- and mice are not nearly as good at these tasks as humans.”

    Researchers would like to be able to study in the lab the basic processes that drive human nerve cell function in both healthy individuals and in those with neurodegenerative diseases. But it’s nearly impossible to harvest neurons from living humans. “Now we’ll be able to take a fibroblast cell from someone with Down syndrome and turn it into a neuron,” he said. Because neurons created in this way would carry the patient’s own DNA, they are expected to behave similarly to the patient’s neurons and be a powerful model for studying that individual’s disease.

    Crabtree pointed out that he and his colleagues were able to generate the specific type of neuron that is often damaged in many neurodegenerative diseases – those that are found in the frontal cortex region of the brain. “These are the [neurons] that have appeared most recently in human evolution, and are the neurons that team up with other neurons to carry out complex associative and synthetic thought,” he explained. “That is the region most compromised in Down syndrome, Alzheimer’s and many other human neurologic diseases. Mice have few of these neurons, making mice poor models for many human neurologic diseases.”

    Crabtree’s lab has long been involved in tracing the pathway neuronal stem cells take to adult differentiation. Neuronal stem cells are constantly dividing cells that can not only reproduce exact copies of themselves, but – when they receive the right signals -- can develop into a variety of fully differentiated cells that play distinct roles in the central nervous system.

    In 2007, Crabtree’s lab revealed a clue about the signals that drive neuronal stem cells’ development into specialized nerve cells. His team focused on a soccer ball-like complex of interchangeable proteins called a chromatin regulatory complex. Chromatin regulatory complexes are the master packers and unpackers of a cell’s long ribbon of DNA.

    In the nucleus of every human cell, there is a little over two yards of DNA, Crabtree explained. If it were untangled and expanded proportionally so that it was the width of spaghetti, that DNA would stretch from San Francisco to Los Angeles. “Imagine packing all that into a suitcase and having to unpack it and find exactly the right spot in a few minutes,” he said. The chromatin assembly complex is in charge of packing yards of DNA into a space about 1/100,000 of an inch. The complexes also play a critical role in unpacking, revealing specific sections of the genetic material to the machinery of gene expression for transcription into RNA.

    Crabtree’s team found that a change in the structure of the chromatin assembly complex coincided with the moment the neuronal stem cells became mature neurons, and identified two specific microRNAs that directed that change: miR-9* and miR-124.

    Crabtree said he realized the potency of microRNA not long after he and Andrew S. Yoo, a postdoctoral researcher in his lab, made that discovery. To test the broader effects of put miR-9* and miR-124, Yoo put into a plate of human fibroblast cells and they learned that microRNA wasn’t just a member of the band in differentiation. It waved the baton.

    “Andrew came to me and asked me to look through the microscope. I saw cells that, to my eye, looked indistinguishable from neurons. He told me, ‘Those cells have just gotten the microRNA and nothing else, and they were fibroblast cultures.’

    “That was our 'Eureka!' moment,” Crabtree said. “At that point we realized there was, to at least some degree, an instructive role for these microRNAs. They were more than just required for the formation of neurons, they were really instructing the formation of neurons.”

    He left the lab a very happy – but cautious -- man. “They look just too good to be true,” he remembers thinking. The fibroblast-derived neurons looked like the real thing, but did they behave like them as well? The lab quickly embarked on further experiments to find out.

    Crabtree tested the cells for a score of proteins that neurons are known to express. All were present. They checked to see if the new neurons formed synapses with other neurons. They did. They tested the cells’ ability to propagate electrical nerve signals. The new neurons behaved exactly like native neurons. “In all the ways we could test them, they were normally functioning neurons,” Crabtree said.

    Although the microRNAs all by themselves are able to turn fibroblasts into neurons, only a few percent of the cells on a laboratory plate make the transition, Crabtree said. He was able to boost the purity of the final population to well over 50 percent with a few tweaks, such as adding regulatory proteins that activate certain neuron-specific genes. With that success, Crabtree’s team is particularly optimistic that their conversion process will be valuable in allowing researchers to create the models they need to study nerve function and disease.

    Source: HHMI News © 2011 Howard Hughes Medical Institute (14/07/11)

    Nervous system stem cells can replace themselves, give rise to variety of cell types, even amplify

    Neural Stem CellsA Johns Hopkins team has discovered in young adult mice that a lone brain stem cell is capable not only of replacing itself and giving rise to specialized neurons and glia - important types of brain cells - but also of taking a wholly unexpected path: generating two new brain stem cells.

    A report on their study appears June 24 in Cell.

    Although it was known that the brain has the capacity to generate both neurons, which send and receive signals, and the glial cells that surround them, it was unclear whether these various cell types came from a single source. In addition to demonstrating that a single radial glia-like (RGL) brain cell is able to generate two very different functional cell types, the Hopkins researchers, by following the fates of single cells over time, found that a single brain stem cell can even produce two stem cells like itself.

    "Now we know they don't just maintain their numbers, or go down in number, but that stem cells can amplify," says Hongjun Song, Ph.D., professor of neurology and neuroscience and director of the Stem Cell Program in the Institute for Cell Engineering, the Johns Hopkins University School of Medicine. "If we can somehow cash in on this newly discovered property of stem cells in the brain, and find ways to intervene so they divide more, then we might actually increase their numbers instead of losing them over time, which is what normally happens, perhaps due to aging or diseases."

    The researchers' findings hinged on a decision to single out and follow lone, radial glia-like cells, instead of labeling and monitoring entire stem cell populations in the mouse brain. They took this approach because they suspected radial glia-like cells were essentially stem cells, having been shown in previous studies to give rise to neurons.

    Using mice genetically modified with special genes that color-code cells for easy labeling and tracking, the Hopkins team injected a very small amount of a chemical into about 50 mouse brains to induce extremely limited cell labeling.

    "It's a simple idea that forced us to confront a lot of complex technical issues," Song says. "With so many millions of cells in the relatively large mouse brain, labeling a single stem cell and then chasing its family history was like finding a needle in a haystack."

    The scientists developed computer programs and devised a new imaging technique that allowed them to examine stained slices of the mouse brain and, ultimately, follow single, randomly chosen radial glia-like stem cells over time. The method allowed them to track down all the new cells derived from a single original stem cell.

    "We reconstituted single stem cells' family trees to look at the progeny they gave rise to," says Guo-li Ming, associate professor of neurology and neuroscience and a member of the Neuroregeneration Program in the Institute for Cell Engineering. "We discovered that single cells in an intact animal nervous system absolutely do exhibit stem-cell properties; they are capable of both replicating themselves and producing different types of differentiated neural progeny."

    The team followed the fates of all the marked radial glia-like stem cells for at least a month or two, and examined some a full year later to discover that even over the long term, the "mother" cell was still generating itself as well as different kinds of progeny.

    In addition, the researchers investigated how these RGLs were activated on a molecular level, focusing, in particular, on the regulatory role of an autism-associated gene called PTEN. Conventional wisdom was that deleting this gene led to an increase in stem-cell activation. However, the scientists demonstrated that was a transient effect in the mouse brains, and that, ultimately, PTEN deletion leads to stem-cell depletion.

    Support for this research came from the National Institutes of Health, the Brain and Behavior Research Foundation, and the Maryland Stem Cell Research Foundation.

    Authors of the paper, in addition to Hongjun Song and Guo-li Ming, are Michael A. Bonaguidi, Michael A. Wheeler, Jason S. Shapiro and Gerald. J. Sun, all of Johns Hopkins.

    Source: Medical News Today © MediLexicon International Ltd 2004-2011 (01/07/11)

    Skin cells 'turned into neurons' by US scientists

    NeuronsA Californian team say they have managed to convert human skin cells directly into functioning brain cells.

    The scientists manipulated the process by which DNA is transcribed within foetal skin cells to create cells which behaved like neurons.

    The technique had previously been demonstrated in mice, says the report in Nature.

    It could be used for neurological research, and might conceivably be used to create brain cells for transplant.

    Reprogrammed skin

    The scientists used genetically modified viruses to introduce four different "transcription factors" into foetal skin cells. These transcription factors play a role in the "reading" of DNA and the encoding of proteins within the cell.

    They found the introduction of these four transcription factors had the effect of switching a small portion of the skin cells into cells which functioned like neurons.

    Unlike other approaches, the process did not involve the reprogramming of the skin cells into stem cells, but rather the direct transformation of skin cells into neurons.

    Marius Wernig, an assistant professor of pathology at Stanford University School of Medicine in California, was one of the researchers.

    "We showed that it is possible to convert human skins cells directly into nerve cells which look and behave like nerve cells which usually only exist in the brain," he told BBC News.

    "It was known that it was possible to change a specialised cell back into a stem cell, what's called an induced pluripotent stem cell (iPS), but it was not known whether a specialised cell could be pushed into another direction, other than backwards."

    Professor Wernig conceded that there were examples, some dating back many years, where specialised cells have been switched into similar cell types, but he believes this is the first example of where cells have undergone such radical conversion.

    He believes the immediate application will be in modelling diseases, whereby skin cells from a patient with a known neurological condition could be used to produce new brain cells for research.

    "It is very very difficult to look into the brain. There is a big skull which protects the brain very well and therefore it's difficult to image," he said.

    "Everything that can be done at a cellular level is only possible after a patient has died, by which time the disease is usually in the final stages and you have no chance of seeing how the disease develops."

    Future treatments

    The technique might one day also be used to create new brain cells which could be transplanted into patients with neurological disorders, he said.

    Created from the patient's own skin, these cells would be an exact match for the patient, although there would be many obstacles to overcome, not least the challenge of producing enough of the right type of brain cells.

    Commenting on the study, Jim Huettner, an associate professor at Washington University School of Medicine, said the research was "convincing and important".

    "They have shown similar things in mice before but in humans they've discovered some subtle differences which often turn up when moving from mice to humans," he said.

    "But the work solidifies the idea that this kind of transition is possible and that it's not just some fluke in the mice model."

    Source: BBC News © British Broadcasting Corporation 2011 (27/05/11)

    Researchers generate functional astrocytes from stem cells

    Brain CellsScientists have developed the chemically defined conditions necessary to prompt human embryonic stem cells (hESCs) and human pluripotent stem cells (hPSCs) to differentiate into immature astrocytes.

    The University of Wisconsin-Madison team claims the immature astrocytes readily develop into mature astrocytes when implanted in the mouse brain, by forming connections with blood vessels. Writing in Nature Biotechnology, Su-Chung Zhang, Ph.D., and colleagues, report on their achievement in a paper titled “Specification of transplantable astroglial subtypes from human pluripotent stem cells.”

    Astroglial cells are the most abundant cell type in the human brain and spinal cord, and different subtypes have been shown to play essential roles in functions such as the formation and insulation of synapses, and the maintenance of a homeostatic environment, the Wisconsin team reports. Abnormalities in astroglial cells have also been linked with a range of human pathologies including neurodegenerative diseases. However, generating these cell types from human pluripotent stem cells (hPSCs) has to date remained elusive.

    Dr Zhang’s team has developed a chemically defined differentiation system for generating immature astrocytes from HPSCs including ESCs and iPSCs. To achieve this the hPSCs were differentiated to neuroepithelial cells, specified to regional progenitors, and then expanded. The researchers claim that in contrast with existing protocols for differentiating astroglial cells from human neural stem cells or fetal tissues, which have limited expansion capacities, the new approach allows the generation of a nearly pure population of astroglial progenitors that can be readily expanded to large quantities. Expansion of astroglial progenitors from the different hESC and iPSC cell lines displayed similar efficiencies.

    The resulting cultures contained minimal neurons and no immune cells, and the hPSC-derived astroglial progenitors could be expanded continuously for at least eight months, and survive freeze-thaw cycles. Importantly, the authors report, the hPSC-derived immature astrocytes could be triggered to differentiate into region-specific astroglia using a neuroepithelial cell patterning and differentiation approach similar to that for generating region-specific neuronal cell types from hPSCs.

    Evaluation of the hPSC-derived astrocytes confirmed that the cells expressed astroglial-specific marker genes, and demonstrated functional properties such as glutamate uptake and the promotion of synaptogenesis. The researchers calculated that if one hPSC was differentiated to neuroepithelial cells, converted to glial cells, and then expanded in suspension, an estimated 2.8 x 1012 immature astrocytes could be generated in about six months, even when taking cell loss into account.

    Interestingly, differentiation of human ESCs into GFAP+ astroglia took at least 12 weeks, which is substantially slower than the two weeks taken to derive cells from mouse ESCs, the authors point out. However, this increased time corresponds to astro­glial development in the human brain. Astroglial progenitors or immature astrocytes could be identified by the expression of relevant genes such as S100β and GFAP at four to eight weeks after hPSC differentiation, and more mature astrocytes were evident by 8-12 weeks. hPSC-derived day 210 astroglia expressed high levels of additional cell-specific genes.

    To determine whether the hPSC-differentiated cells maintain their identity in vivo, immature astrocytes were transplanted into the brains of experimental neonatal mice. Up to 100 days after engraftment, the human cells were found as clusters adjacent to the implantation site, and were migrating into the corpus callosum. The cells also demonstrated the correct gene-expression markers according to their location in the brain. Moreover, hESC-derived astroglia were capable of maturing and participating in blood-brain barrier structure formation in the mouse brain, and retained unique features characteristic of human astrocytes, even though the cells had been implanted into a different species.

    “Our ability to derive and expand an enriched population of astroglial progenitors, as well as differentiating them to immature astrocytes, opens up an avenue for studying the role of human astrocytes in the normal and diseased brain and for the development of transplantation therapy in neurological diseases,” the authors conclude. “In addition, astoglial cells derived from patient-specific iPSCs offer yet another approach for therapeutic discovery.”

    Source: Genetic Engineering & Biotechnology News © 2011 Genetic Engineering & Biotechnology News (24/05/11)

    Scientists create stable, self-renewing neural stem cell

    Stem CellsIn a paper published in the April 25 early online edition of the Proceedings of the National Academy of Sciences, researchers at the University of California, San Diego School of Medicine, the Gladstone Institutes in San Francisco and colleagues report a game-changing advance in stem cell science: the creation of long-term, self-renewing, primitive neural precursor cells from human embryonic stem cells (hESCs) that can be directed to become many types of neuron without increased risk of tumor formation.

    “It’s a big step forward,” said Kang Zhang, MD, PhD, professor of ophthalmology and human genetics at Shiley Eye Center and director of the Institute for Genomic Medicine, both at UC San Diego. “It means we can generate stable, renewable neural stem cells or downstream products quickly, in great quantities and in a clinical grade – millions in less than a week – that can be used for clinical trials and, eventually, for clinical treatments. Until now, that has not been possible.”

    Human embryonic stem cells hold great promise in regenerative medicine due to their ability to become any kind of cell needed to repair and restore damaged tissues. But the potential of hESCs has been constrained by a number of practical problems, not least among them the difficulty of growing sufficient quantities of stable, usable cells and the risk that some of these cells might form tumors.

    To produce the neural stem cells, Zhang, with co-senior author Sheng Ding, PhD, a former professor of chemistry at The Scripps Research Institute and now at the Gladstone Institutes, and colleagues added small molecules in a chemically defined culture condition that induces hESCs to become primitive neural precursor cells, but then halts the further differentiation process.

    “And because it doesn’t use any gene transfer technologies or exogenous cell products, there’s minimal risk of introducing mutations or outside contamination,” Zhang said. Assays of these neural precursor cells found no evidence of tumor formation when introduced into laboratory mice.

    By adding other chemicals, the scientists are able to then direct the precursor cells to differentiate into different types of mature neurons, “which means you can explore potential clinical applications for a wide range of neurodegenerative diseases,” said Zhang. “You can generate neurons for specific conditions like amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), Parkinson’s disease or, in the case of my particular research area, eye-specific neurons that are lost in macular degeneration, retinitis pigmentosa or glaucoma.”

    The new process promises to have broad applications in stem cell research. The same method can be used to push induce pluripotent stem cells (stem cells artificially derived from adult, differentiated mature cells) to become neural stem cells, Zhang said. “And in principle, by altering the combination of small molecules, you may be able to create other types of stem cells capable of becoming heart, pancreas, or muscle cells, to name a few.”

    The next step, according to Zhang, is to use these stem cells to treat different types of neurodegenerative diseases, such as macular degeneration or glaucoma in animal models.

    Funding for this research came, in part, from grants from National Institutes of Health Director’s Transformative R01 Program, the National Institute of Child Health and Development, the National Heart, Lung, and Blood Institute, the National Eye Institute, the National Institute of Mental Health, the California Institute for Regenerative Medicine, a VA Merit Award, the Macula Vision Research Foundation, Research to Prevent Blindness, a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and the Richard and Carol Hertzberg Fund.

    Co-authors of the study include Wenlin Li, Yu Zhang, Wanguo Wei, Rajesh Ambasudhan, Tongxiang Lin, Janghwan Kim, Department of Chemistry, The Scripps Research Institute; Woong Sun, Xiaolei Wang, UCSD Institute for Genomic Medicine and Shiley Eye Center, Department of Anatomy, Korea University College of Medicine, Seoul, Korea; Peng Xia, Maria Talantova, Stuart A. Lipton, Del E. Webb Center for Neuroscience, Aging and Stem Cell Research, Sanford-Burnham Medical Research Institute; Woon Ryoung Kim, Department of Anatomy, Korea University College of Medicine, Seoul, Korea.

    Source: Newswire ©2011 Newswise, Inc (26/04/11)

    How do neural stem cells decide what to be, and when?
    Stem CellsResearchers at Duke-NUS Graduate Medical School in Singapore have uncovered a novel feedback mechanism that controls the delicate balance of brain stem cells.

    Zif, a newly discovered protein, controls whether brain stem cells renew themselves as stem cells or differentiate into a dedicated type of neuron (nerve cell).

    In preclinical studies, the researchers showed that Zif is important for inhibiting overgrowth of neural stem cells in fruit flies (genus Drosophila) by ensuring that a proliferation factor (known as aPKC) maintains appropriate levels in neural stem cells.

    "There is a Zif-related protein in humans, and its function remains to be analyzed," said senior and corresponding author Hongyan Wang, Ph.D. "Our finding has paved the way for future study of this human protein in the context of diseases, including glioblastomas, the most severe form of brain tumors."

    She said it may be "possible to manipulate Zif function into a form of therapy against diseases, including cancer."

    The study was published in the Nov. 16 issue of Developmental Cell journal.

    The findings suggest that a lack of Zif protein expression correlates with neural stem cell overpopulation in Drosophila.

    The mechanism is circular: Zif is a transcription factor that inhibits the manufacture of aPKC. But Zif can also be tagged with a phosphate by aPKC, which excludes Zif from the cell nucleus, and leads to Zif inactivation, which in turn means an overgrowth of stem cells.

    "Next, we would like to investigate the mechanisms of neural stem cells' self-renewal in mammals, and we are looking for the right collaborators," Wang said. "We will also continue to use Drosophila as a powerful model system to uncover critical players in neural stem cell self-renewal so that we can understand the network involved in this regulation."

    Other authors on the paper included four co-lead authors, Kai Chen Chang and Gisela Garcia Alvarez of the Neuroscience and Behavioral Disorder Program at Duke-NUS Graduate Medical School; Gregory Somers of the Department of Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, in Australia; and Rita Sousa-Nunes of the National Institute for Medical Research, Mill Hill, in London. Fabrizio Rossi is from the Cell Division Group, IRB-Barcelona, PCB, in Barcelona, Swee Beng Soon is also with Duke-NUS Neuroscience and Behavioral Disorder Program, and Cayetano Gonzalez is with both the Cell Division Group, IRB-Barcelona, and the Institucio Catalana de Recera Estudis Advancats in Barcelona. William Chia and Kai Chen Chang are both with the Temasek Life Science Laboratory in Singapore.

    This work is supported by the Duke-NUS Neuroscience & Behavioral Disorders Signature Research Program funded by A*STAR and Ministry of Health, Ministry of Education in Singapore, and the Singapore National Research Foundation, as well as by Temasek Life Sciences funding.

    Source: Duke University Medical Center (16/11/10)

    Functional nerve cells generated from adult skin cells

    StemcellsScientists at the University of Connecticut Health Center have successfully converted stem cells derived from the adult skin cells of four humans into region-specific forebrain, midbrain, and spinal cord neurons (nerve cells) with functions. The research is a key step toward realizing the cells’ potential to treat various neurodegenerative diseases.

    The UConn team, led by Dr. Ren-He Xu, director of the Health Center’s Stem Cell Core facility, and Dr. Xuejun Li, a neural scientist in the Neuroscience Department, recently published a paper describing how they used cell reprogramming protocols to first transform the adult tissue into "induced pluripotent stem cells" that are all but identical to embryonic stem cells.

    This involved treating the adult skin cells with a specialized culture that caused them to regress in their development to an embryonic-like “pluripotent” state, capable of differentiating into any of the many tissue types in the body. The researchers then exposed these reprogrammed human cells (hiPSC) to a series of chemical mixtures to drive them into becoming specialized neuronal cells.

    As part of the same research project, Xu’s team also directed two previously established human embryonic stem cell (hESC) lines into neuronal cells, in order to determine whether there were meaningful differences between using human embryonic stem cells and human induced pluripotent cells.

    UConn Health Center scientists who collaborated with Xu and Li on the research included Lixia Yue (a physiologist) and Alexander Lichtler (a geneticist) from the departments of Cell Biology and Regenerative Sciences respectively. Their study was published in PLoS ONE, an international, peer-reviewed online journal of the non-profit Public Library of Science (PLoS).

    The rapid development of iPSCs since they were first produced in 2006 has generated tremendous interest among researchers. The ability to take easily obtainable skin cells and potentially make any tissues in the body eliminates the need to destroy human embryos to obtain hESC. Also, because human iPS cells have the same genetic background as the person they come from, they enable scientists to create perfectly matched cells for patient-specific therapies that would be immune to rejection.

    Yet the research community remains uncertain whether iPS cells have the same quality as hESC. Some biologists suspect that the tissue of origin influences the iPS cells’ ability to develop into different cell lineages; others are not so sure. What they do agree on is that better understanding the mechanisms underlying such epigenetic memory and its consequences is vital to using iPS cells in a clinical setting.

    In their PLoS ONE paper, the UConn researchers contend: “Our results demonstrate that hiPSC, regardless of how they were derived, can differentiate into a spectrum of neurons with functionality, which supports the considerable value of hiPSC for study and treatment of patient-specific neural disorders.”

    Although the differentiation of embryonic stem cells into neuronal cells has been well established in other labs, Li notes that the UConn research is the first to focus on the ability of human iPSC to create functional neurons in region-specific areas of both the brain and spinal cord.

    A key step for using stem cells as therapy in neurological diseases, says Xu, must be developing the ability to direct their differentiation into neural lineages and then to specific neuronal types that are affected by different diseases such as Parkinson’s or Alzheimer’s disease.

    While the UConn study showed that the “efficiency of neural differentiation” among the hiPSC lines was mixed, Xu notes that the process resembled that of the hESC lines in morphology, gene expression, and the chemical signals and conditions needed to regulate how the stem cells programmed to differentiate into neural cells.

    “Together,” he said, “our work has demonstrated that hiPSC, regardless of how they are derived, can generate a spectrum of region-specific neurons.”

    Source: Physorg.com © PhysOrg.com 2003-2010 (19/10/10)

    Genetic discovery could lead to brain treatments

    Stem CellsBritish scientists have discovered a genetic mechanism in the development of the nervous system that they say might one day be part of new treatments for stroke, Multiple Sclerosis, Alzheimer's or brain tumors.

    In a study in the journal Nature Neuroscience, the scientists found that a gene, named Sox9, is key to the development of neural stem cells in the human embryo -- master cells that in turn develop into brain or spinal tissue.

    In experiments in mice, they found that by using the gene they could kick-start the development of these cells, raising the prospect of one day being able to replace or regenerate damaged brain cells in humans.

    "With the knowledge that the gene Sox9 plays a central role in the development of our nervous system, we are one step closer to being able to control stem cells in the brain and regenerate different kinds of nerve cells," said James Briscoe from Britain's Medical Research Council, who led the study.

    "Being able to correct damaged nerve cells would be a huge leap forward for the millions of people with Alzheimer's, stem cell-related brain tumors or who have suffered from a stroke," he said in a statement, although it is likely to be many more years before such treatments for humans are developed.

    Human embryos begin to develop their nervous systems just after two weeks from conception, the researchers explained.

    From this stage until about five weeks, the nervous system is largely made up of so-called neuroepithelial cells, which grow rapidly and lay the foundations for brains and spinal cord.

    It is only after this stage that the various types of nerves and supporting cells that make up the central nervous system begin to appear. These come from stem cells.

    In their study, Briscoe's team found that Sox9 is needed for the neuroepithelial cells to turn into these stem cells.

    It also continues to be needed to allow stem cells in the adult brain to retain their properties, such as the ability to self-renew and differentiate.

    The scientists also found that a gene known as Shh is needed for Sox9 to work.

    By artificially adding Sox9 or Shh to neuroepithelial cells in mouse embryos, they found they were able to kick-start the process of converting them into neural stem cells.

    They also found that if there was a genetic defect in Sox9, it was much harder for the mice in their experiments to be able to renew damaged nerve cells later on.

    The potential of different kinds of stem cells is being examined by experts around the world for many diseases. But the technology is controversial, in part because some stem cell lines are derived from embryos or foetuses.

    Source: Reuters Copyright 2010 Thomson Reuters (27/09/10)

    Stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination

    Stem CellsAbstract

    After central nervous system (CNS) demyelination-such as occurs during multiple sclerosis-there is often spontaneous regeneration of myelin sheaths, mainly by oligodendrocytes but also by Schwann cells.

    The origins of the remyelinating cells have not previously been established. We have used Cre-lox fate mapping in transgenic mice to show that PDGFRA/NG2-expressing glia, a distributed population of stem/progenitor cells in the adult CNS, produce the remyelinating oligodendrocytes and almost all of the Schwann cells in chemically induced demyelinated lesions. In contrast, the great majority of reactive astrocytes in the vicinity of the lesions are derived from preexisting FGFR3-expressing cells, likely to be astrocytes.

    These data resolve a long-running debate about the origins of the main players in CNS remyelination and reveal a surprising capacity of CNS precursors to generate Schwann cells, which normally develop from the embryonic neural crest and are restricted to the peripheral nervous system. 

    Zawadzka M, Rivers LE, Fancy SP, Zhao C, Tripathi R, Jamen F, Young K, Goncharevich A, Pohl H, Rizzi M, Rowitch DH, Kessaris N, Suter U, Richardson WD, Franklin RJ.

    MRC Cambridge Centre for Stem Cell Biology and Regenerative Medicine, Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.

    Source: Pubmed PMID: 20569695 & Cell Stem Cell. 2010 Jun 4;6(6):578-90. (01/07/10)

    Immune system helps transplanted stem cells navigate in central nervous system

    Stem CellsBy discovering how adult neural stem cells navigate to injury sites in the central nervous system, UC Irvine researchers have helped solve a puzzle in the creation of stem cell-based treatments: How do these cells know where to go?

    Tom Lane and Kevin Carbajal of the Sue and Bill Gross Stem Cell Research Center found the answer with the body's immune system.

    Their study not only identifies an important targeting mechanism in transplanted stem cells but also provides a blueprint for engineering stem cell-based therapies for multiple sclerosis and other chronic neurological diseases in which inflammation occurs. Results appear in this week's early online edition of the Proceedings of the National Academy of Sciences.

    "Previously, we've seen that adult neural stem cells injected into the spinal column knew, amazingly, exactly where to go," said Lane, Chancellor's Fellow and professor of molecular biology & biochemistry. "We wanted to find what directed them to the right injury spots."

    The researchers used adult neural stem cells to treat mice with a disease similar to MS that destroys myelin, the protective tissue coating on nerves, causing chronic pain and loss of motor function. Adult neural stem cells have shown the ability to change - or differentiate - into oligodendrocytes, the building blocks of myelin, and repair or replace affected tissue.

    In the mice, inflammatory cells - reacting to the virally induced nerve damage - were observed activating receptors on the adult neural stem cells. These CXCR-4 receptors, in turn, recruited chemokine proteins called CXCL-12 that guided the stem cells to specific sites. Chemokines are produced in acute and chronic inflammation to help mobilize white blood cells.

    As the stem cells migrated through the central nervous system, they began to transform into the precursor cells for oligodendrocytes. Latching onto their repair sites, they continued the differentiation process. Three weeks after the initial treatment, 90 percent of the cells had grown into fully formed oligodendrocytes.

    In earlier work, Lane and colleagues demonstrated that adult neural stem cell treatments improved motor function in mice with chronic MS symptoms.

    "In this study, we've taken an important step by showing the navigational cues in an inflammatory environment like MS that guide stem cells," said Lane. "Hopefully, these cues can be incorporated into stem cell-based treatments to enhance their ability to repair injury."

    Chris Schaumburg and Joy Kane of UCI and Dr. Robert Strieter of the University of Virginia participated in the study, which received support from the National Institutes of Health and the National Multiple Sclerosis Society.

    Lane recently received a Collaborative MS Research Center Award from the National Multiple Sclerosis Society to assemble a team to investigate the use of cell replacement therapy to regenerate MS-ravaged nerve tissue.

    Source: Physorg.com © PhysOrg.com 2003-2010 (02/06/10)

    New brain stem cell discovered

    Stem CellsUCSF scientists have discovered a new stem cell in the developing human brain.

    The cell produces nerve cells that help form the neocortex – the site of higher cognitive function—and likely accounts for the dramatic expansion of the region in the lineages that lead to man, the researchers say.

    Future studies of these cells are expected to shed light on developmental diseases such as autism and schizophrenia and malformations of brain development, including microcephaly, lissencephaly and neuronal migration disorders, they say, as well as age-related illnesses, such as Alzheimer’s disease.

    Studies also will allow scientists to track the molecular steps that the cell goes through as it evolves into the nerve cell, or neuron, it produces. This information could then be used to prompt embryonic stem cells to differentiate in the culture dish into neurons for potential use in cell-replacement therapy.

    The study is reported in a recent issue of the journal Nature, (vol. no. 464, 554-561; issue 7288).

    “This discovery has the potential to transform our understanding of the development and evolution of the human neocortex, the most uniquely human part of the central nervous system,” says the senior author of the study, neurologist Arnold Kriegstein, MD, PhD, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

    “It also should inform our understanding of developmental diseases and advance the creation of cell-based therapies. Many neurological diseases develop in neurons or the neural circuits between them. If we’re going to understand how these disorders develop, we have to better understand how the human and primate cerebral cortex develops.”

    In rodents and humans, the developing cortex contains a layer of neural stem cells called radial glial cells that resides near the fluid-filled ventricles and produces cells that are precursors to neurons. These precursor neurons further proliferate in a region known as the subventricular zone (SVZ), to increase their numbers, and then differentiate into newborn neurons. The neurons then migrate along radial glial fibers up to the neocortex, where they help form the tissue that is the site of sensory perception, motor commands, spatial reasoning, conscious thought and language.

    In human and nonhuman primates, however, the SVZ has a massively expanded outer region, known as the outer subventricular zone (OSVZ). About 20 years ago, scientists presumed that the OSVZ also contained stem cells, but until now they have lacked evidence.

    In the current study, lead authors David V. Hansen, PhD, a postdoctoral fellow, and Jan H. Lui, a graduate student in the Kriegstein lab, examined the OSVZ, using new labeling and tracking techniques to follow individual cells and their progeny over time in cultured tissue slices from fetal cortex tissue that had been donated for research.

    They characterized two kinds of cells within the region—both the novel neural stem cell and its daughter cell, known as the transit amplifying cell. The stem cell closely resembles the radial glial cell in structure and behavior and, like the radial glia, has radial fibers which newborn neurons migrate along up to the neocortex.

    The region is a busy hub of cell proliferation. The stem cell undergoes asymmetrical cell division, giving rise to two distinct daughter cells—one a copy of the original stem cell, the other a transit amplifying cell. The transit amplifying cell undergoes multiple rounds of symmetrical divisions before all of its daughter cells begin the process of differentiating into neurons.

    “We are very interested in understanding how these modes of division are regulated,” says Kriegstein. “We suspect that faults in cell-cycle regulation account for a variety of developmental brain diseases.”

    More broadly, he says the team wants to understand how the new stem cells compare to radial glial cells and how the two sets of neurons they produce integrate in the neocortex. “Neurons are probably being generated in both the SVZ and OSVZ at once,” he says. “They likely end up in the same layer of the neocortex as they migrate into position and start forming circuits.

    “This suggests to us that there may be a mosaic of cell types in the human neocortex, in which there are cells that originate in the traditional zone and cells produced in the newer zone that intermix in the cortex. The complexity of primate neocortex may be significantly increased by the interaction of the evolutionarily-speaking ‘younger’ neurons with those originating in the more primitive zone.”

    The massive number of cells within the OSVZ of humans “tells us we have to be careful when modeling human brain diseases in mice,” says Kriegstein. “Especially in the neocortex—the most highly developed part of the brain in primates and humans – there are going to be important differences between rodents and humans.”

    The other co-author of the study was Philip R. L. Parker, a graduate student in the Kriegstein lab.

    Source: HealthCanal.com (25/05/10)

    Stem cells use GPS to generate proper nerve cells

    Stem CellsAn unknown function that regulates how stem cells produce different types of cells in different parts of the nervous system has been discovered by Stefan Thor, professor of Developmental Biology, and graduate students Daniel Karlsson and Magnus Baumgardt, at Linköping University in Sweden.

    The results improve our understanding of how stem cells work, which is crucial for our ability to use stem cells to treat and repair organs. The findings are publishing next week in the online, open-access journal PLoS Biology.

    Stem cells are responsible for the creation of all cells in an organism during development. Previous research has shown that stem cells give rise to different types of cells in different parts of the nervous system. This process is partly regulated by the so-called Hox genes, which are active in various parts of the body and work to give each piece its unique regional identity - a kind of GPS system of the body. But how does a stem cell know that it is in a certain region? How does it read the body's "GPS" signals? And how is this information used to control the creation of specific nerve cells?

    In order to address these issues, the LiU researchers studied a specific stem cell in the nervous system of the fruit fly. It is present in all segments of the nervous system, but it is only in the thorax, or chest region, that it produces a certain type of nerve cell. To investigate why this cell type is not created in the stomach or head region they manipulated the Hox genes' activity in the fly embryo.

    It turned out that the Hox genes in the stomach region stop stem cells from splitting before the specific cells are produced. In contrast, the specific nerve cells are actually produced in the head region, but the Hox genes turn them into another, unknown, type of cell. Hox genes can thus exert their influence both on the genes that control stem cell division behaviour and on the genes that control the type of nerve cells that are created.

    "We constantly find new regulating mechanisms, and it is probably more difficult than previously thought to routinely use stem cells in treating diseases and repairing organs, especially in the nervous system", says Thor.

    Funding:This work was supported by the Swedish Research Council, by the Swedish Strategic Research Foundation, by the Knut and Alice Wallenberg foundation, by the Swedish Brain Foundation, by the Swedish Cancer Foundation, and by the Swedish Royal Academy of Sciences to ST. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    Competing interests statement: The authors declare that no competing interests exist.

    Citation: Karlsson D, Baumgardt M, Thor S (2010) Segment-Specific Neuronal Subtype Specification by the Integration of Anteroposterior and Temporal Cues. PLoS Biol 8(5): e1000368. doi:10.1371/journal.pbio.1000368

    Eureka Alert! (12/05/10)

    Stem cells could be used to repair brain damage

    StemcellsIt may soon be possible to repair damage to the human brain by reactivating stem cells within the body that can grow on specially constructed "biological scaffolding" inserted into the brain, scientists say.

    The hope is that the brain could be regenerated in the same way that tissue can regrow in animals such as salamanders and fish where nerves are capable of repairing themselves in the same way the human body can repair skin or bone. Mike Modo, of the Institute of Psychiatry, in London said that medical scaffolds made of synthetically made biological materials inserted into the brain could provide the structural framework for naturally existing stem cells to repair damaged regions caused by strokes or trauma.

    "If we have damage to the brain, we are trying to put biomaterials in there to provide a structure for these cells to attach and to start forming connections between each other and eventually, hopefully, to regenerate the tissue that has been lost," Dr Modo said.

    "Theoretically the hope is that these biomaterials can be guided to support these cells and that they can be engineered to secrete particular [growth] factors," he said.

    More than 180,000 people each year in Britain suffer from brain damage caused by strokes. Brain damage is often permanent because at present there is no way of regenerating nervous tissue to repair the cells that have been killed.

    Professor Andrea Brand of the Gurdon Institute at Cambridge University said that the human brain was known to contain inactive stem cells and one possibility was to reactivate them so that they could begin to replace lost cells, which was what probably happens in the brains of salamanders and fish.

    "We know there are stem cells in the human brain. If we can reactivate stem cells that are in the right place at the right time, that would be ideal," said Professor Brand, who is speaking at the British Neuroscience Association meeting in London.

    "We know that stem cells will sometimes go to sleep and we're studying ways of reactivating them. This is really key because what we'd like to do eventually in terms of repairing the brain is to reactivate someone's own stem cells in situ to give rise, hopefully, to the neurons that will replace those that have been damaged," Professor Brand said.

    "In particular, we are interested in how these stem cells can generate all the different types of nerve cells that you find in the human brain," she said.

    The human brain contains about 100 billion neurons, or nerve cells, and scientists are studying the simpler nervous systems of laboratory animals, such as fruit flies, to find the genes that are involved in turning stem cells off and on.

    Source: The Indenpent ©independent.co.uk 2010 (15/04/10)

    New period of brain 'plasticity' created with transplanted embryonic cells

    Stem CellsUCSF scientists report that they were able to prompt a new period of 'plasticity,' or capacity for change, in the neural circuitry of the visual cortex of juvenile mice. The approach, they say, might some day be used to create new periods of plasticity in the human brain that would allow for the repair of neural circuits following injury or disease.

    The strategy - which involved transplanting a specific type of immature neurone from embryonic mice into the visual cortex of young mice - could be used to treat neural circuits disrupted in abnormal foetal or postnatal development, stroke, traumatic brain injury, psychiatric illness and ageing.

    Like all regions of the brain, the visual cortex undergoes a highly plastic period during early life. Cells respond strongly to visual signals, which they relay in a rapid, directed way from one appropriate cell to the next in a process known as synaptic transmission. The chemical connections created in this process produce neural circuitry that is crucial for the function of the visual system. In mice, this critical period of plasticity occurs around the end of the fourth week of life.

    The catalyst for the so-called critical period plasticity in the visual cortex is the development of synaptic signalling by neurones that release the inhibitory neurotransmitter GABA. These neurones receive excitatory signals from other neurones, thus helping to maintain the balance of excitation and inhibition in the visual system.

    In their study, published in the journal Science, (Vol. 327. no. 5969, 2010), the scientists wanted to see if the embryonic neurones, once they had matured into GABA-producing inhibitory neurones, could induce plasticity in mice after the normal critical period had closed.

    The team first dissected the immature neurones from their origin in the embryonic medial ganglionic eminence (MGE) of the embryonic mice. Then they transplanted the MGE cells into the animals' visual cortex at two different juvenile stages. The cells, targeted to the visual cortex, dispersed through the region, matured into GABAergic inhibitory neurones, and made widespread synaptic connections with excitatory neurones.

    The scientists then carried out a process known as monocular visual deprivation, in which they blocked the visual signals to one eye in each of the animals for four days. When this process is carried out during the critical period, cells in the visual cortex quickly become less responsive to the eye deprived of sensory input, and become more responsive to the non-deprived eye, creating alterations in the neural circuitry. This phenomenon, known as ocular dominance plasticity, greatly diminishes as the brain matures past this critical postnatal developmental period.

    The team wanted to see if the transplanted cells would affect the visual system's response to the visual deprivation after the critical period. They studied the cells' effects after allowing them to mature for varying lengths of time. When the cells were as young as 17 days old or as old as 43 days old, they had little impact on the neural circuitry of the region. However, when they were 33-39 days old, their impact was significant. During that time, monocular visual deprivation shifted the neural responses away from the deprived eye and toward the non-deprived eye, revealing the state of ocular dominance plasticity.

    Naturally occurring, or endogenous, inhibitory neurones are also around 33-39 days old when the normal critical period for plasticity occurs. Thus, the transplanted cells' impact occurred once they had reached the cellular age of inhibitory neurones during the normal critical period.

    The finding, the team says, suggests that the normal critical period of plasticity in the visual cortex is regulated by a developmental program intrinsic to inhibitory neurones, and that embryonic inhibitory neurone precursors can retain and execute this program when transplanted into the postnatal cortex, thereby creating a new period of plasticity.

    'The findings suggest it ultimately might be possible to use inhibitory neurone transplantation, or some factor that is produced by inhibitory neurones, to create a new period of plasticity of limited duration for repairing damaged brains,' says author Sunil P. Gandhi, PhD, a postdoctoral fellow in the lab of Michael Stryker, PhD, professor of physiology and a member of the Keck Centre for Integrative Neurosciences at UCSF. 'It will be important to determine whether transplantation is equally effective in older animals.'

    Likewise, 'the results raise a fundamental question: how do these cells, as they pass through a specific stage in their development, create these windows of plasticity?' says author Derek G. Southwell, PhD, a student in the lab of Arturo Alvarez-Buylla, PhD, Heather and Melanie Muss Professor of Neurological Surgery and a member of the Eli and Edythe Broad Centre of Regeneration Medicine and Stem Cell Research at UCSF.

    The findings could be relevant to understanding why learning certain behaviours, such as language, occurs with ease in young children but not in adults, says Alvarez-Buylla. 'Grafted MGE cells may some day provide a way to induce cortical plasticity and learning later in life.'

    The findings also complement two other recent UCSF studies using MGE cells to modify neural circuits. In a collaborative study among the laboratories of Scott Baraban, PhD, professor of neurological surgery; John Rubenstein, MD, PhD, professor of psychiatry, and Alvarez-Buylla, the cells were grafted into the neocortex of juvenile rodents, where they reduced the intensity and frequency of epileptic seizures. (Proceedings of the National Academy of Science, vol. 106, no. 36, 2009). Other teams are exploring this tactic, as well.

    In the other study (Cell Stem Cell, vol. 6, issue 3, 2010), UCSF scientists reported the first use of MGEs to treat motor symptoms in mice with a condition designed to mimick Parkinson's disease. The finding was reported by the lab of Arnold Kriegstein, MD, PhD, UCSF professor of neurology and director of the Eli and Edythe Broad Centre of Regeneration Medicine and Stem Cell Research at UCSF, in collaboration with Alvarez-Buylla and Krys Bankiewicz, MD, PhD, UCSF professor of neurological surgery.

    Source: Science Centric  © 2007—2010 Agency Science (29/03/10)

    UK firm gets final green light for neurological stem cell trial

    Stem CellsBritish biotech company ReNeuron and a team of doctors in Scotland have won final approval to start a pioneering clinical trial to assess whether stem cell therapy can help patients disabled by stroke.

    The treatment involves injecting neural stem cells developed from human fetuses into patients' brains in the hope they will repair areas damaged by stroke, thereby improving both mental and physical function.

    The final green light from Britain's Gene Therapy Advisory Committee (GTAC), announced on Wednesday, follows months of delays and questions, reflecting the ground-breaking nature of the research.

    ReNeuron received an okay from Britain's main drugs watchdog back in January 2009 but still needed a recommendation from the GTAC before it could start the Phase I clinical trial.

    The first patient in the study is now expected to receive treatment through the National Health Service at the Institute of Neurological Sciences, Southern General Hospital, Glasgow, during the second quarter of this year.

    In total, 12 patients will get ReNeuron's ReN001 cell therapy between six and 24 months after having an ischemic stroke -- caused by a blockage of blood flow in the brain -- and their progress will be followed for two years.

    The procedure involves the direct injection of millions of cells into the affected brain region. The initial tests will look primarily at the safety and feasibility of the treatment.

    If the first study is successful, researchers plan to pursue accelerated clinical development in later-stage clinical trials, focusing initially on more severely disabled stroke patients.

    About half of all stroke survivors are left with permanent disabilities as a result of brain damage.

    The potential of different kinds of stem cells -- master cells that can develop into specialized tissue in the body -- is being examined by experts around the world for many diseases.

    But the technology is controversial, in part because some stem cell lines are derived from embryos or fetuses.

    ReNeuron had initially hoped to test its stroke treatment in the United States. It decided to switch its efforts to Britain in 2008, however, following delays at the Food and Drug Administration.

    The group became Europe's first stem cell company to float in 2000, but was taken private in 2003 after a series of clinical setbacks and the bursting of the technology bubble hammered its share price. It relisted in 2005.

    Source: Reuters Copywrite Thomson Reuters 2010 (10/02/10)

    Skin cells turned directly into neurons

    Stem CellsStem cell scientists at Stanford University in California announced "a huge step forward", with the publication of research that turned skin into nerve cells without any intermediate step.

    The production of neurons [nerve cells] directly from other adult cells, without making stem cells en route, could transform "regenerative medicine" - providing a plentiful supply of neurons for treating people with degenerative brain diseases such as Parkinson's or those with spinal injuries.

    "We actively and directly induced one cell type to become a completely different cell type," said Marius Wernig of Stanford's Institute for Stem Cell Biology and Regenerative Medicine. "These are fully functional neurons. They can do all the principal things that neurons in the brain do."

    This includes making connections with and signalling to other nerve cells - critical functions if the cells are eventually to be used as therapy for brain disease. The study is published online in the journal Nature .

    Although research had suggested that specialised cells could be coaxed to show properties of other cell types, this is the first time skin cells have been converted into neurons in a laboratory.

    The change happened within a week of treating mouse skin cells with a mixture of three genes, with an efficiency of up to nearly 20 per cent. The scientists are now working to duplicate the feat with human cells.

    Until recently, scientists believed cellular differentiation was a one-way process, with primitive and versatile embryonic stem cells giving rise to all the body's more specialised cells.

    Then, in 2007 they discovered how to turn the clock back, reversing the specialisation process by converting adult cells to "induced pluripotent stem cells", which could then become a different type of cell.

    The latest discovery shows that this intermediate step is unnecessary. But many years of work will be needed before direct conversion reaches the clinic.

    Source: The Financial Times Copyright The Financial Times Limited 2010. (29/01/10)

    Rewiring the brain with stem cells

    Stem CellsNew research finds that in mice, transplanted neurons grown from embryonic stem cells can form proper connections with other brain parts.

    Writing in The Journal of Neuroscience, researchers described an experiment in which they successfully grew neurons from stem cells in Petri dishes, then transplanted those neurons into the brains of young mice.

    James Weimann, one of the authors of the study, said that the work was a hopeful sign for stem cell based treatments on the horizon.

    "These stem cell-derived neurons can grow nerve fibers between the brain’s cerebral cortex and the spinal cord, so this study confirms the use of stem cells for therapeutic goals," he said.

    However, the researchers cautioned that this work was so far only performed in young mice, and it remained to be seen whether the approach would work in older mice or in other animals.

    Source: Science Friday Copywrite  ScienceFriday Inc. (21/01/10)

    New source discovered for the generation of nerve cells in the brain

    Neural Stem Cells
    The research group of Professor Magdalena Gotz of Helmholtz Zentrum Munchen and Ludwig-Maximilians-Universitat (LMU) Munich has made a significant advance in understanding regeneration processes in the brain. The researchers discovered progenitor cells which can form new glutamatergic neurons following injury to the cerebral cortex. Particularly in Alzheimer's disease, nerve cell degeneration plays a crucial role.

    In the future, new therapeutic options may possibly be derived from steering the generation and/or migration mechanism. These findings have been published in the current issue of the renowned journal Nature Neuroscience.

    Until only a few years ago, neurogenesis - the process of nerve cell development - was considered to be impossible in the adult brain. The textbooks asserted that dead nerve cells could not be replaced. Then researchers discovered regions in the forebrain in humans in which new nerve cells can be generated throughout life. These so-called GABAergic cells use gamma-aminobutyric acid (GABA), a neurotransmitter of the central nervous system.

    A research team of scientists led by Magdalena Götz, director of the Institute of Stem Cell Research at Helmholtz Zentrum München and chair of the Department of Physiological Genomics of LMU, has now taken a closer look at this brain region in the mouse model. Their findings: Even in the forebrain, there are other nerve cells that are regularly generated - the so-called glutamatergic nerve cells, which use glutamate as neurotransmitter. The stem cell researchers could prove this by means of a specific transcription factor: Tbr2 is only present in progenitor cells of glutamatergic nerve cells.

    The newly generated nerve cells in the adult organism are located in the olfactory bulb, the region of the brain involved in the sense of smell. Nerve cells that use glutamate as a neurotransmitter are also responsible for memory - storing and retrieving information. In Alzheimer dementia, alterations in the signal transduction pathways of these special cells play a significant role.

    Magdalena Götz explained the reason why this finding is so important: "Neural progenitor cells can generate these newly discovered glutamatergic nerve cells for the neighboring cerebral cortex - for example after brain injury." The research group was able to demonstrate this on the mouse model: There the cells migrated into the damaged neighboring cerebrum tissue and generated mature neurons. Accordingly, progenitor cells could then replace degenerate nerve cells.

    "Now it will be interesting to find out whether this process also takes place in humans, particularly in Alzheimer's patients," said Magdalena Götz, "and also whether the process can be kept under control to avoid massive cell death." One therapeutic approach would then be to attempt to stimulate the body's own replacement mechanism.

    Further Information

    Original Publication: Monika S Brill, Jovica Ninkovic, Eleanor Winpenny, Rebecca D Hodge, Ilknur Ozen, Roderick Yang, Alexandra Lepier, Sergio Gascón, Ferenc Erdelyi, Gabor Szabo, Carlos Parras, Francois Guillemot, Michael Frotscher, Benedikt Berninger, Robert F Hevner, Olivier Raineteau & Magdalena Götz: Nature Neuroscience, Volume 12 No 11 pp1351-1474 (doi:10.1038/nn.2416)

    Source: Medical News Today © 2009 MediLexicon International Ltd (03/12/09)

    Neural stem cells can be administered nasally

    Stem CellsWhen surgeons need to deliver a payload directly to a patient's brain, it usually involves a rather invasive procedure that opens the skull and leaves the delicate grey matter inside inflamed. But researchers at the University of Minnesota have discovered that patients with brain maladies can simply snort stem cells through the nose and directly to the brain, offering an effective and fast alternative to complicated neuro-surgical procedures.

    The researchers discovered that when suspended in fluid and snorted, stem cells migrate quickly to the brain, arriving within an hour in most cases. Researchers initially tested the procedure on mice, having them sniff adult rat stem cells suspended in solution. An hour later, the inhaled stem cells were visible within the brain. Testing a second time using stem cells from a human tumor, the cells again migrated straight to the brain, also within an hour's time.

    The stem cells likely reach the brain by way of the olfactory nerves, which give us our sense of smell. Fluid-filled spaces surrounding blood vessels that pass from the nose to the brain are also a likely conduit. Only 584 of 300,000 cells reached the brain initially, but researchers found that when they added an enzyme called hyaluronidase that makes connective tissue more permeable, the number of cells that reached the brain nearly tripled.

    The convenience of the procedure is a boon to neurosurgeons, but there are added advantages over surgical implanting that go beyond the ease of execution. For one, if a certain treatment doesn't take hold, doctors can easily try again without having to wait for the patient to recover from surgery (and without then conducting a second tricky surgery). The procedure also has vast implications for many neurological diseases like Alzheimer's, Huntington's and Multiple Sclerosis, that currently enjoy few treatment options.

    There are no approved stem-cell therapies for brain disorders currently, but intra-nasal cell delivery could help persuade the FDA that such procedures can be performed safely. As such, the next step for researchers is to ensure intra-nasal stem cell technology doesn't cause any inflammation or infection of brain tissue, or precipitate any autoimmune response. Even so, the right cocktail of stem cells and anti-inflammatories or antibiotics could mean the next generation of nuero-treatments could be administered as easily as over-the-counter nasal decongestants.

    Source: Popular Science © 2009 Popular Science (24/09/09)

    Watching stem cells repair the human brain

    Stemcells

    There is no known cure for neurodegenerative diseases such as Huntington's, Alzheimer's, Parkinson's and Multiple Sclerosis.
    But new hope, in the form of stem cells created from the patient's own bone marrow, can be found — and literally seen — in laboratories at Tel Aviv University.

    Dr. Yoram Cohen of TAU's School of Chemistry has recently proven the viability of these innovative stem cells, called mesenchymal stem cells, using in-vivo MRI. Dr. Cohen has been able to track their progress within the brain, and initial studies indicate they can identify unhealthy or damaged tissues, migrate to them, and potentially repair or halt cell degeneration. His findings have been reported in the journal Stem Cells.

    "By monitoring the motion of these cells, you get information about how viable they are, and how they can benefit the tissue," he explains. "We have been able to prove that these stem cells travel within the brain, and only travel where they are needed. They read the chemical signalling of the tissue, which indicate areas of stress. And then they go and try to repair the situation."

    Tracking live cells in the brain

    To test the capabilities of this innovative new stem cells, Dr. Cohen created a study to track the activity of the live cells within the brain using the in-vivo MRI at the Strauss Centre for Computational Neuro-Imaging. Watching the live, active cells has been central to establishing their viability as a therapy for neurodegenerative disease.

    Dr. Cohen and his team of researchers took magnetic iron oxide nanoparticles and used them to label the stem cells they tested. When injected into the brain, they could then be identified as clear black dots on an MRI picture. The stem cells were then injected into the brain of an animal that had an experimental model of Huntington's disease. These animals suffer from a similar neuropathology as the one seen in human Huntington's patients, and therefore serve as research tool for the disease.

    On MRI, it was possible to watch the stem cells migrating towards the diseased area of the brain. "Cells that go toward a certain position that needs to be rescued are the best indirect proof that they are live and viable," explains Dr. Cohen. "If they can migrate towards the target, they are alive and can read chemical signalling."

    An ethically viable stem cell

    This study is based on differentiated mesenchymal cells (MSC), which were discovered at Tel Aviv University. Bone marrow cells are transformed into NTFs-secreting stem cells, which can then be used to treat neurodegenerative diseases. This advance circumvents the ethical debate caused by the use of stem cells obtained from embryos.

    Although there is a drawback to using this particular type of stem cell — the higher degree of difficulty involved in rendering them "neuron-like" — the benefits are numerous. "Bone marrow-derived MSCs bypass ethical and production complications," says Dr. Cohen, "and in the long run, the cells are less likely to be rejected because they come from the patients themselves. This means you don't need immunosuppressant therapy."

    Working towards a real-life therapy

    Dr. Cohen says the next step is to develop a real-life therapy for those suffering from neurodegenerative diseases. The ultimate goal is to repair neuronal cells and tissues. Stem cell therapy is thought to be the most promising future therapy to combat diseases such as Multiple Sclerosis, Huntington's, Alzheimer's and Parkinson's diseases, and researchers may also be able to develop a therapy for stroke victims. If post-stroke cell degeneration can be stopped at an early stage, says Dr. Cohen, patients can live for many years with a good quality of life.

    In collaboration with Dr. Cohen, this work on tracking live stem cells in the brain was done by Noam Shemesh, a Ph.D. candidate in the School of Chemistry at Tel Aviv University, and Dr. Ofer Sadan from the group of Drs. Daniel Offen and Eldad Melamed from the Felsenstein Medical Research Center at the Rabin Medical Center.

    Source: Science Daily © 1995-2009 ScienceDaily LLC (20/08/09)

    Progress is reported on repairing damaged nerves with stem cells

    Neural Stem Cells

    Moving one step closer to developing a possible therapy for repairing spinal cord injuries and neurological diseases, scientists at the University of California San Diego say they have successfully guided regenerating nerve axons to cell targets, where they re-establish connections essential to any recovery.

    “It was a breakthrough a few years ago to finally get axons to regenerate,” said Dr. Mark Tuszynski, a professor of neurosciences and part of a team of scientists from UCSD, the San Diego Veterans Affairs Medical Center and UCLA that reported the achievement in yesterday's online edition of the journal Nature Neuroscience.
    “With this advance, we've shown it's possible to direct an axon to find the correct target from among potentially millions of incorrect ones in the spine and brain and make the right connection.”

    Axons are long, fragile fibers connecting nerve cells. They are the conduits through which electrical signals pass between neurons, from stimulus to brain and back. In spinal cord injuries, axons are damaged and severed, cutting off neural communications. The result is sensory loss and possible paralysis.

    A survey this year by the Christopher & Dana Reeve Foundation found 1.275 million Americans have suffered a spinal cord injury and more than 5.6 million Americans live with some form of paralysis. Stroke was the leading cause of paralysis (29 percent), followed by spinal cord injuries (23 percent) and multiple sclerosis (17 percent).

    Tuszynski and colleagues were able to restore severed neural connections in laboratory rats through a painstaking combination of therapies. They injected a benign virus carrying a natural growth factor called neurotrophin-3, a type of chemical hormone, into the targeted tissue site. The growth factor behaves like a magnet, attracting growing axons to it.

    At the same time, the researchers placed a graft or bridge of cells across the injury site to support axon growth and stimulated genes in the affected nerves to turn up axon growth.

    “What this work dramatically shows is that it will take a combination of things to effectively repair spinal cord injuries,” said Naomi Kleitman, a program officer at the National Institute of Neurological Disorders and Stroke who is familiar with the UCSD research.

    “It's one important step in a long process of many steps. There are still many things we don't know. There are likely more elements that will be needed before it's possible to translate this research to humans. The process, even now, sounds like a lot. But compared to being paralyzed for the rest of your life, maybe it's not asking too much.”

    Tuszynski's research focused on sensory neurons, which convey information about touch, position and pain. He and his colleagues are now investigating whether the same combination works with motor neurons, which govern movement and are tougher to manipulate.

    UCSD's success was not complete. Although the regenerated axons could be precisely guided to their targets and form obvious synapses with other cells, the resulting connections were not electrically active. They did not work.

    The problem, Tuszynski theorizes, may be that the regenerated axons lack a myelin sheath – a fatty coating that serves the same function that rubber insulation does for electrical wiring. Myelin sheathing focuses and speeds electrical impulses through axons.

    “Just as an electrical circuit needs insulation so it doesn't short-circuit, it appears that these regenerating axons require restoration of the myelin sheath to ultimately restore function,” Tuszynski said. The solution, Tuszynski said, might be to introduce another element to the therapeutic combination: a cell, perhaps, that triggers or produces myelin formation at the injury site.

    This year, first-phase clinical trials were approved for one such possible approach. Geron, a biotechnology company based in Menlo Park, will conduct first-phase safety trials for a procedure involving the injection of embryonic stem cells into human patients with spinal cord injuries. The hope is that the stem cells will mature into oligodendrocytes, a kind of spinal cord cell that produces myelin.

    Source: The San Diego Union-Tribune Copyright 2009 The San Diego Union-Tribune, LLC

    Healing our brains, changing our selves?

    Stem Cells

    In using stem cells to treat brain disorders, scientists might be tampering unwittingly with the deepest reaches of human experience: our personality, our mood and behaviour, perhaps even our sense of self. While nobody knows how likely such side effects are, a group of scientists and philosophers at Johns Hopkins University in Baltimore, Md., says they are a cause for concern and need to be addressed.

    Until now, the public debate about stem cells has centered on the moral problems of harvesting the most potent cell type—embryonic stem cells—from human embryos. But the science has already moved ahead. Earlier this year, California biotech company Geron received approval to use embryonic stem cells in an attempt to treat spinal cord injuries; and on June 8, StemCells Inc., another California biotech, completed the first clinical trial using neural stem cells to treat Batten disease, a rare and fatal disorder that gradually breaks down brain tissue. Stem cell trials are also lined up or ongoing for stroke, Parkinson’s disease and Huntington’s disease.

    In any clinical trial, safety is the first issue scientists study. But as they race to develop treatments for neurological disorders, they might miss the philosophical fine print.

    “Scientists certainly don’t always think through all of the implications of their work,” says Debra Mathews, the geneticist-turned-bioethicist who convened the working group at Hopkins. In their latest paper, published in the May issue of The American Journal of Bioethics, Mathews and her colleagues suggested that grafting stem cells into a person’s brain might lead to forgetting important memories and facts, to a more subdued or aggressive personality, or to altered sexual desire.

    Although the risk of such changes may appear low, Mathews says, “there aren’t any data. We can extrapolate from preclinical trials, but I don’t think that’s particularly useful, because, you know, we can’t ask a mouse how he’s feeling today.”

    Before having the idea for the working group, Mathews had been intrigued by the faulty rewiring that sometimes bungles brain function after a stroke. “You end up with very odd psychological effects like someone meaning to laugh but they cry,” she says.

    Existing therapeutic technologies, such as deep brain stimulation, have also caused widespread personality changes in some cases, Mathews adds. “We know that it happens, and it’s not something that has been looked at, although deep brain stimulation has been around for a decade.”

    How grafts will affect brain function depends on the number and injection site of the transplanted cells—both variables that doctors can control. But once the newcomers are in place, it is difficult to predict exactly how they will interact with the cells already present. Will they upset local brain circuitry or integrate smoothly?

    In any case, explains Mathews, it is more than unlikely that a person would wake up from a transplant feeling like, in a sense being, the donor of the stem cells. “It’s not going to happen, because the way that our brains hold or represent our personalities or our thoughts or our memories are in complex networks of cells, not in individual cells, and certainly not in the DNA of individual cells.”

    Other researchers add that the Hopkins group’s speculations should not cause undue alarm among patients. “Everything that involves interfering with the brain tends to feel scary to people,” says Dr. Maartje Schermer, a physician and ethicist at Erasmus University Rotterdam in the Netherlands. “I’m not worried that something terrible might happen, but we should look at it of course.”

    Schermer says that many of the concerns raised by the group apply equally well to treatments that are common today, such as psychiatric medication. In a recent project, she interviewed a group of people who were taking drugs for Attention Deficit Hyperactivity Disorder, a common psychiatric diagnosis. “They really seemed to wrestle with their sense of identity: ‘Who am I? Am I me on the medication or off the medication?’” Schermer recalls. “Maybe we have neglected these kinds of changes too long.”

    Drugs used to treat another neurological disorder, Parkinson’s disease, have been linked to more arresting personality changes. In people afflicted by the disease, a large portion of the brain cells that produce dopamine, a chemical used by the cells to communicate with each other, die off for unknown reasons. The first symptoms are increasingly jerky movements and tremor, and later dementia can arise.

    In 2005, doctors from the Mayo Clinic in Rochester, Minn., described 11 people with the disease who had developed pathological gambling habits after taking dopamine-like medication. One patient, a 50-year-old married man who had never gambled before, began spending all his time at casinos, saying he felt unable to pull himself away from the tables. When he wasn’t gambling, he was drinking and eating excessively, and he started having sex with his wife four times daily instead of only once a week. When the doctors stepped down his medication, he stopped gambling as suddenly as he had begun, and returned to his normal sex life.

    “The drugs used to treat Parkinson’s can cause behavioural side effects in about 10 or 15 percent of people,” says Dr. Curt Freed, director of the Neurotransplantation Program for Parkinson’s Disease at the University of Colorado. Partly because the drugs stop working in the long run, and partly because of their side effects—including serious movement disturbances—Freed began transplanting fetal dopamine cells deep into the brains of his patients in the late 1980s. If he could confine the new cells to the small movement-related area that needed dopamine, the treatment might have fewer side effects than a drug that bombards the entire brain.

    “We did cognitive testing before and after the transplant,” says Freed, “and there was no hint of any effect on cognitive function or emotional state, depression and that sort of thing.” He adds that avoiding behavioural and psychological side effects is a matter of scientific know-how. “We understand the brain areas that are responsible for different functions, so I would argue it’s not a philosophic issue but a target issue. You don’t have to say, ‘Oh my goodness, if we put in new cells is this person going to become somebody different?’—you’d have to have that as your goal.”

    The transplants weren’t perfect—they only worked in people who responded to dopamine drugs and even then didn’t completely bring them back to normal—but “for most patients they can relieve the most severe symptoms and provide a reservoir of dopamine for the patients,” Freed says. He is now working on converting stem cells into dopamine cells for transplantation, because the supply of fetal cells in severely limited.

    But the limited size and function of the area targeted in Parkinson’s disease present a special case. In Batten disease, for instance, stem cells have been injected at multiple sites in the cortex, and the psychological consequences remain unknown.

    In most cases, though, they would probably be a small price to pay if the treatments turn out to be successful. “But at the same time, folks should know about [the psychological side effects],” says Mathews of Hopkins. “We want people to make a fully informed, autonomous choice.”

    Source: Scienceline © NYU Journalism (16/07/09)

    UCLA stem cells scientists make electrically active motor neurons from iPS cells

    Stem Cells

    Stem cells scientists at UCLA showed for the first time that human induced pluripotent stem (iPS) cells can be differentiated into electrically active motor neurons, a discovery that may aid in studying and treating neurological disorders.

    Additionally, the motor neurons derived from the iPS cells appeared to be similar in function and efficiency to those derived from human embryonic stem cells, although further testing needs to be done to confirm that. If the similarities are confirmed, the discovery may open the door for new treatments for neurological disorders using patient-specific cells.

    The study appears today in the early online edition of the journal Stem Cells.

    “It is clear from the literature that you can make at least immature versions of many different kinds of cells from human iPS cells,” said William Lowry, a Broad Stem Cell Research Center scientist, an assistant professor of molecular, cell and developmental biology and senior author of the study. “But there is not a lot of data published describing the generation of fully functional cells from human iPS cells.”

    Lowry and his team used skin fibroblasts and reprogrammed them back into an embryonic state, with the ability to differentiate into any cell type in the human body. They then took those cells and differentiated them into motor neurons.

    Neurons are the responsive cells in the nervous system that process and transmit information by electrochemical signaling. Motor neurons receive signals from the brain and spinal cord and regulate muscle contraction.

    The study demonstrates the feasibility of using iPS-derived motor neurons and their progenitors to replace damaged or dead motor neurons in patients with certain disorders. It also opens the possibility of studying motor neuron-related diseases in the laboratory to uncover their causes. Motor neurons are lost in many conditions, including spinal cord injury, Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy.

    “A primary objective of human embryonic stem cell and human iPS cell technology is to be able to generate relevant cell types to enable the repair of tissue damage and in vitro modeling of human disease processes,” the study states. “Here, we demonstrate the successful generation of electrically active motor neurons from multiple human iPS cell lines and provide evidence that these neurons are molecularly and physiologically indistinguishable from motor neurons derived from human embryonic stem cells.”

    Much may be learned from studying the iPS-derived motor neurons and comparing them to motor neurons derived from patients with neurological disorders to see how they differ. The next step for Lowry and his team is to combine the motor neurons with muscle cells to see if they can stimulate a response. If they do, researchers should be able to see the muscle cells contract.

    Source: University of California - Los Angeles (25/02/09)

    Surgical device invented in Halifax, Nova Scotia, transplants neural stem cells

    Ivar Mendez

    A surgical tool designed and built in Halifax is already being used to help Nova Scotians with neurological disorders and could become the gold standard around the world, says the head of the Brain Repair Centre.

    Dr. Ivar Mendez showed off the instrument, called the Halifax Injector, at the Queen Elizabeth II Health Sciences Centre last week.

    The device can be programmed by a touch screen to deliver precise quantities of stem cells to very specific areas deep inside the brain.

    "This is the instrument that’s going to allow all the neurosurgeons in the future to repair the brain using cellular restoration," Dr. Mendez said. "When the time of stem cells comes and they’re ready for broader applications, the idea is that every operating room in the world will have the Halifax Injector."

    The Brain Repair Centre has already pioneered a technique for transplanting stem cells into the brain to treat Parkinson’s disease. Video of a patient before and five years after a transplant shows a dramatic transformation: The man regained control of his hands and was able to walk normally.

    Examinations of brain tissue in patients who have had the treatment also show the stem cells caused brain cells to resume producing dopamine and restore connections that were lost as a result of Parkinson’s, said Dr. Mendez.

    But without an automated device like the injector it was difficult to precisely deliver the cells to the areas they needed to reach. A surgeon had to manually adjust the mechanisms that drove the needle into the brain, he said.

    "We had to build an instrument that will allow us to do this, because there is nothing available," Dr. Mendez said. "To be able to put the right amount of cells in the right area without damaging the brain, and being safe, we created the Halifax Injector."

    The device includes a frame that is fitted to the patient’s head and precisely holds the injection system and the micro-motors that drive it. The mechanism is connected to a computer with which a surgeon can program exactly how deeply the needle should enter the brain, how many deposits of stem cells to make, and where, and the volume of the deposits in micro-litres.

    Each procedure is practised and mapped out beforehand in virtual reality.

    Once the patient is prepared for surgery, the injection can proceed with one touch of a screen.

    Dr. Mendez said accurate placement of the stem cells is of paramount importance, and giving surgeons this level of control is a major achievement.

    The injector has been in development for at least three years with all of the work, including the machining of the components, done in Halifax.

    There are plans to test the instrument at five different universities in the United Kingdom, Sweden, Germany and the United States.

    Dr. Mendez said medical technology companies are interested in acquiring the rights to the patented device, and he’s already heard from surgeons wondering about its use in other areas of the body.

    Dr. Murray Hong, part of the design team along with Ron Hill, Luis Bustamente and others, said the injector also has the potential to deliver drugs, genes or other compounds that need to be precisely targeted for treatment.

    Source: The Chronical Herald.ca © 2008 The Halifax Herald Limited (15/12/08)

    Neurons derived from embryonic stem cells restore muscle function after injury

    Stem Cells

    Dalhousie Medical School researchers have discovered that embryonic stem cells may play a critical role in helping people with nerve damage and motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), regain muscular strength.

    Motor neurons reside in the spinal cord and control limb movements by enabling muscles to contract. Diseases like ALS cause them to degenerate, resulting in muscle weakness, atrophy, and eventual paralysis.

    “This study builds on a series of studies in which we demonstrated that motor neurons can be generated from mouse embryonic stem cells,” says Dr. Victor Rafuse, associate professor of anatomy & neurobiology. “It’s very exciting that these neurons can be used for transplantation to prevent degeneration of muscle.”

    The research team used embryonic stem cells from mice to grow motor neurons in the laboratory. They then transplanted the neurons into mouse nerves that were separated from the spinal cord. After separation, it would be expected that the nerves and muscles they control die. However, the Dalhousie group was the first in the world to find that the muscles not only were preserved by the transplantation, but they could produce about half their normal force to contract.

    “This opens the door for a variety of different treatments,” says Dr. Rob Brownstone, professor of surgery and anatomy & neurobiology. “We’ve learned that muscles are preserved by stem cells; now we’re studying how this method can be applied to humans so that we can better treat people with nerve injuries and paralysis. Additionally, we’re looking at combining stem cell treatment with electrically-stimulated implants, which could stimulate nerves to produce movement.”

    The study, which was also authored by graduate student Damien Yohn and former post-doctoral fellow Gareth Miles, was funded by New York-based Project A.L.S. It was published in today’s edition of Journal of Neuroscience.

    Source: Science Daily © 1995-2008 ScienceDaily LLC (20/11/08)

    Stem Cells From Monkey Teeth Can Stimulate Growth And Generation Of Brain Cells

    Stem cells

    Researchers at the Yerkes National Primate Research Center, Emory University, have discovered dental pulp stem cells can stimulate growth and generation of several types of neural cells. Findings from this study, available in the October issue of the journal Stem Cells, suggest dental pulp stem cells show promise for use in cell therapy and regenerative medicine, particularly therapies associated with the central nervous system.

    Dental stem cells are adult stem cells, one of the two major divisions of stem cell research. Adult stem cells have the ability to regenerate many different types of cells, promising great therapeutic potential, especially for diseases such as Huntington’s and Parkinson’s. Already, dental pulp stem cells have been used for regeneration of dental and craniofacial cells.

    Yerkes researcher Anthony Chan, DVM, PhD, and his team of researchers placed dental pulp stem cells from the tooth of a rhesus macaque into the hippocampal areas of mice. The dental pulp stem cells stimulated growth of new neural cells, and many of these formed neurons. “By showing dental pulp stem cells are capable of stimulating growth of neurons, our study demonstrates the specific therapeutic potential of dental pulp stem cells and the broader potential for adult stem cells,” says Chan, who also is assistant professor of human genetics in Emory School of Medicine.

    Because dental pulp stem cells can be isolated from anyone at any age during a visit to the dentist, Chan is interested in the possibility of dental pulp stem cell banking. “Being able to use your own stem cells for therapy would greatly decrease the risk of cell rejection that we now experience in transplant medicine,” says Chan.

    Chan and his research team next plan to determine if dental pulp stem cells from monkeys with Huntington’s disease can enhance brain cell development in the same way dental pulp stem cells from healthy monkeys do.

    Source: Science Daily © 1995-2008 ScienceDaily LLC (12/11/08)

    Japanese researchers make brain tissues from stem cells

    Brain stem cells

    Japanese researchers said Thursday they had created functioning human brain tissues from stem cells, a world first that has raised new hopes for the treatment of disease.

    Stem cells taken from human embryos have been used to form tissues of the cerebral cortex, the supreme control tower of the brain, according to researchers at the government-backed research institute Riken.

    The tissues self-organised into four distinct zones very similar to the structure seen in human foetuses, and conducted neuro-activity such as transmitting electrical signals, the institute said.

    Research on stem cells is seen as having the potential to save lives by helping to find cures for diseases such as cancer and diabetes or to replace damaged cells, tissues and organs.

    The team's previous studies showed stem cells differentiated into different cells but until now they had never organised into functioning tissues.

    "In regenerative therapy, only a limited number of diseases can be cured with simple cell transplants. Transplanting tissues could raise hopes for greater functional recovery," the institute said in a statement.

    "Cultivated tissues are still insufficient and too small to be used to treat stroke patients. But study of in-vitro cultivation of more mature cortex tissues, such as those with six zones like in the adult human brain, will be stepped up," it said.

    The tissues could also serve as "a mini organ" for use in studying the cause of the Alzheimer's disease and developing vaccines, it said.

    Embryonic stem cells are harvested by destroying a viable embryo, a process that some people find unacceptable.

    Riken said cortex tissues were also obtained from "induced pluripotent stem cells," which are similar to embryonic stem cells but artificially induced, typically from adult cells such as skin cells.

    The research was led by Yoshiki Sasai at Riken Centre for Development Biology in western Japan's Kobe.

    Source: AFP © 2008 AFP. (06/11/08)

    Stem cells dramatically reduce brain damage in study

    By injecting stem cells extracted from bone marrow, scientists were able to coordinate the genetic response of animals, dramatically reducing the amount of brain damage triggered by a sudden interruption in the blood supply.

    Researchers had theorized that an injection of bone marrow cells would spur the creation of new brain cells. Instead, the scientists noted that the mice involved in the study reacted with a tamped down inflammatory and immune system response--significantly reducing the damage done. The results could influence research into new methods for limiting stroke damage.

    "The big thing was finding out how these cells were helping," said senior author Dr. Darwin Prockop. "This dramatic crosstalk was very surprising. The human cells specifically turned down immune and inflammatory reactions."

    Source: Fierce Bioresearcher (17/09/08)

    New insights on new neurons

    Two studies on mice shed light on the role of neurogenesis in memory, olfactory sensing and antidepressant efficacy.

    Most of the brain does fine with its original brain cells, but parts involved in smelling and remembering sometimes need some new recruits.

    In mice, new neurons are needed to remember mazes and keep their scent-sensing organs plump (but aren’t necessary for detecting smells), a new study shows. Another recent study demonstrates that some antidepressants require neurogenesis — the creation of fresh neurons — to work.

    Both studies are part of a new wave of research that shows neurogenesis — once thought to be impossible in the brain — plays an important role in the organ’s function.

    “These are both very good papers and consistent with the growing appreciation for the importance of adult neurogenesis in general and in particular in behavior,” says Fred “Rusty” Gage, a neuroscientist at the Salk Institute for Biological Sciences in La Jolla, Calif.

    Neurogenesis creates new neurons in the hippocampus, a part of the brain linked to learning and memory, and in the olfactory bulb, an organ that detects smells and pheromones. But scientists didn’t know why it was necessary to make new cells in those brain regions.

    Japanese researchers led by Ryoichiro Kageyama, a neuroscientist at Kyoto University, report August 31 in an advance online publication of Nature Neuroscience that neurogenesis plays different roles in the two brain structures.

    Nearly all of the cells in the olfactory bulb are replaced, and that refreshing of neurons is required to maintain the shape and volume of the bulb, the researchers report. But mice with shrunken olfactory bulbs had no trouble sniffing out sweet treats, suggesting that a few old neurons are all that’s needed to maintain a sense of smell.

    Neural stem cells that make new olfactory bulb neurons seem to act like the adult stem cells that maintain skin, blood and gut, says Kageyama. But the researchers don’t yet understand why a breakdown in maintenance doesn’t destroy the mice’s sense of smell.

    “Smell is so important for mice that redundancy in olfaction could be intensive,” Kageyama says. “It is also possible that the mice have some olfactory defect that we are so far not aware of.” The team has not yet tested whether mice with atrophied olfactory bulbs can still detect pheromones.

    In contrast to the olfactory bulb, far fewer new neurons are added to the hippocampus. More than 10 percent of neurons are replaced in the hippocampus, but their addition doesn’t make the brain region bigger, and blocking neurogenesis doesn’t make the hippocampus shrink, Kageyama and his colleagues found. There might be only a few new neurons, but they are important for mice to form memories, the researchers say. Blocking neurogenesis impaired mice’s ability to remember a maze for more than week, while mice with intact hippocampuses remembered the maze two weeks after learning to run it.

    “It’s not a straightforward linkage between neurogenesis and memory,” says Paul Frankland, a neuroscientist at the Hospital for Sick Children Research Institute in Toronto, who was not involved in the new studies.Memories can still form in the absence of neurogenesis, but may be subtly different from those made when new neurons are present, he says. Neurogenesis may help form a timeline for memories, with new neurons helping to keep track of memories formed at the time the cells joined the hippocampus.

    Neurogenesis in the hippocampus slows down as mice age. Similar slowing in people could help explain why memory fails as people get older, Kageyama says.

    Another mystery about neurogenesis concerns antidepressants known as selective serotonin reuptake inhibitors or SSRIs, the class of drug that includes Prozac. Those drugs were previously shown to stimulate neurogenesis in the hippocampus, but scientists were not sure if that was a side effect of the medication or necessary for its action.

    Now, a study on mice in the Aug. 14 Neuron shows that neurogenesis in the hippocampus depends on the action of a protein called TRKB, and that neurogenesis is required for the antidepressant effects of SSRIs.

    That doesn’t mean that depression is caused by a defect in neurogenesis, says Luis Parada, who led the study with colleagues at the University of Texas Southwestern Medical Center in Dallas. But the research could shed light on why some people don’t respond to antidepressant therapy and lead to the development of new drugs to treat depression.

    “There is exciting evidence that in a variety of animal models neurogenesis accompanies response to antidepressants,” he says. “We’re getting an idea of what molecules mediate this.”

    Source: Science News © Society for Science & the Public 2000 - 2008 (01/09/08)

    UCI neuroscientist awarded $3 million state stem cell grant
    Dr. Edwin Monuki to research brain cells with goal of treating neurological disorders

    California’s stem cell research funding agency today awarded a UC Irvine neuroscientist $3 million to study and generate a cell type that keeps the brain and spinal cord healthy.

    Dr. Edwin Monuki, assistant professor of pathology & laboratory medicine and developmental & cell biology, was one of 23 scientists from 12 institutions to receive a New Faculty Award from the Independent Citizens Oversight Committee, the governing body of the California Institute for Regenerative Medicine. In all, the ICOC approved grants totaling $59 million. The awards support promising young scientists embarking on stem cell research.

    Total CIRM funding to UCI reached $51.2 million with this award, ranking it fourth for total CIRM funding among 27 institutions statewide.

    “This award is a godsend for my research program, given the historically tough funding climate we are currently in,” Monuki said. “As a neuropathologist and physician-scientist, my work has involved diagnosing and understanding disease, but not intervening. Being given the opportunity to potentially intervene is particularly gratifying and motivating.”

    Monuki plans to study the formation of choroid plexus epithelial cells. Located in the brain, these cells produce the cerebrospinal fluid that bathes the brain and spinal cord with nourishing chemicals to promote normal nervous system health and function, learning and memory, and neural repair following injury. The cells also protect the brain and spinal cord from toxins, including those associated with Alzheimer’s disease.

    Choroid plexus function diminishes with normal aging and more rapidly in diseases such as Alzheimer’s. As the choroid plexus diminishes, neurologic and neuropsychiatric disorders can occur or become worse.

    With the CIRM funding, Monuki will study how these cells develop normally in mice, then use both mouse and human stem cells to generate choroid plexus epithelial cells in laboratory culture dishes. Success in producing these cells could lead to clinical therapies and screens for new drugs for neurological and neuropsychiatric disorders.

    “This gives my research program a very tangible goal and opportunity to directly impact human health,” Monuki said.

    In May, the state awarded UCI $27.2 million to build a dedicated stem cell research facility. It will be modeled after the existing Hewitt Hall and located within the heart of UCI’s Biomedical Research Center in the Health Sciences complex.

    When completed, the new building will house the Sue & Bill Gross Stem Cell Research Center, as many as 26 laboratory-based and clinical researchers, a stem cell techniques course for young scientists, a master’s program in biotechnology with an emphasis on stem cell research, and an array of programs and activities that involve and educate patients and the general public. UCI is raising money to support the new building.

    UCI began its stem cell research program in the 1970s and moved into human stem cell research in 2000. Today, more than 60 UCI scientists use stem cells in current or planned studies. UCI’s stem cell scientists are pioneers in regeneration, in large-scale production of specialized cells with very high purity, and in methods for using such cells to treat damaged tissues.

    Source: WebWire® 1995 - 2008 (15/08/08)

    Yale Researchers Discover Tiny Cellular Antennae Trigger Neural Stem Cells

    Yale University scientists reported evidence suggesting that the tiny cilia found on brain cells of mammals, thought to be vestiges of a primeval past, actually play a critical role in relaying molecular signals that spur creation of neurons in an area of the brain involved in mood, learning and memory. The findings are published online in the journal Proceedings of the National Academy of Science.

    The cilia found on brain cells of mammals until recently had been viewed as a mysterious remnant of a distant evolutionary past, when the tiny hair-like structures were used by single-celled organisms to navigate a primordial world.

    "Many neuroscientists are shocked to learn that cells in the brain have cilia. Thus it was even more exciting to show that cilia have a key function in regulating the birth of new neurons in the brain," said Matthew Sarkisian, post doctoral fellow in the department of neurobiology and co-first author on the study.

    In the past decade, scientists have discovered primary cilia may have important functions in many animals. For instance, in 2000, Yale University scientists discovered defects in these cilia could lead to rare type of kidney disease. Researchers have been finding new functions for primary cilia ever since.

    In the present study, researchers discovered that in mice, primary cilia act like antennae to receive and coordinate signals that spur creation of new brain cells. These cilia receive signals from a key protein required in development called "sonic hedgehog." When the Yale team deleted genes needed to form primary cilia, they discovered that mice developed significant brain abnormalities including hydrocephalus. They also found that the absence of primary cilia on neural stem cells disrupted the ability of sonic hedgehog to signal neural stem cells to initiate creation of new neurons in the brain.

    Furthermore, this group also observed cilia on dividing brain tumor cells. Postdoctoral fellow and co-first author Joshua Breunig said, "Considering sonic hedgehog is also heavily implicated in brain tumor formation, our study places the primary cilium at the crossroads of both regenerative neurobiology and neuro-oncology."

    Authors include: Jon Arellano, Yury Morozov, Albert Ayoub, Sonal Sojitra, Baolin Wang, Richard Flavell, Pasko Rakic (corresponding author) and Terrence Town
    The study was funded by the National Institutes of Health and the Kavli Institute.

    Source: Medical News Today © 2008 MediLexicon International Ltd (12/08/08)

    Scientists report a breakthrough in stem cell production

    Stem Cells

    Reaching a milestone in stem cell research, scientists at Harvard and Columbia universities reported yesterday that they created the first stem cell lines from a sick person, then coaxed these cells to become nerve cells genetically matched to those that had gone bad in a patient's spinal cord.

    In a paper published online in the journal Science, the team claimed success at what researchers have long been racing to do: create in the laboratory a plentiful supply of cells that have the same genetic makeup as a patient with a particular disease.

    The work was done with patients suffering from ALS, or Lou Gehrig's disease, but the researchers said the same technique can be used to study many other genetic diseases. By comparing diseased cells to normal cells in a Petri dish, scientists hope to better understand what causes disease and test new drugs.

    A series of dramatic discoveries over the past two years has pushed stem cell science forward, so this advance was expected. Still, the scientists were thrilled to have accomplished a task that was a fundamental reason for doing stem cell research in the first place.

    "Since the cloning of Dolly the sheep and the first derivation of a human embryonic stem cell line by Jamie Thomson some 10 years ago, it's been the hope of scientists . . . to generate stem cell lines that have the genes of a patient," said Kevin Eggan, coauthor of the paper and a principal faculty member of the Harvard Stem Cell Institute. "This really suggests that it's going to be possible to make these cells from patients suffering from other diseases," whether it is Parkinson's disease, diabetes, or genetic heart maladies.

    To accomplish their task, Eggan and his colleagues took advantage of a technique developed two years ago by Japanese stem cell researchers that avoids some of the ethical issues that come with embryonic stem cell research. They had planned to create genetically matched stem cells through cloning patients' cells, a process that not only involves some medical risk to women who serve as egg donors, but also requires the destruction of embryos, which some consider the equivalent of murder.

    The new technique is much simpler. Researchers insert four genes into a patient's cells, reprogramming them into embryonic- like stem cells. These cells, called iPS cells, appear to have the same capability as embryonic stem cells to develop into any type of tissue in the body.

    Eggan and his colleagues created iPS cells from skin cells taken from an 82-year-old ALS patient, then prompted the stem cells to become motor neurons, the type of cells that die off in ALS.

    The scientists will study the motor neurons derived from the ALS patient's stem cells, hoping to observe the disease develop in the cells. The progressive neurodegenerative disease causes motor neurons in the brain and spinal cord to die, and can lead to paralysis or death. The ALS Association estimates 30,000 people in the United States have the disease.

    "It's our lack of understanding of that disease process which is, we believe, preventing us from developing more effective cures," said Christopher Henderson, a coauthor of the paper and codirector of the Center for Motor Neuron Biology and Disease at Columbia University. "We now have in the culture dish cells which have the same genetic makeup as do the ALS patients, and they are the very cells that are affected in the disease. There's no way we could go to an ALS patient and take a sample of their motor neurons."

    A more distant goal is to fix defects in the cells and transplant them back into patients, but the technique currently used to create the iPS cells requires adding viruses and genes that can cause cancer.

    Jose Cibelli, a professor of animal biotechnology at Michigan State University, said researchers now have a valuable new way to study disease.

    "It's one of the papers that is predictable, but until someone actually shows it works, it's up in the air," he said.

    The work also shows the overall shift in stem cell research because of political barriers.

    When they began working on the experiment more than two years ago, Eggan's team had planned to use somatic cell nuclear transfer, a technique that involves taking human eggs, removing the genetic material inside, and replacing it with genetic material from a patient. Eggan says such work is still crucial, and his laboratory continues to work on that technique, which is considered the "gold standard" for stem cell work. But because of legislation restricting scientists from paying women for their eggs, only one woman has donated her eggs, he said.

    The technique using iPS cells "is so much easier, [with] so many fewer restrictions and problems - ethical as well as others," said Rudolf Jaenisch, a stem cell scientist and member of the Whitehead Institute in Cambridge. "I think we'll probably be moving in this direction."

    Source: boston.com © Copyright 2008 Globe Newspaper Company. (01/08/08)

    Adult Stem Cells Activated In Mammalian Brain

    Adult ependymal cell

    Adult stem cells originate in a different part of the brain than is commonly believed, and with proper stimulation they can produce new brain cells to replace those lost to disease or injury, a study by UC Irvine scientists has shown.

    Evidence strongly shows that the true stem cells in the mammalian brain are the ependymal cells that line the ventricles in the brain and spinal cord, rather than cells in the subventricular zone as biologists previously believed. Brain ventricles are hollow chambers filled with fluid that supports brain tissue, and a layer of ependymal cells lines these ventricles.

    Knowing the cell source is crucial when developing stem cell-based therapies. Additionally, knowing that these normally dormant cells can be coaxed into dividing lays the groundwork for future therapies in which a patient’s own stem cells produce new brain cells to treat neurological disorders and injuries such as Parkinson’s disease, stroke or traumatic brain injury.

    “With such a therapy, we would know which cells in the body to target for activation, and their offspring would have all the properties necessary to replace damaged or missing cells,” said Darius Gleason, lead author of the study and a graduate student in the Department of Developmental and Cell Biology. “It is a very promising approach to stem cell therapy.”

    Study results appear this month online in the journal Neuroscience.

    Stem cells are the “master cells” that produce each of the specialized cells within the human body. If researchers could control the production and differentiation of stem cells, they may be able to use them to replace damaged tissues.

    One focus of stem cell research is transplantation, which entails injecting into the body healthy cells that may or may not genetically match the patient. Transplantation of nonmatching stem cells requires the use of drugs to prevent the body from rejecting the treatment.

    But, working with a patient’s own cells would eliminate the need for transplantation and immunosuppressant drugs and may be a better alternative, scientists say. Ependymal cells line the fluid-filled ventricles, so a drug to activate the cells could theoretically travel through this fluid directly to the stem cells.

    “The cells already match your brain completely since they have the same genetic make-up. That is a huge advantage over any other approach that uses cells from a donor,” Gleason said. “If they are your cells, then all we are doing is helping your body fix itself. We’re not reinventing the repair process.”

    In this study, Gleason and Peter Bryant, developmental and cell biology professor, used rats treated to develop the animal equivalent of Parkinson’s disease. They chose this type of rat because in a previous study by UCI collaborator James Fallon, a small protein given to the brain-damaged rats sparked a rapid and massive production and migration of new cells, and significantly improved motor behavior.

    First, the UCI researchers sought to determine the true location of stem cells in the rats by looking for polarized cells, which have different sets of proteins on opposite sides so that when one divides it can produce two different products. Polarization gives rise to asymmetric cell division, which produces one copy of the parent and a second cell that is programmed to turn into another cell type. Asymmetric cell division is the defining characteristic of a stem cell.

    On rat brain samples, the researchers applied antibodies to identify proteins that may be involved in asymmetric cell division, and they found that polarization exists on the ependymal cells. “It couldn’t have been a stronger signal or clearer message. We could see that the only cells undergoing asymmetric cell division were the ependymal cells,” Gleason said.

    Next, they gave a drug to induce cell division in the rats and examined their brains at intervals ranging from one to 28 days after the treatment. At each interval, they counted cells that were dividing in the ependymal layer. They found the most division at 28 days, when about one-quarter of the ependymal cells were dividing. Previous studies by researchers at other institutions were successful in getting only a few cells to divide in that layer.

    “One interpretation of previous studies is there are scattered stem cells in the ependymal layer, and it is hard to locate them,” Bryant said. “But we believe that all of the ependymal cells are stem cells, and that they all have the ability to be activated.”

    Researchers don’t know yet what sparks cell division at the molecular level, but learning that process and how to control it could lead to a safe, effective stem cell therapy.

    Fallon, psychiatry and human behavior professor, and researchers Magda Guerra and Jian-Chang Liu contributed to this study. All of the scientists are affiliated with the UCI Sue and Bill Gross Stem Cell Research Center.

    Source: Science Daily © 1995-2008 ScienceDaily LLC (25/07/08)

    MIT identifies cells for spinal-cord repair, could lead to Multiple Sclerosis treatment
    A researcher at MIT's Picower Institute for Learning and Memory has pinpointed stem cells within the spinal cord that, if persuaded to differentiate into more healing cells and fewer scarring cells following an injury, may lead to a new, non-surgical treatment for debilitating spinal-cord injuries.

    The work, reported in the July issue of the journal PLoS (Public Library of Science) Biology, is by Konstantinos Meletis, a postdoctoral fellow at the Picower Institute, and colleagues at the Karolinska Institute in Sweden. Their results could lead to drugs that might restore some degree of mobility to the 30,000 people worldwide afflicted each year with spinal-cord injuries.

    In a developing embryo, stem cells differentiate into all the specialized tissues of the body. In adults, stem cells act as a repair system, replenishing specialized cells, but also maintaining the normal turnover of regenerative organs such as blood, skin or intestinal tissues.

    The tiny number of stem cells in the adult spinal cord proliferate slowly or rarely, and fail to promote regeneration on their own. But recent experiments show that these same cells, grown in the lab and returned to the injury site, can restore some function in paralyzed rodents and primates.

    The researchers at MIT and the Karolinska Institute found that neural stem cells in the adult spinal cord are limited to a layer of cube- or column-shaped, cilia-covered cells called ependymal cells. These cells make up the thin membrane lining the inner-brain ventricles and the connecting central column of the spinal cord.

    "We have been able to genetically mark this neural stem cell population and then follow their behavior," Meletis said. "We find that these cells proliferate upon spinal cord injury, migrate toward the injury site and differentiate over several months."

    The study uncovers the molecular mechanism underlying the tantalizing results of the rodent and primate and goes one step further: By identifying for the first time where this subpopulation of cells is found, they pave a path toward manipulating them with drugs to boost their inborn ability to repair damaged nerve cells.

    "The ependymal cells' ability to turn into several different cell types upon injury makes them very interesting from an intervention aspect: Imagine if we could regulate the behavior of this stem cell population to repair damaged nerve cells," Meletis said.

    Upon injury, ependymal cells proliferate and migrate to the injured area, producing a mass of scar-forming cells, plus fewer cells called oligodendrocytes. The oligodendrocytes restore the myelin, or coating, on nerve cells' long, slender, electrical impulse-carrying projections called axons. Myelin is like the layer of plastic insulation on an electrical wire; without it, nerve cells don't function properly.

    "The limited functional recovery typically associated with central nervous system injuries is in part due to the failure of severed axons to regrow and reconnect with their target cells in the peripheral nervous system that extends to our arms, hands, legs and feet," Meletis said. "The function of axons that remain intact after injury in humans is often compromised without insulating sheaths of myelin."

    If scientists could genetically manipulate ependymal cells to produce more myelin and less scar tissue after a spinal cord injury, they could potentially avoid or reverse many of the debilitating effects of this type of injury, the researchers said.

    Source: Massachusetts Institute of Technology (22/07/08) 

    Stem cells help keep the brain healthy and active
    For some years, scientists have been speculating over why stem cells exist in the brain, as brain regeneration is limited. A German team of neuroscientists believe these stem cells help keep the brain healthy and active.

    Speaking at Europe's major neuroscience conference, Professor Gerd Kempermann from the Center for Regenerative Therapies in Dresden explained that the emerging hypothesis for the function of these neural stem cells is for maintenance of a healthy brain, rather than regeneration. The hippocampus - the region of the brain that is central to memory - requires modifications (plasticity) at a cellular level, a much more complex process than synaptic plasticity at the junction of the neurons used by other brain regions. In the adult hippocampus, stem cells produce new neurons throughout life, a process known as 'adult neurogenesis'. Surprisingly, cognitive activity, as well as physical exercise, stimulate this process.

    "Our idea is that new neurons in the adult hippocampus allow this system to remain flexible to the cognitive challenges an individual might meet during his or her life. New neurons might add to a particular reserve that allows better compensation in the face of degeneration and loss," Professor Kempermann proposed.

    He suggests that on the other hand if this neural stem-cell based system fails, this loss of cellular plasticity might contribute to some aspects of psychiatric disorders such as depression, schizophrenia and dementia. Stimulating adult neurogenesis might thus be a way to deal with these disorders.

    "New neurons in the adult hippocampus might help to explain why mental and physical activity is good for the aging brain", he said.

    This research so far is in mice. Very little is known about this process in humans, but Professor Kempermann is fairly confident that the same regulatory principles apply in humans too.

    Source: News-Medical.net © 2008 News-Medical.Net (14/07/08)

    Stem Cell Therapeutics Announces Issuance of Keystone Prolactin Patents

    Stem Cell Therapeutics Corp. ("SCT") is pleased to announce the Company has been issued two corresponding patents to strengthen its intellectual property landscape through United States and Australia.

    The U.S. patent, numbered 7,393,830 and entitled "Prolactin induced increase in neural stem cell numbers" was issued July 1, 2008. The Australian patent, numbered 2002325711 and entitled "Prolactin induced increase in neural stem cell numbers and therapeutical use thereof" was issued January 10, 2008. These are the first patents to issue in this patent family.

    Dr. Alan Moore, President and CEO of SCT commented as follows:

    "What is particularly important about these patents is that they cover the use of prolactin alone, as well as in combination with other therapeutics that augment recovery and therefore provide a broad base of protection. We have the exclusive right to the use of prolactin for treating neurodegenerative diseases and therefore have a strong foundation to develop many possible products using prolactin, either as a single therapeutic or in combination with other neurogenic agents. For example, this intellectual property supports programs currently under development using prolactin alone or with anti-inflammatories to treat multiple sclerosis and using a combination of prolactin and EPO to treat other neurodegenerative diseases."

    Source: Stem Cell Therapeutics Corp (07/07/08)

    Adult stem cells reprogrammed in the brain, hopes for diseases such as Multiple Sclerosis
    In recent years, stem cell researchers have become very adept at manipulating the fate of adult stem cells cultured in the lab. Now, researchers at the Salk Institute for Biological Studies achieved the same feat with adult neural stem cells still in place in the brain.

    They successfully coaxed mouse brain stem cells bound to join the neuronal network to differentiate into support cells instead.

    The discovery, which is published ahead of print on Nature Neuroscience's website, not only attests to the versatility of neural stem cells but also opens up new directions for the treatment of neurological diseases, such as multiple sclerosis, stroke and epilepsy that not only affect neuronal cells but also disrupt the functioning of glial support cells.

    "We have known that the birth and death of adult stem cells in the brain could be influenced be experience, but we were surprised that a single gene could change the fate of stem cells in the brain," says the study's lead author, Fred H. Gage, Ph.D., a professor in the Laboratory for Genetics and the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases.

    Throughout life, adult neural stem cells generate new brain cells in two small areas of mammalian brains: the olfactory bulb, which processes odors, and the dentate gyrus, the central part of the hippocampus, which is involved in the formation of memories and learning.

    After these stem cells divide, their progenitors have to choose between several options remaining a stem cell, turning into a nerve cell, also called a neuron, or becoming part of the brain's support network, which includes astrocytes and oligodendrocytes.

    Astrocytes are star-shaped glia cells that hold neurons in place, nourish them, and digest parts of dead neurons. Oligodendrocytes are specialized cells that wrap tightly around axons, the long, hair-like extensions of nerve cell that carry messages from one neuron to the next. They form a fatty insulation layer, known as myelin, whose job it is to speed up electrical signals traveling along axons.

    When pampered and cosseted in a petri dish, adult neural stem cells can be nudged to differentiate into any kind of brain cell but within their natural environment in the brain career options of neural stem cells are thought to be mostly limited to neurons.

    "When we grow stem cells in the lab, we add lots of growth factors resulting in artificial conditions, which might not tell us a lot about the in vivo situation," explains first author Sebastian Jessberger, M.D., formerly a post-doctoral researcher in Gage's lab and now an assistant professor at the Institute of Cell Biology at the Swiss Federal Institute of Technology in Zurich. "As a result we don't know much about the actual plasticity of neural stem cells within their adult brain niche."

    To test whether stem cells in their adult brain environment can still veer off the beaten path and change their fate, Jessberger used retroviruses to genetically manipulate neural stem cells and their progeny in the dentate gyrus of laboratory mice. Under normal conditions, the majority of newborn cells differentiated into neurons. When he introduced the Ascl1, which had previously been shown to be involved in the generation of oligodendrocytes and inhibitory neurons, he successfully redirected the fate of newborn cells from a neuronal to an oligodendrocytic lineage.

    "It was quite surprising that stem cells in the adult brain maintain their fate plasticity and that a single gene was enough to reprogram these cells," says Jessberger. "We can now potentially tailor the fate of stem cells to treat certain conditions such as multiple sclerosis."

    In patients with multiple sclerosis, the immune system attacks oligodendrocytes, which leads to the thinning of the myelin layer affecting the neurons' ability to efficiently conduct electrical signals. Being able to direct neural stem cells to differentiate into oligodendrocytes may alleviate the symptoms.

    Source: Huliq News © 2008 Huliq.com (01/07/08)

    Nerve Cells Derived From Stem Cells And Transplanted Into Mice May Lead To Improved Brain Treatments
    Scientists at the Burnham Institute for Medical Research have, for the first time, genetically programmed embryonic stem (ES) cells to become nerve cells when transplanted into the brain, according to a new study published in The Journal of Neuroscience.

    The research, an important step toward developing new treatments for stroke, Alzheimer's, Parkinson's and other neurological conditions showed that mice afflicted by stroke showed tangible therapeutic improvement following transplantation of these cells. None of the mice formed tumors, which had been a major setback in prior attempts at stem cell transplantation.

    The team was led by Stuart A. Lipton, M.D., Ph.D., professor and director of the Del E. Webb Neuroscience, Aging, and Stem Cell Research Center at Burnham. Dr. Lipton is also a clinical neurologist who treats patients with these disorders. Collaborators included investigators from The Scripps Research Institute.

    "We found that we could create new nerve cells from stem cells, transplant them effectively and make a positive difference in the behavior of the mice," said Dr. Lipton. "These findings could potentially lead to new treatments for stroke and neurodegenerative diseases such as Parkinson's disease."

    Conditions such as stroke, Alzheimer's, Parkinson's and Huntington's disease destroy brain cells, causing speech and memory loss and other debilitating consequences. In theory, transplanting neuronal brain cells could restore at least some brain function, just as heart transplants restore blood flow.

    Prior to this research, creating pure neuronal cells from ES cells had been problematic as the cells did not always differentiate into neurons. Sometimes they became glial cells, which lack many of the neurons' desirable properties. Even when the neuronal cells were created successfully, they often died in the brain following transplant--a process called programmed cell death or apoptosis. In addition, the cells would sometimes become tumors.

    Dr. Lipton solved these problems by inducing ES cells to express a protein, discovered in his laboratory called myocyte enhancer factor 2C (MEF2C). MEF2C is a transcription factor that turns on specific genes which then drive stem cells to become nerve cells. Using MEF2C, the researchers created colonies of pure neuronal progenitor cells, a stage of development that occurs before becoming a nerve cell, with no tumors. These cells were then transplanted into the brain and later became adult nerve cells. MEF2C also protected the cells from apoptosis once inside the brain.

    "To move forward with stem cell-based therapies, we need to have a reliable source of nerve cells that can be easily grown, differentiate in the way that we want them to and remain viable after transplantation," said Dr. Lipton. "MEF2C helps this process first by turning on the genes that, when expressed, make stem cells into nerve cells. It then turns on other genes that keep those new nerve cells from dying. As a result, we were able to produce neuronal progenitor cells that differentiate into a virtually pure population of neurons and survive inside the brain."

    The next step was to determine whether the transplanted neural progenitor cells became nerve cells that integrated into the existing network of nerve cells in the brain. Performing intricate electrical studies, Dr. Lipton's investigative team showed that the new nerve cells, derived from the stem cells, could send and receive proper electrical signals to the rest of the brain.

    They then determined if the new cells could provide cognitive benefits to the stroke-afflicted mice. The team executed a battery of neurobehavioral tests and found that the mice that received the transplants showed significant behavioral improvements, although their performance did not reach that of the non-stroke control mice. These results suggest that MEF2C expression in the transplanted cells was a significant factor in reducing the stroke-induced deficits.

    The work was supported in part by National Institutes of Health (NIH) grants and a Senior Scholar Award in Aging Research from the Ellison Medical Foundation.

    Source: Science Daily © 1995-2008 ScienceDaily LLC (25/06/08)

    Scientists create molecule that causes nerve stem cells to mature
    Researchers at UT Southwestern Medical Center claim to have made a small molecule that stimulates nerve stem cells to begin maturing into nerve cells in culture.

    The researchers hope that someday their work might open the door for a potential new technology to grow a person’s own nerve stem cells outside the body, stimulate them into maturity, and then re-implant them as working nerve cells to treat various diseases.

    "This provides a critical starting point for neuro-regenerative medicine and brain cancer chemotherapy," Nature magazine quoted Dr. Jenny Hsieh, assistant professor of molecular biology, as saying.

    She said that creation of the molecule helped her team uncover some of the biochemical steps that happen as nerve cells mature, and showed that large-scale screening of compounds could provide starting points for developing drugs to treat disorders like Huntington's disease, Multiple Sclerosis, traumatic brain injury or cancer.

    She revealed that the research group started work on this project as a result of a separate study wherein 147,000 compounds were being screened to see which of them could stimulate stem cells cultivated from rodent embryos to become heart cells.

    Dr. Hsieh said that five molecules were found to stimulate the cells to transform into forms resembling nerve cells.

    She added that the team then created a variation of those molecules, a new compound called Isx-9 (for isoxazole-9).

    According to her, it was easier to use Isx-9 than its initially discovered relatives, as it worked at a much lower concentration and dissolved more easily in water.

    "It was completely serendipitous that we uncovered this neurogenic [nerve-creating] small molecule. I think it's one of the most powerful neurogenic small molecules on the planet. In theory, this molecule could provoke full maturation, to the point that the new nerve cells could fire, generating the electrical signals needed for full functioning," she said.

    Dr. Hsieh revealed that she and her colleagues cultured rodent nerve cells from an area of the brain called the Hippocampus with Isx-9.

    She said that the cells clustered together, and developed spiky appendages called neuritis, which typically happens when nerve cells are grown in culture.

    The study also showed that Isx-9 prevented the stem cells from developing into non-nerve cells, and that it was more potent than other neurogenic substances in stimulating nerve-cell development.

    The molecule generated two to three times more nerve cells than other commonly used compounds, said Dr. Hsieh.

    She further said that Isx-9 appeared to act like a neurotransmitter-like signal which, when sent by a mature nerve cells, enabled the immature cells to begin maturing.

    When the researchers cultured the stem cells with the compound, said Dr. Hsieh, they identified a possible biochemical pathway whereby stem cells begin to become nerve cells.

    Dr. Hsieh and her colleagues are now planning to test Isx-9 on a large number of different combinations of RNA, the chemical cousin of DNA, to see on which genes the compound might be working.

    The research team has also applied for a patent on Isx-9 and its relatives.

    Source: TopNews.in (16/06/08)

    Compounds Inhibit And Stimulate Neural Stem Cell Growth
    Scientists at Schepens Eye Research Institute have identified specific molecules in the brain that are responsible for awakening and putting to sleep brain stem cells, which, when activated, can transform into neurons (nerve cells) and repair damaged brain tissue. Their findings are published online this week in the Proceedings of the National Academy of Science (PNAS).

    A previous paper by the same group found stem cells in many more parts of the brain than stem cells were previously know to exist. This suggests more parts of the brain are repairable via mechanisms already there if we can only find ways to get control of those mechanisms.

    An earlier paper (published in the May issue of Stem Cells) by the same scientists laid the foundation for the PNAS study findings by demonstrating that neural stem cells exist in every part of the brain, but are mostly kept silent by chemical signals from support cells known as astrocytes.

    "The findings from both papers should have a far-reaching impact," says principal investigator, Dr. Dong Feng Chen, who is an associate scientist at Schepens Eye Research Institute and an assistant professor of ophthalmology at Harvard Medical School. Chen believes that tapping the brain¹s dormant, but intrinsic, ability to regenerate itself is the best hope for people suffering from brain-ravaging diseases such as Parkinson¹s or Alzheimer¹s disease or traumatic brain or spinal cord injuries.

    Until these studies, which were conducted in the adult brains of mice, scientists assumed that only two parts of the brain contained neural stem cells and could turn them on to regenerate brain tissue-- the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). The hippocampus is responsible for learning and memory, while the SVZ is a brain structure situated throughout the walls of lateral ventricles (part of the ventricular system in the brain) and is responsible for generating neurons reponsible for smell. So scientists believed that when neurons died in other areas of the brain, they were lost forever along with their functions.

    Molecules named ephrin-A2 and ephrin-A3 inhibit neural stem cell growth. So inhibitors of those molecules might help to activate stem cells for brain repair. Sonic hedgehog (which the press release below misspells as sonic hedghoc) stimulates neural stem cell growth. Inhibit the ephrins and stimulate sonic hedgehog and the result would be much more neural stem cell growth.

    In the second (PNAS) study, the team went on to discover the exact nature of those different chemical signals. They learned that in the areas where stem cells were sleeping, astrocytes were producing high levels of two related molecules--ephrin-A2 and ephrin-A3. They also found that removing these molecules (with a genetic tool) activated the sleeping stem cells.

    The team also found that astrocytes in the hippocampus produce not only much lower levels of ephrin-A2 and ephrin-A3, but also release a protein named sonic hedghoc that, when added in culture or injected into the brain, stimulates neural stem cells to divide and become new neurons.

    The eventual development of techniques to create youthful neural stem cells will provide stem cells that can be safely stimulate to grow without running a cancer risk. But How to replace the old stem cells with young ones? It is not enough to add the newer younger stem cells to the brain (and just getting the new stem cells into all the spots in the brain they need to go is a challenge). We need to get rid of the old stem cells so that a drug that boosts stem cell growth will only stimulate the new stem cells and not the old stem cells too.

    Source: FuturePundit (08/06/08)

    Neurologically Impaired Mice Improve After Receiving Human Stem Cells
    Scientists report a dramatic success in what may be the first documented rescue of a congenital brain disorder by transplantation of human neural stem cells. The research, published by Cell Press in the June issue of the journal Cell Stem Cell, may lead the way to new strategies for treating certain hereditary and perinatal neurological disorders.

    Nerve cell projections are ensheathed by a fatty substance called myelin that is produced by oligodendrocytes, a type non-nerve cell in the brain and spinal cord. Myelin enhances the speed and coordination of the electrical signals by which nerve cells communicate with one another. When myelin is missing or damaged, electrical signals are not properly transmitted. Previous studies have explored the potential utility of cell transplantation for restoring absent or lost myelination to diseased nerve fibers. Much of this research has made use of the 'shiverer mouse' animal model which lacks normal myelin and typically dies within months of birth. Yet to date, no transplantation of human neural stem cells or of their derivatives, called glial progenitor cells, have ever altered the condition or fate of recipient animals.

    Dr. Steve Goldman and colleagues from the Departments of Neurology and Neurosurgery at the University of Rochester Medical Center, along with collaborators at Cornell, UCLA and Baylor, built on this earlier work by devising a more robust method for the acquisition and purification of human fetal glial progenitor cells. In addition, they developed a new cell delivery strategy, based on multiple injection sites, to encourage widespread and dense donor cell engraftment throughout the central nervous system of recipient mice. The researchers transplanted human glial stem cells into neonatal shiverer mice that also had a genetically deficient immune system. Immunodeficient mice were used to minimize the rejection of the transplanted cells.

    The researchers found that the new transplant procedure resulted in infiltration of human glial progenitor cells throughout the brain and spinal cord. The engrafted mice exhibited robust, efficient and functional myelination. Most notably, many of the mice displayed progressive, neurological improvement and a fraction of the mice were actually rescued by the procedure. "The neurological recovery and survival of the mice receiving transplants was in sharp contrast to the fate of their untreated controls, which uniformly died by five months," explains Dr. Goldman. Upon histological examination well over a year after the procedure, the white matter of the surviving mice had been essentially re-myelinated by human cells.

    "To our knowledge, these data represent the first outright rescue of a congenital hypomyelinating disorder by means of stem or progenitor cell transplantation," offers Dr. Goldman. "Although much work needs to be done to maximize the number of individuals that respond to transplantation, I think that these findings hold great promise for the potential of stem cell-based treatment in a wide range of hereditary and ischemic myelin disorders in both children and adults."

    Source: ScienceDaily © 1995-2008 ScienceDaily LLC (05/06/08)

    New Stem Cell Therapy May Aid Repair Of Damaged Brains
    According to some experts, newly born neuronal stem cells in the adult brain may provide a therapy for brain injury. But if these stem cells are to be utilized in this way, the process by which they are created, neurogenesis, must be regulated.

    A new study, led by Laurence Katz, Co-Director of the Carolina Resuscitation Research Group at the University of the North Carolina School of Medicine, suggests a way in which this might be achieved.

    According to the research, neurogenesis can be regulated through induced hypothermia. In rat subjects, a mild decrease in body temperature was found to substantially decrease the proliferation of newly-born neurons, a discovery that marks a major step forward for the development of neuronal stem cell-based brain therapies.

    Since the 1930s, brain damage from stroke, head injury, near drowning and cardiac arrest was considered to be permanent because of a lack of repair mechanisms like other parts of the body. However, discovery of neuronal stem cells in the adult brain challenges that belief.

    “Many questions remain before we adequately understand how to control these cells to repair a damaged brain,” says Katz. “However, the findings represent an important step in demonstrating that these cells can be controlled by simple external forces like hypothermia.”

    The presentation entitled “Hypothermia Decreases Neurogenesis” was given by Laurence Katz from The University of North Carolina School of Medicine. This paper was presented at the 2008 SAEM Annual Meeting, Washington, D.C. on May 31, in the Neurovascular emergencies forum. Abstracts are published in Vol. 15, No. 5, Supplement 1, May 2008 of Academic Emergency Medicine, the official journal of the Society for Academic Emergency Medicine.

    Source: ScienceDaily © 1995-2008 ScienceDaily LLC (02/06/08)

    Stem cell find linked to memory
    Australian researchers have discovered stem cells in the brain that are vital for learning and memory.

    They have also worked out how to activate the cells so they produce new neurons, a discovery that could eventually lead to better treatments for degenerative brain conditions of ageing, such as dementia.

    The director of the Queensland Brain Institute, Perry Bartlett, said neuroscientists knew there had to be stem cells somewhere in the hippocampus - the part of the brain involved in important functions such as learning and memory - because people and other animals produced large numbers of new neurons in this region throughout life.

    But the stem cells had proved extremely difficult to find.

    Professor Bartlett now understands why. His team has discovered that mice have only eight to 10 of these cells in this region of the brain. "And in humans there is probably not a lot more. You don't need a large number," he said.

    As people get older they make fewer new brain cells, which reduces their mental functioning, particularly in navigation and short-term memory.

    "But we think that even though there is a loss in the ability to make new nerve cells, the machinery is still there. The exciting part is that we're starting to discover ways to activate the stem cells, even in aged animals," Professor Bartlett said.

    Working with live mice and their brain tissue in the lab, his team produced a threefold increase in the number of cells in the hippocampus producing new neurons. "It's a pretty massive effect," said Professor Bartlett, of the University of Queensland, whose team's findings are published in The Journal of Neuroscience.

    Source: The Sydney Morning Herald © 2008. The Sydney Morning Herald. (19/05/08)

    Neuralstem Announces Issuance of Core Technology Patent in Europe

    Stem cell company, Neuralstem, Inc., announced today that the European Patent Office has granted Neuralstem a European patent EP0915968, covering the "Isolation, Propagation and Directed Differentiation of Stem Cells from Embryonic and Adult Central Nervous System of Mammals." The European patent has been validated in several European countries including France, Germany, Ireland, Spain, Sweden, Switzerland and the United Kingdom.

    "We are pleased to see our core technology patent validated in these European countries," said Neuralstem CEO, Richard Garr. "We expect this to be the first of many as our entire patent portfolio makes its way through the European process. In allowing this patent, the European Patent Office has now joined with the U.S. Patent Office in rejecting any arguments that the body of Stem Cells Inc. patents and publications, noted in the examinations, in any way prevents Neuralstem's patents from issuing."

    About Neuralstem

    Neuralstem's patented technology enables, for the first time, the ability to produce neural stem cells of the human brain and spinal cord in commercial quantities, and the ability to control the differentiation of these cells into mature, physiologically relevant human neurons and glia.

    Major Central Nervous System diseases targeted by the Company with research programs currently underway include: Ischemic Paraplegia, Traumatic Spinal Cord Injury and ALS. The company's cells have extended the life of rats with ALS (Lou Gehrig's disease) as reported the journal TRANSPLANTATION, in collaboration with Johns Hopkins University researchers, and also reversed paralysis in rats with Ischemic Spastic Paraplegia, as reported in NEUROSCIENCE on June 29, 2007, in collaboration with researchers at University of California San Diego.

    The company has also developed immortalized human neural stem cells for in-vitro use in drug development for the academic and pharmaceutical markets.

    Source: Neuralstem, Inc (29/04/08)

    Post brain injury: New nerve cells originate from neural stem cells

    Most cells in the human brain are not nerve cells, but supporting cells (glial cells). They serve as a framework for nerve cells and play an important role in the wound reaction that occurs with injuries to the brain. However, what these ‘reactive glial cells’ in the brains of mice and men originate from, and which cells they evolve into was hitherto unknown.

    Now, the study group of Prof. Dr. Magdalena Götz is able to show that after injury, these reactive glial cells in the brains of mice restart their cell division. They then become stem cells from which nerve cells can form yet again under favourable cell culture conditions.

    With this came the ground-breaking proof that, in an injured region of the brain, adult neural stem cells exist that could later serve as a source of new nerve cells.

    In her study group, the stem cell expert, Magdalena Götz, examines the molecular bases of cerebral development, in particular in the cerebral cortex. Götz proved in earlier investigations that glial brain cells can act as stem cells, and nerve cells emerge from glial cells. She also pointed out which factors play a role in the cross-over from glial to neural cells. “Now, thanks to these results, the distant goal of being able to use the processes therapeutically is getting a little closer” stresses Götz.

    Annalisa Buffo, Inmaculada Rite, Pratibha Tripathi, Alexandra Lepier, Dilek Colak, Ana-Paula Horn, Tetsuji Mori, and Magdalena Götz: "Origin and progeny of reactive gliosis: a source of multi-potent cells in the injured brain“; PNAS published 25 February, 2008, 10.1073/pnas.0709002105 (Neuroscience)

    Source: EurekaAlert! (12/03/08)

    Human Stem Cells Produce Healthy Neural Stem Cells In Rats
    Neural cells derived from human embryonic stem cells helped repair stroke-related damage in the brains of rats and led to improvements in their physical abilities after a stroke, in a new study by researchers at the Stanford University School of Medicine.

    This study marks the first time researchers have used human embryonic stem cells to generate neural cells that grow well in the lab, improve a rat’s physical abilities and consistently don’t form tumors when transplanted.

    Though the authors caution that the study is small and that more work is needed to determine whether a similar approach would work in humans, they said they believe it shows the potential for using stem cell therapies in treating strokes.

    Senior author Gary Steinberg, MD, PhD, the Bernard and Ronni Lacroute-William Randolph Hearst Professor of Neurosurgery and the Neurosciences, said that with 750,000 people having strokes in the United States each year, the disease creates a massive burden for stroke victims, their families and the medical system.

    “Human embryonic stem cell-based therapies have the potential to help treat this complex disease,” Steinberg said, adding that he hopes the cells from this study can be used in human stroke trials within five years.

    Human embryonic stem cells are able to form any cell type in the body. Pushing those cells to form neural stem cells rather than other types of cells has been a substantial hurdle, as has avoiding the cells’ tendency to form tumors when transplanted. Because embryonic stem cells are still immature and retain the ability to renew themselves and produce all tissue types, they tend to grow uncontrollably into tumors consisting of a mass of different cells.

    First author Marcel Daadi, PhD, a senior scientist in Steinberg’s lab, said the team overcame those obstacles by growing the embryonic stem cells in a combination of growth hormones that nudged the cells to mature into stable neural stem cells. After six months in a lab dish, those neural stem cells continued to form only the three families of neural cells—neurons, astrocytes and oligodendrocytes—and no tumors.

    Convinced that the cells appeared safe, Daadi and co-author Anne-Lise Maag, a former research assistant, transplanted those cells into the brains of 10 rats with an induced form of stroke. At the end of two months, the cells had migrated to the damaged brain region and incorporated into the surrounding tissue. None of those transplanted cells formed tumors.

    Once in place, the transplanted cells helped repair damage from the induced stroke. The researchers mimicked a stroke in a region of the brain that left one forelimb weak. This model parallels the kinds of difficulties people experience after a stroke.

    Testing at four weeks and again at eight weeks after the stem cell transplants showed the animals were able to use their forelimbs more normally than rats with similarly damaged brain regions that had not received the transplants.

    “The great thing about these cells is that they are available in unlimited supply and are very versatile,” Daadi said. The neural cells the group generated grew indefinitely in the lab and could be an ongoing source of cells for treating stroke or other injuries, he added.

    In previous studies, Steinberg and others have implanted cells from cord blood, bone marrow, fetal and adult brain tissue or cells derived from mouse embryonic stem cells into stroke-damaged rats, but none of those cell types appear as promising as the cells in this study, the researchers said. Those cells aren’t as easy to produce in large scale, don’t repair damage as effectively and are prone to forming tumors.

    Before researchers can begin testing these neural cells in human stroke patients, Steinberg and Daadi said they need to verify that the cells are effective in other animal stroke models and don’t form tumors. They are working with industry groups to grow the cells in accordance with U.S. Food and Drug Administration guidelines, which would be necessary before they could move on to human trials.

    Source: Stanford University School of Medicine. (20/02/08)

    Stem cells safely made into nerve tissues

    Korean scientists on Monday (Feb. 18) said they have successfully used nano and bio technologies to grow nerve, muscle and liver tissues from stem cells.

    The discovery made by a team led by Park Se-pill, a life engineering professor at Cheju National University, used magnetized nano particles to insert genes into stem cells of laboratory animals that differentiated into specific tissues.

    The research published in the latest issue of the international Stem Cells and Development journal is noteworthy because it did not use the dangerous retrovirus or inefficient chemical-electrical techniques that are currently employed in these experiments.

    Retroviruses are used in so-called gene delivery systems, but they are believed to cause serious side effect since the tainted stem cells could trigger cancer and immune disorders. In the chemical-electrical technique, a high percentage of genes are lost in the delivery process.

    Park’s team, which includes researchers from Mirae Biotech Research Institute in Seoul and Konkuk University, said they used 20 nanometer particles that were combined with specific genes of laboratory mice and placed on top of a plate that emitted a magnetic field. This process allowed the genes to be safety mixed with stem cells and grown into nerve, muscle and liver tissues. A nanometer is one-billionth of a meter.

    Stem cell research may result in cures for numerous diseases such as Alzheimer’s and diabetes and could help people suffering from paralysis caused by damaged vertebrae.       

    Park said the success rate using nano technology reached 45 percent, much higher than the 15 percent attained by the chemical-electrical technique.

    He added that in the 50 laboratory experiments conducted, all genes transplanted into the stem cells survived and grew into tissue.

    The team, meanwhile, said that while nanotechnology is used in cell research, its experiments were the first to use the technology to help differentiate stem cells.

    The technique has been submitted for patent protection.

    Source: Korea.Net © Korea.Net 1999 - 2008 (18/02/08)

    USM Announces Findings On Use Of Stem Cells In Neuro Treatment

    A group of researchers at Universiti Sains Malaysia (USM) created a milestone in the field of neuroscience with their findings on the use of embryonic and bone marrow stem cells to treat neuro diseases.

    These two stem cells can be used in the treatment of paralysis, brain injury or backbone injury, according to Prof Jafri Malin Abdullah who led the team of researchers.

    Announcing the outcome after a year of research today, Prof Jafri said the two stem cells could be used to treat neuro diseases by replacing the damaged cells.

    There are four categories of stem cells -- embryonic stem cells, fetal stem cells, umbilical cord stem cells and adult stem cells which could be obtained from the bone marrow, intestines, heart, skin, brain, pancreas and eyes, he added.

    He said the treatment could be used on humans in three to five years' time.

    "A lot of researches have been done on stem cells but this is the first involving neuroscience in Malaysia," he added.

    Meanwhile, USM Vice Chancellor Prof Datuk Dzulkifli Abdul Razak said the finding by the team was another success by USM Hospital in the field of medical research.

    "We hope the outcome of this research can be used to treat human in the future," he added.

    The research is funded by the Higher Education Ministry under the Basic Education Fund involving an allocation of RM250,000.

    Source: Bernama.com © 2008 BERNAMA (11/02/08)

    Stem cell scaffolding repairs nerves

    A Monash University PhD student has developed a new technique that could revolutionise stem cell treatment for Multiple Sclerosis, Parkinson's disease and spinal cord injuries.

    David Nisbet from Monash University's Department of Materials Engineering has used existing polymer-based biodegradable fibres, 100 times smaller than a human hair, and re-engineered them to create a unique 3-D scaffold that could potentially allow stem cells to repair damaged nerves in the human body more quickly and effectively.

    Mr Nisbet said a combined process of electrospinning and chemical treatment was used to customise the fibre structure, which can then be located within the body.

    "The scaffold is injected into the body at the site requiring nerve regeneration. We can embed the stem cells into the scaffold outside the body or once the scaffold is implanted. The nerve cells adhere to the scaffold in the same way ivy grips and weaves through a trellis, forming a bridge in the brain or spinal cord. Over time, the scaffold breaks down and is naturally passed from the body, leaving the newly regenerated nerves intact," Mr Nisbet said.

    Mr Nisbet said the existing processes released stem cells into the nervous system where they 'floated' around.

    "Our studies show that stem cells anchored to a scaffold not only attach more easily, but rapidly adapt to their environment and regenerate effectively. We are very excited about the therapeutic outcomes that could be obtained from our research," Mr Nisbet said.

    "We are at the interface of two once separate disciplines -- nanotechnology and stem cell research -- combining into a new exciting era of discovery which could be the first step towards a cure for conditions such as MS,  Parkinson's disease and spinal cord injury.

    "Repairing damaged neural pathways is the holy grail of many researchers. It is a very long road to success, which will require small steps from many people, but it's wonderful to know we're making such a significant contribution here at Monash University," Mr Nisbet said.

    The potential of Nisbet's scaffold design has captured the interest of colleagues. The University of Toronto in Canada and the Melbourne-based Howard Florey Institute are conducting further tests, with preliminary results showing strong potential.

    Another collaboration, with the Mental Health Research Institute of Victoria, is investigating the use of scaffolds in the potential treatment of damaged brain nerve cells.

    Mr Nisbet said biodegradable fibres were commonly used in biomedical sciences and regenerative technologies, but his technique of re-engineering them into a 3-D structure is a world first.

    Source: Monash University Copyright © 2007 Monash University (31/01/08)

    Identification of a novel neural stem cell type

    Researchers from the Sloan-Kettering Institute, led by Dr. Lorenz Studer, have discovered a novel type of neural stem cell, which has a broader differentiation potential than previously identified neural stem cells.

    In culture, neural stem cells (NSCs) can readily differentiate into neuronal and glial subtypes, but their ability to differentiate into region-specific neuronal cell types is limited. Dr. Studer and colleagues isolated and cloned a population of neural rosette cells (R-NSCs), which have an expanded neuronal subtype differentiation potential.

    Dr. Studer and colleagues demonstrate that R-NSCs can differentiate along both the CNS and PNS lineages, and are capable of in vivo engraftment. Furthermore, the researchers identified biomarkers unique to the R-NSC type, as well as signaling pathways required for the maintenance of the R-NSC type.

    “Our data suggest that R-NSCs may represent the first neural cell type capable of recreating the full cellular diversity of the mammalian nervous system. As such, R-NSCs should have a major impact for applications in regenerative medicine and have the potential to become the "embryonic stem cell equivalent" of the nervous system,” explains Dr. Studer.

    Source: EurekaAlert! (15/01/08)

    UCSC faculty receive $4.5 million in new grants for stem cell research

    Two young faculty members at the University of California, Santa Cruz, have received major grants for stem cell research from the California Insitute for Regenerative Medicine (CIRM). The five-year grants totalling $4.5 million will support the research of Bin Chen, assistant professor of molecular, cell, and developmental biology, and Camilla Forsberg, assistant professor of biomolecular engineering.

    The grants are among 22 New Faculty Awards announced yesterday by CIRM to fund stem cell research at various California institutions. UCSC has now received a total of more than $9 million from CIRM to fund the campus's growing stem cell research program.

    "It is really remarkable how successful we've been at getting started in this new area of research," said Stephen Thorsett, dean of physical and biological sciences at UCSC. "Our proposals to CIRM have garnered more funding than those of any other institution that doesn't have a medical school."

    Stem cell research has enormous potential to produce new therapies and cures for a wide range of diseases. Stem cells are unspecialized cells that are able to renew themselves indefinitely and can also differentiate into specialized cell types with specific functions, such as a nerve cell or liver cell. Eventually, stem cells may be used to replace damaged or dysfunctional cells in the body with healthy new ones.

    The latest CIRM grants are intended for scientists in the critical early stages of their careers as independent investigators and faculty members. Designed to encourage and foster the next generation of clinical and scientific leaders in stem cell research, the New Faculty Awards support research across the range of stem cell types--human and animal, adult and embryonic. The work supported by Chen and Forsberg's grants will not involve human embryonic stem cells.

    Forsberg, who joined the UCSC faculty in July, is studying how stem cells make the decision to become a particular type of mature blood cell, and how this process can go wrong to cause disease. She uses special lines of mice genetically engineered to allow her to track the development of mature blood cells from their stem cell progenitors. Forsberg said two of the fundamental challenges in using stem cells to treat diseases are to get the cells established in the body, and then to direct the cells to differentiate into the desired cell type.

    "Our long-term goal is to provide a comprehensive understanding of stem cell fate decisions and, ultimately, to be able to manipulate those decisions after transplantation of stem cells into the body," Forsberg said.

    Chen's research focuses on the development of corticospinal motor neurons, which control voluntary muscle movements and are affected in neurodegenerative diseases and spinal cord injuries. Earlier this year, she received one of the first CIRM research grants: $500,000 for research on embryonic stem cells. She also uses mouse models to study how stem cells differentiate into specialized neurons.

    "One of the most exciting possibilities in stem cell biology is the potential to replace damaged or diseased neural tissues affected by neurodegenerative disorders," Chen said. "Neurons derived from stem cells provide a potentially limitless supply for cell replacement, if we could guide stem cells cultured in a laboratory toward specific differentiation pathways to produce specific types of neurons."

    Chen's new grant will provide research funding of $436,000 in the first year and a total of $2.2 million over five years. Forsberg's grant will provide $467,000 in the first year and a total of $2.3 million over five years. Forsberg noted that the awards were the result of a team effort involving a large group of people working to build UCSC's stem cell research program. The interdisciplinary program involves researchers in biology and engineering, as well as contributions from humanities faculty in the area of bioethics.

    "This is team building at its best. I feel very supported by the campus and the engineering school," Forsberg said.

    Source: UC Santa Cruz (14/12/07)

    The Birth of a Brain Cell: Scientists Witness Neurogenesis

    For the first time, researchers have developed a way to view stem cells in the brains of living animals, including humans—a finding that allows scientists to follow the process neurogenesis (the birth of neurons). The discovery comes just months after scientists confirmed that such cells are generated in adult as well as developing brains.

    "I was looking for a method that would enable us to study these cells through[out a] life span," says Mirjana Maletic-Savatic, an assistant professor of neurology at Stony Brook University in New York State, who specializes in neurological disorders such as cerebral palsy that premature and low-weight babies are at greater risk of developing. She says the new technique will enable her to track children at risk by monitoring the quantity and behavior of these so-called progenitor cells in their brains.

    The key ingredient in this process is a substance unique to immature cells that is neither found in mature neurons nor in glia, the brain's nonneuronal support cells. Maletic-Savatic and her colleagues collected samples of each of the three cell types from rat brains (stem cells from embryonic animals, the others from adults) and cultured the varieties separately in the lab. They were able to determine the chemical makeup of each variety—and isolate the compound unique to stem cells—with nuclear magnetic resonance (NMR) spectroscopy. (NMR helps to determine a molecule's structure by measuring the magnetic properties of its subatomic particles.) Although the NMR could identify the biomarker, but not its makeup, Maletic-Savatic speculates it is a blend of fatty acids in a lipid (fat) or lipid protein.

    After pinpointing their marker, the team ran two tests to determine the method's sensitivity and accuracy: First, they injected a bevy of stem cells into a rat's cerebral cortex, an outer brain layer where neurogenesis does not normally occur. They then passed an electric current through the animals' brains; electric currents induce neurogenesis in the hippocampus, a forebrain structure that is one of two sites (the other being the subventricular zone) where new neurons are believed to arise.

    After performing each procedure, the team used NMR spectroscopy to capture images of the living rats' brains. There was, however, too much visual interference on the scans to find their biomarker. The researchers called upon Stony Brook electrical engineering professor Petar Djurić to help them come up with an algorithm to cut through the clutter and glean a clear picture of their target compound.

    With the analytical method helping to decode their scans, they could clearly see increased biomarker levels in the cortex after a neural stem cell injection. Similarly, after the animals were given electric shocks, levels of the compound clearly went up in the hippocampus.

    The team next turned its attention to humans, enlisting 11 healthy volunteers, ranging in age from eight to 35, who each spent 45 minutes in an NMR scanner. Hippocampal scans turned up more of the marker than the cortical images. In addition, the older subjects showed lower levels of the biomarker than younger ones (a finding consistent with earlier studies). "This is the first technique that allows detection of these cells in the living human brain," says Maletic-Savatic.

    Fred Gage, a genetics professor at the Salk Institute for Biological Studies in La Jolla, Calif., and co-author a 1998 report in Nature Medicine that announced the discovery of neurogenesis in the adult human brain, praises the new approach. "It seems that they are measuring proliferation rather then maturation based on their results," he says. "It will be important for them to knock down neurogenesis in a mouse and show that [this] signal disappears to confirm the causal link with neurogenesis."

    If the new work is replicated and confirmed, it may allow for faster diagnosis and tracking of myriad psychiatric and neurological conditions. Among them: chronic depression. Study co-author Grigori Enikolopov, an associate professor of molecular biology at Cold Spring Harbor Laboratory in Long Island, N.Y., showed last year that antidepressants lead to new nervous system cells, raising questions about the role these cells play in the causation of the ailment.

    "Although we are only just beginning to test applications, it is clear that this biomarker may have promise in identifying cell proliferation in the brain, which can be a sign of cancer," Enikolopov says. "In other patients, it could show us how neurogenesis is related to the course of diseases such as depression, bipolar disorder, Alzheimer's, Parkinson's, MS, and post-traumatic stress disorder."

    Source: Scientific American © 1996-2007 Scientific American Inc. (14/11/07)

    Scientists develop non-invasive method to track nerve-cell development in live human brain
    A team of scientists including researchers at Cold Spring Harbor Laboratory (CSHL) have identified and validated the first biomarker that permits neural stem and progenitor cells (NPCs) to be tracked, non-invasively, in the brains of living human subjects. This important advance could lead to significantly better diagnosis and monitoring of brain tumors and a range of serious neurological and psychiatric disorders.

    The biomarker is a lipid molecule whose presence the scientists were able consistently to detect in a part of the brain called the hippocampus where new nerve cells are known to be generated. The marker was not detected in the cortex and other parts of the brain where this process, called neurogenesis, does not occur in healthy adults.

    As elsewhere in the body, the rise of new cells in the brain is a process that can be traced to stem cells, which, through mechanisms still only partly grasped, give birth to “daughter” progenitor cells that undergo repeated division and maturation into “adult” cells. As recently as a few years ago, most scientists did not believe that new nerve cells were created anywhere in the adult brain.

    The newly discovered marker can be detected when NPCs – stem-like “progenitor” cells – are actively dividing, a mark that new nerve cells are being created. “Until now, there was no way to identify and track these cells in living people, to get a dynamic picture of neurogenesis,” said Grigori Enikolopov, Ph.D.

    A fuller understanding of neural stem and progenitor cells could one day unlock the secret to nervous-system regeneration following stroke or massive trauma. In the nearer-term, discovery of the neural stem-cell biomarker just reported is likely to yield more powerful diagnostics.

    “The technique the team has developed is based on MRI technology that is currently in widespread use to perform non-invasive scans of the living brain and can tell us where stem-like cells are dividing,” said Dr. Enikolopov, whose CSHL lab specializes in the study of stem cells, in the brain and in other tissues. “Although we are only just beginning to test applications, it is clear that this biomarker may have promise in identifying cell proliferation in the brain, which can be a sign of cancer. In other patients, it could show us how neurogenesis is related to the course of diseases such as depression, bipolar disorder, Alzheimer’s, Parkinson’s, Multiple Sclerosis, and post-traumatic stress disorder.”

    In 2006, Dr. Enikolopov demonstrated that the antidepressant fluoxetine (Prozac) stimulates the creation of new nerve cells in the hippocampus of depressed patients. He later demonstrated that an even more pronounced effect was brought about by other depression treatments, electroconvulsive therapy and deep-brain stimulation.

    “The recent finding that neural progenitor cells exist in adult human brain has opened a whole new field in neuroscience,” said Walter J. Koroshetz, M.D., deputy director of the NIH's National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the work. “The ability to track these cells in living people would be a major breakthrough in understanding brain development in children and continued maturation of the adult brain. It could also be a very useful tool for research aimed at influencing NPCs to restore or maintain brain health.”

    Discovery of the neural stem cell marker relied heavily upon the development of an ingenious algorithm devised by Dr. Petar M. Djuric of SUNY Stony Brook. That mathematical formula made the marker’s spectroscopic “image” stand out amid a field filled with visual “noise,” in much the same way as algorithms used in submarine sonar equipment filter out all ambient noise save that of other subs. Filtering out “noise” in the brain enabled the team to demonstrate the presence of the biomarker in live animals and in human subjects.

    Source: Cold Spring Harbor Laboratory (09/11/07)

    Bystander Stem Cells Keep Original Neurons Humming
    A new study finds that neural stem cells may be able to save dying brain cells without transforming into new brain tissue, at least in rodents. Researchers from the University of California, Irvine, report that stem cells rejuvenated the learning and memory abilities of mice engineered to lose neurons in a way that simulated the aftermath of Alzheimer's disease, stroke and other brain injuries.

    Researchers expect stem cells to transform into replacement tissue capable of replacing damaged cells. But in this case, the undifferentiated stem cells, harvested from 14-day-old mouse brains, did not simply replace neurons that had died off. Rather, the group speculates that the transplanted cells secreted protective neurotrophins, proteins that promote cell survival by keeping neurons from inducing apoptosis (programmed cell death). Instead, the once ill-fated neurons strengthened their interconnections and kept functioning.

    "The primary implication here is that stem cells can help rescue memory deficits that are due to cell loss," says Frank LaFerla, a professor of neurobiology and behavior at U.C. Irvine and the senior author on a new study published in The Journal of Neuroscience. If the therapeutic benefit was indeed solely due to a neurotrophic factor, the door could be opened to using that protein alone as a drug to restore learning ability.

    LaFerla's team genetically engineered mice to lose cells in their hippocampus, a region in the forebrain important for short-term memory formation. These mice were about twice as likely than unaltered rodents to fail a test of their ability to discern whether an object in a cage had been moved since their previous visit.

    But when the mutant mice were injected with about 200,000 stem cells directly into their hippocampi and retested up to three months later, the injured animals performed up to par with their normal counterparts.

    LaFerla's team found that in healthy mice that were similarly injected, the stem cells (which were marked with a green fluorescent dye) had spread throughout the brain. In the brains of the diseased mice, however, nearly all the cells congregated in the hippocampi. "Somehow, in the damaged region, there is some kind of signal that's telling the stem cells to stay local," LaFerla explains.

    Curiously, the researchers discovered that only about five percent of the stem cells injected into the brain-addled mice matured into adult neurons. The surrounding neurons that were there all along, however, had sprouted a denser set of connections with other cells, presumably allowing for better transmission of information and recovery of function. "We think it's some neurotrophic factor being secreted by the [stem] cells," LaFerla says. If his group can identify it, he adds, they can answer the question: "Can that substance [alone] be provided to the brain and rescue the memory deficit?"

    Eugene Redmond, a professor of psychiatry and surgery at Yale University School of Medicine notes the new work is "certainly well done. Their conclusion is similar to our study in Parkinsonian monkeys." He notes that in his study there was evidence of stem cells replacing lost neurons as well as other benefits conferred by the transplant.

    Source: Scientific American.com © 1996-2007 Scientific American, Inc. (02/11/07)

    New nerves grown from fat cells
    New nerves grown from stem cells taken from a patient's fat could be available by 2011, researchers have said.

    They could potentially be used to repair peripheral nerves left severed by surgery or accidents.

    Manchester University scientists plan to place the new nerve tissue inside a biodegradable plastic tube, which can be used to rejoin the two broken ends.

    The findings of their study on rats, in Experimental Neurology, could help hundreds of people a year, they say.

    At the moment, only limited techniques are available to help repair nerves outside the spinal cord, even though they have a limited capacity to regrow.

    Other nerves from elsewhere in the patient are often used, which does not restore perfect function and can cause further damage.

    The Manchester technique uses stem cells - immature cells which the body naturally uses to create different tissue types.

    So far, the team has extracted stem cells from fat tissue taken from rats, and managed to coax the cells into becoming neurons - nerve cells - in the laboratory.

    Their next step is to repeat this in stem cells from human fat, and then create a full replacement nerve, using a biodegradable "sheath" to surround it.

    This nerve-filled tube could then be implanted to re-join the ends of a severed nerve virtually anywhere in the body, they claim.

    Large tumour

    Dr Paul Kingham, who led the research, said: "The differentiated stem cells have great potential for future clinical use, initially for treatment of patients with traumatic injuries of nerves in the arms and legs."

    He said that the treatment might be available in four or five years, as a study to test the biodegradable tube is already under way.

    Dr Kingham said it could also work in cases where surgeons have had to remove a large tumour close by a nerve, damaging or cutting the nerve in the process.

    Professor Giorgio Terenghi, the director of the university's Centre for Tissue Regeneration, said: "This new research is a very exciting development that will improve the lives of many different types of patients - and therefore many, many people.

    "The frequency of nerve injury is one in every 1,000 of the population - or 50,000 cases in the UK every year.

    "The patients will not be able to tell that they had ever 'lost' [the feeling to] their limb, and will be able to carry on exactly as they did before."

    Source: BBC Health © BBC 2007 (22/10/07)

    Repressor Protein Blocks Neural Stem Cell Development
    A protein known to repress gene transcription at the molecular level in a variety of processes also blocks embryonic neural stem cells from differentiating into neurons, according to a study by University of California, San Diego and Howard Hughes Medical Institute (HHMI) researchers published online October 10 in Nature.

    The research team focused on a repressor protein called SMRT (silencing mediator of retinoic acid and thyroid hormone receptor), which has been shown to repress gene expression in a number of molecular pathways. By creating a strain of "knock-out" mice missing the SMRT gene, the team was able to pinpoint significant alterations in brain development in the absence of SMRT. These findings demonstrate the important role of this protein in preventing premature differentiation of specific brain cells from undifferentiated neural stem cells in utero.

    "By showing that SMRT prevents differentiation by maintaining neural stem cells in a basic stem cell state, we now have a target to study further how stem cells restrict themselves from differentiating," said first author Kristen Jepsen, Ph.D., an assistant research scientist at the UC San Diego School of Medicine.

    The research team also noted that in the SMRT-deficient mice, the brain exhibited signs of excessive exposure to retinoic acid--naturally occurring vitamin A, which is a known teratogen (an agent which causes birth defects). This finding suggests that in addition to maintaining neural stem cells in a pre-differentiated state, the SMRT protein controls retinoic-acid induced differentiation and, when missing, abnormalities that mimic vitamin A exposure occur.

    This finding provides scientists with one more important key to understanding how stem cells maintain their potential to grow into specific cells.

    "Incremental steps such as this lay the groundwork for continuing studies investigating the potential of stem cells to be used therapeutically to replace damaged or deficient cells associated with disease," said Jepsen.

    Co-authors of the Nature paper are Derek Solum, Ph.D., Tianyuan Zhou, Ph.D., Robert McEvilly, Ph.D. and Hyun-Jung Kim, Ph.D., of HHMI and UC San Diego; Christopher Glass, M.D., Ph.D., professor of cellular and molecular medicine at UC San Diego; Ola Hermanson, Ph.D. of the Karolinska Institutet in Sweden, and senior author Michael G. Rosenfeld, M.D., HHMI investigator and professor of medicine at UC San Diego.

    Source: University of California - San Diego (11/10/07)

    Stem Cell Sciences to lead EU-funded drug discovery
    Stem Cell Sciences plc will lead an EU-funded, multinational novel drug screening collaboration using stem cells.

    The project, named NEUROscreen, will use Stem Cell Sciences' proprietary neural stem (NS) cell technology and has received a contribution from the EU's 6th Framework Program for Research and Technical Development (FP6).

    The EU's contribution to the NEUROscreen project is worth 2.4 million euro over three years, of which approximately 420,000 euro will flow directly to SCS over the three year period.

    NEUROscreen brings together a partnership of leading European academic research institutes and biotech companies from several nations, including the UK, Germany and Italy.

    The program involves designing unique bioassays based on SCS' neural stem cell technology, which will then be used to discover new candidate medicines for the treatment of cancer, Alzheimer's disease, stroke and epilepsy.

    Neural stem cells can differentiate into neurons and glia, therefore offer potential in treating CNS disorders.

    Source: Trading Markets.com © 2007 The Connors Group, Inc. (26/09/07)

    NZ researchers probe brain cell regeneration

    A team of Auckland researchers which has spent two years growing cultures of cells taken from adult human brains is investigating whether stem cells could be used to combat neurodegenerative disorders such as multiple sclerosis or Alzheimer's disease.

    Professor Mike Dragunow's Auckland University team is one of only a handful of laboratories worldwide pioneering work with human brain cells.

    It plans to use a three-year Marsden Fund grant of $750,000 from the Government to work on nerve cells called astrocytes, which support and feed neurons, with process and transfer signals in the brain.

    In recent years scientists have come to accept that adult humans can create new neurons, during normal brain function as well as after brain injury.

    This has raised the important question of where these new neurons are made, and some research has suggested that the star-shaped astrocytes, the "glue" that usually provide support and nutrition in the brain, may be able to form neurons after changing into neural stem cells.

    Stem cells are the body's master cells, and neural stem cells can be directed to form various types of nerve cells -- and potentially even manipulated to repair damaged areas of the brain,

    The team is looking for confirmation that astrocytes can form neural stem cells, and is investigating the conditions required for converting these cells to neurons.

    Such a capability would be a fundamental advance in understanding of the brain in both its normal and diseased forms.

    Source: Yahoo!Xtra Copyright © 2007 Yahoo! All rights reserved. Yahoo!Xtra (07/9/07)

    One Step Closer To Transplanting Stem Cells In The Brain

    Stem cells transplanted into the brains of mice generate more numerous and more mature nerve cells if the brain cells called astrocytes are not activated. This discovery at the Sahlgrenska Academy is an important step forward for stem cell research.

    The study was performed by a research team at the Center for Brain Repair and Rehabilitation at the Sahlgrenska Academy. The findings are being published in the journal Stem Cells.

    Many see the transplantation of stem cells and activation of the body's own stem cells as a promising future treatment for several neurological disorders.

    "Intensive research is under way around the world to find ways to get stem cells to develop into the right kind of cells, to migrate through brain tissue to the right place and then survive. Even though much work remains to be done before patients benefit from this knowledge, our findings are an important step in that direction," says Milos Pekny, professor at the Sahlgrenska Academy, Göteborg University in Sweden.

    Astrocytes are a type of cells in the central nervous system that control many neurological functions, including the capacity of the brain to repair itself. The research team has previously shown that reduced activation of astrocytes leads to prolonged healing of the damage, but that ultimately the regeneration of the nerve fibers and synapses of nerve cells is enhanced. Decreased activation of astrocytes also yields better results when cells are transplanted into the retina.

    "Astrocytes are also activated when stem cells are transplanted into the brain, and we show that this negatively affects the development of the stem cells," says Milos Pekny.

    The scientists used genetically modified mice whose astrocytes are unable to produce two proteins called GFAP and vimentin. Such astrocytes have a limited capacity to become activated. When neural stem cells are cultured with these modified astrocytes, the generation of nerve cells was increased by 65 percent. At the same time, the formation of new astrocytes rose by 124 percent.

    In the study, stem cells were transplanted into the mouse hippocampus, an area where new nerve cells are generated also in adults. When mice with limited astrocyte activation were used as recipients, there was an increase in the number of nerve cells and astrocytes generated from the transplanted stem cells. The newly generated nerve cells were also more mature than those in normal mice.

    "These studies were carried out in collaboration with Professor Peter Eriksson, a great friend, a fantastic colleague, and a pioneer in human neural stem cell research, whom we lost very suddenly just a few days ago," says Milos Pekny.

    Reference: Journal: Stem Cells, Title of article: Increased Neurogenesis and Astrogenesis from Neural Progenitor Cells Grafted in the Hippocampus of GFAP-/-Vimentin-/- Mice, Authors: Åsa Widestrand, Jonas Faijerson, Ulrika Wilhelmsson, Peter L. P. Smith, Lizhen Li, Carina Sihlbom, Peter S. Eriksson, Milos Pekny

    Source: Science Daily Copyright © 1995-2007 ScienceDaily LLC — All rights reserved (19/08/07)

    Study may help brain disorders
    Promising Treatment: A researcher said that if successful, G-CSF therapy could open up a new avenue of Alzheimer's treatment that is less invasive and more effective

    A team of scientists from the National Science Council have found that a human growth factor that triggers the release of stem cells from bone marrow shows potential as a treatment for Alzheimer's disease and other degenerative brain disorders.

    Shen Che-kun, a researcher at Academia Sinica's institute of molecular biology, told a press conference yesterday that the team's studies showed that Granulocyte-colony stimulating factor (G-CSF) appeared to reverse Alzheimer's-like symptoms induced in mice.

    This is the first piece of research that applies G-CSF therapy, most often used to accelerate recovery from chemotherapy, to Alzheimer's disease, he said.

    "Studies conducted on mice show that G-CSF not only arrests deterioration in mental capacity but allows the affected mice to recover lost mental capacity to levels comparable to normal mice of the same age," Shen said.

    The team induced Alzheimer's-like symptoms in mice in two ways -- by injecting the brains of normal mice with beta-amyloid protein and by using a strain of transgenic mice which naturally exhibit Alzheimer's-like neuronal apoptosis.

    The study, co-authored by Shen and Tsai Kuen-jer, also of the institute of molecular biology, was published in the June issue of the Journal of Experimental Medicine.

    G-CSF is a growth factor that is naturally present in the body in small quantities and is thought to be linked with the regeneration of brain tissue, Shen said.

    During their study, researchers injected G-CSF directly into the mice's thorax. Its presence in the bloodstream facilitated the release of hematopoietic stem cells from bone marrows, Shen said.

    Although Shen and Tsai said that they have not conclusively proved the mechanism by which the damage was repaired, Shen said that he thought it was most likely that the stem cells released by the G-CSF injection from the bone marrow passed into the brain from the bloodstream, where they attached to sites of damage and became differentiated into new cells.

    "There have been previous studies where injections of G-CSF into the bloodstream was found to repair damaged heart tissue," Shen said. "In our case, we saw that the G-CSF injection appeared to cause new cells to grow where the neuron damage was the greatest."

    If successful, G-CSF therapy could open up a new avenue of Alzheimer's treatment that is less invasive and more effective than current therapies, Shen said.

    "However, remember that it has only been found effective in mice so far," cautioned Shen, who said that further trials on human subjects were needed to determine the treatment's efficacy and safety.

    If the drug proves to be effective in clinical testing, it may become available on the market in as little as five years, the researchers said.

    Because G-CSF is already widely used to treat neutropenia in chemotherapy patients, the drug does not have to undergo pre-clinical toxicological testing or phase I clinical testing.

    Source: Taipei Times Copyright © 1999-2007 The Taipei Times. All rights reserved (10/08/07)

    Functioning Neurons From Human Embryonic Stem Cells Produced
    Scientists with the Institute of Stem Cell Biology and Medicine at UCLA were able to produce from human embryonic stem cells a highly pure, large quantity of functioning neurons that will allow them to create models of and study diseases such as Alzheimer's, Parkinson's, Multiple Sclerosis, prefrontal dementia and schizophrenia, etc.

    Researchers previously had been able to produce neurons - the impulse-conducting cells in the brain and spinal cord - from human embryonic stem cells. However, the percentage of neurons in the cell culture was not high and the neurons were difficult to isolate from the other cells.

    UCLA's Yi Sun, an associate professor of psychiatry and biobehavioral sciences, and Howard Hughes Medical Institute investigator Thomas Südhof at the University of Texas Southwestern Medical Center were able to produce 70 to 80 percent of neurons in cell culture. Sun and Südhof also were able to isolate the neurons and determine that they had a functional synaptic network, which the neurons use to communicate. Because they were functional, the neurons can be used to create a variety of human neurological disease models.

    "Previously, the system to grow and isolate neurons was very messy and it was unknown whether those neurons were functioning," Sun said. "We're excited because we have been able to purify so many more neurons out of the cell culture and they were, surprisingly, healthy enough to form synapses. These cells will be excellent for doing gene expression studies and biochemical and protein analyses."

    Sun's method prodded human embryonic stem cells to differentiate into neural stem cells, the cells that give rise to neurons. When the time was right, Sun's team added protein growth factors into the cell culture that stopped the neural stem cells from self-renewing and prodded them into differentiating into neurons.

    To isolate the cells, Sun and her team added an enzyme that digests a sort of protein matrix that holds cells in culture together. The neurons could then be separated from the neural stem cells that had not yet differentiated, a sort of chemical round-up that isolated the neurons. The cells were then put into a cell strainer that allowed passage through of the isolated neurons.

    The large number of pure neurons produced will allow Sun and her team to study their biological form and structure, the genes they express, the development of synapses and the electric and chemical communication activities within the synapse network.

    "We will be able to study the cellular properties of neurons in a very defined way that will maybe tell us what goes wrong in diseases such as Alzheimer's and Parkinson's," Sun said. "We're currently creating many models of human neurological diseases that may provide the answers we're looking for. We don't know what causes prefrontal dementia, Huntington's disease or schizophrenia. The key is likely in the quality of neuronal communications. By studying the chemical and electrical transmissions, we may be able to determine what goes wrong that leads to these debilitating diseases and find a way to stop or treat it."

    Sun will be among the first researchers to be able to study true neuron function.

    A second important discovery in Sun's study showed that two embryonic stem cells lines derived in similar manners, and therefore expected to behave similarly when differentiating, did not. Using the same techniques to prod the two embryonic stem cells lines to differentiate, Sun found that one line had a bias to become neurons that are found in the forebrain. The other line differentiated into neurons found in rear portions of the brain and spinal cord. The finding was surprising, and significant, Sun said.

    "The realization that not all human embryonic stem cell lines are born equal is critical," Sun said. "If you're studying a disease found in a certain part of the brain, you should use a human embryonic stem cell line that produces the neurons from that region of the brain to get the most accurate results from your study. Huntington's disease, for example, is a forebrain disease, so the neurons should be differentiated from a cell line that is biased to produce neurons from the forebrain."Sun said there are ways to prod an embryonic stem cell line biased to become neurons found in the rear brain to become neurons found in the forebrain. However, there are limits to how much prodding can be done.

    Sun and her team confirmed that the two embryonic stem cell lines were different through gene expression analysis -- neurons that perform different functions in different parts of the brain express different genes. The cell line prone to becoming neurons found in the forebrain expressed genes typically found those neurons, while the other line expressed genes found in the rear brain and spinal cord.

    Sun and her team now are studying why the two human embryonic stem cell lines have biases to become different types of neurons.

    "If we knew that, we might be able to tweak or alter whatever is driving the bias so that limitation in the stem cell line could be bypassed," Sun said.

    Study results were recently published in an early online edition of the journal Proceedings of the National Academy of Sciences.

    Source: University of California - Los Angeles (10/08/07)

    Less plasticity in adult stem cells
    Adult neural stem cells in mice are a diverse, restricted set of progenitors.

    Adult neural stem cells in the mouse brain are less plastic than previously thought, according to a study published online this week in Science. The authors found that a stem cell's position in the brain determines the type of neuron it generates.

    As a result, it may be more difficult to coax adult neural stem cells into becoming various types of neurons than some researchers have predicted, according to senior author Arturo Alvarez-Buylla of the University of California, San Francisco.

    "The whole idea of flexibility among adult neural stem cells has to be, I think, reconsidered," Alvarez-Buylla told The Scientist. Instead, there appears to be a "mosaic of different types of primary progenitors giving rise to all of these different types of neurons," he said.

    Neural stem cells in the subventricular zone (SVZ) of the mammalian brain generate neurons throughout the animal's life that migrate to the olfactory bulb and differentiate into several different cell types. Many researchers have believed that these stem cells are homogenous and multipotent until they mature in the olfactory bulb, Alvarez-Buylla said. "That was the model that many people, including ourselves, were working under."

    Recent work, however, suggested that newly born neurons become distinct from one another before they reach the olfactory bulb. To see if the stem cells that generate these neurons in the SVZ are also diverse, researchers led by Florian T. Merkle, also of UCSF, labeled them with green fluorescent protein in different areas of the SVZ and followed their progeny. They found that each region of the SVZ gave rise to a specific subset of neurons in the olfactory bulb.

    The researchers next dissected labeled stem cells out of one SVZ region and grafted them onto a different region in a donor mouse. They found that the stem cells' original positions still specified the fates of the mature neurons, showing that a factor intrinsic to the cells governs their fates.

    Last, the researchers found that the cells retained memory of their regions of origin even when they were cultured with no environmental cues.

    Merkle and his colleagues speculate that transcription factors could encode positional information in the stem cells and their progeny.

    "The results are convincing," said Michael Sofroniew of the University of California, Los Angeles, who was not involved in the work. "In a sense, this is not surprising at all. It fits in with what people in development have been saying for some time," he said.

    Studies have shown that the potential of neural progenitors during embryonic brain development is also determined by a spatial code.

    "Probably the same rules apply in the adult brain as do in the embryonic brain," agreed Kenneth Campbell of Children's Hospital Research Foundation in Cincinnati, Ohio, also not a co-author. "There's been a kind of disconnect in the field of adult neurogenesis, with those notions that you could procure stem cells and then generate any type of neuron," he told The Scientist. "Their data suggest that that's maybe not the case and rather that a lot of these progenitor cells... have really specific programs that they're going to run as they start to differentiate."

    The paper's findings predict difficulties in using adult stem cells to treat neurological disease, Campbell said. "I think now most people are starting to really realise that that's not something that's going to easily be done."

    It remains possible, however, that scientists could manipulate adult neural stem cells in vitro to make them more flexible, Sonofriew said. "If you take these cells out of the brain and put them in tissue culture, you can make them do all sorts of things that they might not necessarily do in vivo."

    Source: The Scientist © 1986-2007 The Scientist (06/07/07)

    StemCells, Inc. Announces Publication Describing Non-Invasive Tracking of Human Neural Stem Cells Transplanted in Vivo

    StemCells, Inc. today announced the publication of a paper describing a new technique for non-invasive tracking of human neural stem cells transplanted into the brains of mice.

    The technique involves tagging the human neural stem cells with Feridex(R), a commonly used magnetic resonance imaging agent approved by the United States Food and Drug Administration (FDA) for use in humans. Tagging the human neural stem cells in this way does not appear to alter the stem cells' function or viability. The paper, entitled "Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with magnetic resonance imaging," appears in this week's online edition of the Proceedings of the National Academy of Sciences.

    The lead authors of the paper are Raphael Guzman, M.D., Clinical Instructor, Department of Neurosurgery, and Gary Steinberg, M.D., Ph.D, Bernard and Ronni Lacroute-William Randolph Hearst Professor of Neurosurgery and the Neurosciences and Chair, Department of Neurosurgery, both of Stanford University School of Medicine. Several researchers at StemCells, Inc. also worked on these studies and the human neural stem cells used were supplied by the Company.

    "This is an important contribution to the field of human cellular transplantation. The ability to track non-invasively human neural stem cells transplanted into the brain could enhance our knowledge and understanding of where the cells go, how they get there and how they behave when they get to their final destination," said Stephen Huhn M.D., F.A.C.S., F.A.A.P., Vice President and Head of Neural Program at StemCells, Inc.

    "Ultimately, this could help the adoption of human cellular transplants into clinical practice. We are currently investigating the Company's proprietary HuCNS-SC(TM) human neural stem cell product in a clinical trial for Batten disease and future studies could potentially employ this labeling agent."

    About StemCells, Inc.

    StemCells, Inc. is a clinical-stage biotechnology company focused on the discovery, development and commercialisation of cell-based therapeutics to treat diseases of the nervous system, liver and pancreas. The Company's programs seek to repair or repopulate neural, liver or other tissue that has been damaged or lost as a result of disease or injury. StemCells has pioneered the discovery and isolation of the human neural stem cell. The cells are expandable into cell banks for therapeutic use, which offers the potential of using normal, non-genetically modified cells as cell-based therapies. StemCells has approximately 50 U.S. and 100 non-U.S. patents.

    Source: Genetic Engineering & Biotecnology News © 2007 Genetic Engineering & Biotechnology News, All Rights Reserved (05/06/07)

    ReNeuron Announces New Data Concerning its ReNcell Neural Stem Cell Lines
    ReNeuron Group plc today announces new data concerning its ReNcell CX and ReNcell VM neural cell lines. These cell lines are marketed through Millipore Corporation as drug discovery tools for academic and commercial research.

    The data were generated in collaboration with Drs Roberta Donato and Frances Edwards at the Department of Physiology, University College London (UCL). The results demonstrate that the ReNcell®CX and ReNcell®VM lines can be continuously expanded in monolayer culture and will differentiate into the three principal neural cell types: neurons, astrocytes and oligodendrocytes. In the case of the ReNcell®VM line, a renewable source of stable, functional and electrophysiologically active dopaminergic neurons was demonstrated.

    The results are published in the on-line journal, BMC Neuroscience (http://www.biomedcentral.com/1471-2202/8/36/abstract)

    Dr John Sinden, Chief Scientific Officer of ReNeuron, said:

    "We are pleased to have further validated the utility of our first generation ReNcell neural cell lines through this collaboration with UCL. The ability of the ReNcell® lines to functionally differentiate in vitro makes them potentially powerful research tools in the discovery of new therapies targeting diseases of the central nervous system, including Parkinson's Alzheimer's and Huntington's diseases as well as schizophrenia and depression"

    Source: Thearapeutics Daily ©2005 PharmaLive.com (04/06/07)

    Neuralstem's Cells Restore Motor Function in Spinal Ischemia-Paralyzed Rats

    Three rats paralyzed due to spinal ischemia returned to near normal ambulatory function six weeks after having received human spinal stem cells (hSSCs) developed by Neuralstem, Inc.

    Researchers reported online in the journal, NEUROSCIENCE (http://www.neuroscience-ibro.com/). Three other rats, while not able to stand up two months after treatment, showed significant improvement in the mobility of all three lower extremity joints and increased muscle tone. In all the grafted animals, the majority of transplanted hSSCs cells survived and became mature neurons. The study was conducted at the University of California at San Diego.

    The rats suffered from Ischemic Spastic Paraplegia (ISP), a painful form of extreme spasticity and rigidity that causes permanent and untreatable loss of motor function and paralysis. In humans, ISP can result from surgery to repair aortic aneurysms, an operation that is performed on thousands of patients a year in the United States.

    "Other human stem cell transplants in the spinal cord have focused on repairing the myelin-forming cells," commented Dr. Karl Johe, Neuralstem Founding Scientist, and a study author. "In this breakthrough study, we are reconstructing the neural circuitry, which has not been done before. This novel approach is one for which our technology, which generates highly neurogenic human stem cell lines, is uniquely suited." Dr. Johe went on to say, "Human ISP patients, unlike the rat subjects of this study, will be able to receive physical therapy once treated. We believe this will accelerate integration of the grafted stem cells with the host tissue and enhance the therapeutic benefit of the cells. The goal is to provide a significant gain in functional mobility of the patient's legs."

    According to lead investigator Dr. Martin Marsala, "In this study, we demonstrated that grafting human neural cells directly into the spinal cord leads to a progressive recovery of motor function. This could be an effective treatment for patients suffering from the same kind of ischemia-induced paralysis. We are currently studying hSSCs in paralyzed mini-pigs, who have similar spinal cord anatomy as human spinal cords."

    According to Neuralstem CEO, Richard Garr, "Neuralstem is a second generation stem cell company, built primarily to optimize our discovery of neural stem cells, and take them into the clinic and into patients. We believe, as this study demonstrates, that our technology answers many of the issues that have held the field back, and makes it possible to build a stem cell company around a true product focus. We expect to file an IND for our first human trial to treat paraplegic patients in 2007," he concluded.

    About the study

    In a two-month study of sixteen rats with induced spinal cord ischemia, nine were injected with hSSCs 21 days after paralysis (ten injections, 30,000 cells per injection). Seven additional rats were injected with medium containing no stem cells as the control group. The recovery of motor function was evaluated in seven-day intervals using a well-accepted locomotor scale and showed a progressive recovery of ambulatory functions in the hSSC animals. Three of nine rats receiving hSSCs had returned to walking at six weeks. Three others had improved mobility in all lower extremity joints. All animals grafted with hSSCs achieved significantly better motor scores than those in the control group. The hSSC-grafted animals showed a consistent presence of transplanted cells in the spinal area.

    In an additional three-month study to assess the recovery of motor function and spasticity, thirteen rats were grafted with the hSSCs (25-30 injections, 10,000 cells per injection). A control group of six was injected with medium only. Seven of the grafted rats showed a time-dependent improvement in motor function and were able to move their lower extremities. This directly correlated with the degree of reduced spasticity (measured by motor evoked potentials (MEPs)), although these rats did not return to walking. Researchers speculate that response differences could be due to the role of subtle differences such as graft position. They further noted that, at the end of the study, transplanted neurons were still maturing, leading them to speculate that a longer term post-grafting period (6-12 months) and physical rehabilitation would likely be associated with a higher degree of functional recovery. In contrast with the grafted groups, no recovery was seen in any animals injected with medium only.

    About Neuralstem

    Neuralstem's patent-protected technology enables, for the first time, the ability to produce neural stem cells of the human brain and spinal cord in commercial quantities, and the ability to control the differentiation of these cells into mature, physiologically relevant human neurons and glia.

    The Company expects that its first Investigational New Drug (IND) application will be for the treatment of Ischemic Paraplegia, a form of paraplegia that sometimes results from the surgery to repair aortic aneurysms and for which there is no effective treatment The Company hopes to submit its initial IND application to the FDA and begin its first human trial during calendar year 2007.

    Major Central Nervous System diseases targeted by the Company with research programs currently underway include: Ischemic Paraplegia, Traumatic Spinal Cord Injury, ALS, and Parkinson's Disease. The company's cells recently extended the life of rats with ALS (Lou Gehrig's disease) in a paper published in the journal TRANSPLANTATION, and were deemed viable for continued work in neurodegenerative spinal conditions. The company has also developed immortalized human neural stem cells for in-vitro use in drug development for the academic and pharmaceutical markets.

    Source Neuralstem, Inc. (30/05/07)

    Stem Cell Propagation And Neurogenesis Can Now Be Studied In Cell Culture

    Researchers are now able to study stem cells from the brains of adult mice and their neurogenesis in long-term cell cultures.

    Harish Babu an Dr. Gerd Kempermann, from the Max Delbrück Center for Molecular Medicine, have developed a new method which allows them to generate exactly those neurons from stem cells in cell culture as those that would develop in the living brain.

    They isolated the stem cells from a region of the hippocampus, the dentate gyrus, which is an island for neurogenesis in the adult brain. First, they demonstrated that the hippocampus of adult mice does indeed have cells with stem cell properties – which had previously been debated upon – and, furthermore, that these stem cells develop into neurons of the hippocampus under certain conditions.

    These stem cell cultures from which neurons can be generated are a powerful tool to study stem cells and their regulatory mechanisms in the hippocampus, the region for learning and memory.

    Several years previously, Dr. Kempermann and other researchers were able to show that even the adult brains can build new neurons. The researchers assume that the new neurons in the hippocampus help the brain adjust to new challenges in life. If and how these new cells or their precursor cells, the stem cells, can be used to develop therapies against dementia remains to be seen.

    Enriched monolayer precursor cell cultures from micro-dissected adult mouse dentate gyrus yield functional granule cell-like neurons, Harish Babu1, 2, Giselle Cheung1, Helmut Kettenmann1, Theo D. Palmer3, and Gerd Kempermann1,2. See: Plos One (DOI 10.1371/journal.pone.0000388, 25. April 2007).

    Source: Max Delbrück Center for Molecular Medicine. (30/04/07)

    When smell cells fail they call in stem cell reserves
    Hopkins researchers have identified a backup supply of stem cells that can repair the most severe damage to the nerves responsible for our sense of smell. These reservists normally lie around and do nothing, but when neighbouring cells die, the scientists say, the stem cells jump into action. A report on the discovery will appear online next week in Nature Neuroscience.

    “These stem cells act like the Army Reserves of our nose,” explains lead author Randall Reed, Ph.D., a professor of neuroscience at Johns Hopkins, “supporting a class of active-duty stem cells that help repair normal wear and tear. They don’t come in until things are really bad.”

    The only nerve cells in the body to run directly from the brain to the outside world, olfactory cells are under constant assault from harsh chemicals that one might happen to catch a whiff of by accident, risking damage or death.

    To figure out how the olfactory system repairs severely damaged nerve cells, Reed’s team exposed mouse olfactory nerves to a cloud of toxic methyl-bromide gas. Methyl bromide kills not only olfactory nerve cells but also neighbouring, non-nerve cells in the nasal passage. Three weeks after chemical exposure, the researchers examined nasal cells to see which, if any, had grown back.

    They discovered that the newly grown cells, both nerve and non-nerve, grew from HBCs-a population of cells not previously known for repair abilities. “We were stunned because HBCs normally don’t grow much or do anything,” says Reed. “And the most surprising thing is that HBCs can grow into both nerves and non-nerve cells; they do so by generating the other active type of nasal stem cell.”

    The team then went back and looked at nerve repair under less damaging circumstances where only the olfactory nerve cells are killed. In this situation, the HBCs did nothing to repair the damaged cells; rather, they allowed the previously known stem cells to do all the repair work.

    “The ability to smell is crucial for eating, mating and survival, and it’s important that the olfactory system be fully operational all the time,” explains Reed. “The HBCs act as a fail-safe to ensure continued function of the sense of smell.”

    The discovery of these two distinct types of stem cells in one neural tissue is a first, says Reed, who is interested to see if other types of nerves in the body have similar repair mechanisms in play.

    Source: Johns Hopkins Medicine (29/04/07)

    Schepens Scientists Identify Key to Integrating Transplanted Nerve Cells Into Injured Tissue
    Scientists at the Schepens Eye Research Institute, an affiliate of Harvard Medical School, have identified a key mechanism for successfully transplanting tissue into the adult central nervous system. The study found that a molecule known as MMP-2 (which is induced by stem cells) has the ability to break down barriers on the outer surface of a damaged retina and allow healthy donor cells to integrate and wire themselves into remaining recipient tissue. The finding, reported in the current issue (April 25, 2007) of the Journal of Neuroscience, holds great promise not only for patients with retinal disease, but also for those suffering from spinal cord injuries and neurodegenerative disorders such as Parkinson's and Multiple Sclerosis and Alzheimer's Diseases.

    "This is a very significant finding," says Dr. Michael Young, associate scientist at the Schepens Eye Research Institute and principal investigator of the study. "We believe that it will ultimately make retinal transplantation and restoration of vision a possibility." He adds that transplantation of donor photoreceptors (in whole retina transplants) may prove to be more beneficial than transplanting stem cells alone, as these retinal transplants contain a complete organised supply of cells necessary for proper vision.

    The regenerative capacity of central nervous system tissue in adult mammals, including human beings, is extremely limited. This is partly due to the formation of barriers, known as "glial" scars, which are triggered by the body to protect the injured retina or other nerve tissue from further damage. This dense scar tissue throws up a blockade to foreign cells, including transplants meant to heal and regenerate. This is what has made previous attempts to transplant whole donor retinas so difficult, according to Young.

    On the other hand, in recent years, stem cells have been shown to overcome these physical barriers, easily penetrating the scar and integrating into the injured tissue.

    For instance, in studies published several years ago, Young and his colleagues demonstrated this special stem-cell talent in damaged mouse retinas. In those studies cells injected into injured retinas quickly integrated into the existing retinal tissue.

    Intrigued by this phenomenon, Young and his team believed that if they could identify and harness the key molecules used by stem cells to gain access into the injured retina, they could potentially improve the success of non- stem cell transplants. Based on this idea, the team conducted a series of experiments.

    In their initial experiments, the team compared the chemicals that were generated when stem cells were injected into damaged retinas and those produced when they attempted to transplant whole retina tissue into the eyes of mice with degenerated retinas. They found-in the stem cell injected retinas-an increase in the amount of and the level of activity of the molecule MMP-2 in host tissue. They concluded that this molecule dissolved the scar on the outer surface of the retina. There was no increase in MMP-2 when they attempted whole-retina transplants.

    The team went on to transplant a layer of stem cells between the degenerating mice retinas and healthy donor tissue (whole retina). They found that MMP-2 induced removal of the scar barrier and allowed healthy donor cells (of the whole retina) to make new connections with the damaged retinas in the mice.

    "These are very powerful results," says Young. "We are convinced that the increase of this molecule is a major key to creating a permissive environment for central nervous system regeneration."

    The team is now investigating therapeutic approaches that would eliminate the need for stem cells. This would involve the use of just the MMP-2 molecule, which is already available in the pharmaceutical market, to foster a receptive transplant environment in the eye, and, in other CNS tissues.

    Other scientists involved in the study include: Yiqin Zhang, Henry J. Klassen, Budd A. Tucker, and Maria-Thereza R. Perez.

    Schepens Eye Research Institute is an affiliate of Harvard Medical School and the largest independent eye research institute in the world.

    Source: Schepens Eye Research Institute (27/04/07)

    Millipore licenses neural stem cells
    A new licensing deal will allow Millipore to supply researchers with a commercial source of neural stem cells for the first time.

    Millipore believe the neural stem cells will provide an important tool for neural research, especially with regards to Alzheimers, spinal cord injury and depression research.

    Under the deal with Aruna Biomedical, the ENStem neural stem cells will be sold and marketed by Millipore as a kit with an optimised serum-free growth media and substrates.

    A major problem for neuroscientists has been the availability of human brain cells, who have had to rely on animal models or small amounts of human cells which are hard to culture. This has slowed research into neurodegenerative diseases and made the study of new drug targets more difficult.

    "The potential impact of this product on the neural research community could be astounding," commented Dr Steven Stice, CEO of Aruna.

    "By accelerating the pace of neurological research for tens of thousands of scientists, we hope to provide patients with possible therapies and treatments for debilitating neurological diseases and spinal cord injuries sooner than imagined."

    The stem cells provide a reliable source of human neural cells for research into disease models and allow the testing of potential drug candidates.

    In addition, because the cells are derived from a National Institute of Health (NIH) approved human embryonic stem cell (hESC) source, there is no barrier for NIH funded researchers to use the cells.

    Millipore have an optimised procedure to differentiate the cells into neurons, with optimisation of the differentiation of the cells into glial cells and astrocytes ongoing.

    According to Michelle Green, director of Stem Cell Product Management: "we are providing enabling technologies that enable stem cells to be used as a tool in the laboratory, allowing researchers that aren't stem cell scientists but neurologists access to the cells they need."

    The neural stem cells, which can differentiate into neurons, glial cells and astrocytes, were developed by Dr Steven Stice, of the University of Georgia Research Foundation and CEO of Aruna.

    Stice's start-up company, Aruna Biomedicals, licensed the cell line from the University of Georgia earlier this year before agreeing to the exclusive worldwide marketing and distribution license with Millipore. Financial details of the agreement have not been disclosed.

    The cell line is covered by the WARF patent in the US as they are produced from hESCs and is covered under the license Millipore took from WARF in 2005.

    The licensing deal with Aruna Biomedical confirms Millipore's continuing push into the drug discovery products and services market after their $1.4bn acquisition of Serologicals last year.

    "This agreement further supports Millipore's commitment to providing tools that accelerate stem cell research worldwide," said Patrick Schneider, vice president of Millipore's Research Reagents Division.

    Source: Decision News Media © 2003/2007 – Decision News Media SAS – All Rights Reserved. (16/03/07)

    Chemical cues turn embryonic stem cells into cerebellar neurons

    Neural Stem Cells

    When differentiated embryonic stem cells were implanted into the cerebellums of newborn mice (green), they migrated to the internal granule layer -- the area where fully differentiated granule neurons extend dendrites (bottom right). Credit: The Rockefeller University.

    In order to differentiate and specialise, stem cells require very specific environmental cues in a very specific order, and scientists have so far been unable to prod them to go through each of the necessary steps. But now, for the first time, a study in mice by Rockefeller University scientists shows that embryonic stem cells implanted in the brain appear to develop into fully differentiated granule neurons, the most plentiful neuron in the cerebellum. The findings were reported Feb. 20 in the online edition of Proceedings of the National Academy of Sciences.

    Embryonic stem cells have shown a great deal of promise for alleviating heart disease and regenerating organs. But for some of the conditions for which people hold out the most hope -- Alzheimer's and Parkinson's, for example -- there's been little evidence to date that stem cells can work. Part of the problem is that neural stem cells, especially those involved in brain development, specialise as they mature and lose their ability to diversify. 

    The cerebellum, which is tucked into the lower, rear portion of the mammalian brain, contains neural circuits that are responsible for motor learning, motor memory and sensory perception. It's also the location of 40 percent of paediatric brain tumors. Mary E. Hatten, Rockefeller's Frederick P. Rose Professor and head of the Laboratory of Developmental Neurobiology, has been studying granule cells for 30 years; she sees her results as a step toward understanding how embryonic stem cells could be regulated in vivo and ultimately used for cell replacement therapy, especially after childhood tumors, in the central nervous system.

    Hatten and postdoc Enrique Salero found that in order to get the embryonic stem cells to differentiate, progressing through each of the known steps of granule neuron maturation as they did so, the cells had to be treated with signals that induce specific transcription factors - proteins that can turn genes on and off - in a specific order. The researchers then implanted the newly differentiated cells into a specific spot in the brains of newborn mice, the grey layer on the surface of the cerebellum called the cerebellar cortex. Once in the brain, the cells extended parallel fibres, migrated to and incorporated themselves into the internal granule cell layer, and extended short projections called dendrites, something that neurons use to communicate with each other. Each of these steps, Hatten says, is characteristic of a typical granule cell.

    Salero and Hatten then looked for evidence that their embryonic stem cells had not just gone through the developmental steps of young granule neurons, but that they also had the known markers of young granule neurons, including those indicating that the neurons had formed in the cerebellum. "We're excited about this paper because it's the first time that anybody has shown that a cell not only migrates to where it's supposed to go, but extends dendrites," Hatten says. "So they're actually in the synaptic network that's sitting on the cortex."

    Hatten isn't yet convinced that the cells differentiated into true granule neurons. "There is such wild-eyed enthusiasm over stem cells," she says, "but it's very hard to know when you've provided sufficient evidence that a cell is actually what you say it is." So her next step will be to work with Nathaniel Heintz, an HHMI investigator and Rockefeller's James and Marilyn Simons Professor, to determine how close a genetic match the native granule cells are to the embryonic stem cell-derived versions.

    "This whole field of stem cell biology is exciting, but also frightening because of the potential harm that could be done," Hatten says. "We have made a lot of progress with stem cells outside the brain, especially with the heart and skin. But neurons in the brain seem to undergo more complicated genetic changes as they progress through a long series of maturation steps. So we want to be absolutely sure that we're generating neurons that will aid, rather than hamper, brain function."

    Source: Rockefeller University (14/03/07)

    Neurons produced from skin stem cells
    Canadian scientists have produced neurons from human skin stem cells in a breakthrough that might revolutionise neurodegenerative disease treatments.

    The Laval University researchers succeeded in producing neurons in vitro using stem cells extracted from adult human skin. That marks the first time such an advanced state of nerve cell differentiation has been achieved from human skin, according to lead researcher professor Francois Berthod.

    The scientists say the breakthrough could eventually lead to revolutionary advances in the treatment of neurodegenerative illnesses such as Parkinson's disease and Multiple Sclerosis.

    Berthod and his team described the method used to produce the neurons in a recent issue of the Journal of Cellular Physiology.

    Source: United Press International © Copyright 2007 United Press International, Inc. All Rights Reserved.(22/02/07).

    Brain creates 'new' nerve cells
    Researchers have discovered a type of brain cell that continuously regenerates in humans.

    A pool of "resting cells" migrate to create new nerve cells in the part of the brain which deals with smell.

    The system has been shown in mice and rats but it was believed it did not exist in the human brain.

    Experts said the findings, published in Science, opened up the potential for research into repairing brains in conditions such as Alzheimer's disease and Multiple Sclerosis.

    The researchers from the University of Auckland, New Zealand and the Sahlgrenska Academy in Sweden showed stem cells rest in certain areas of the brain, just beneath large fluid-filled chambers called ventricles.

    But then they needed to work out how they got to the right part of the brain. 

    In many species, it was known that a tube filled with brain fluid enabled these cells to travel to the olfactory bulb - the region of the brain that registers smells - turning into nerve cells as they went.

    But until now, this system had not been shown in humans.

    Using several techniques, including a powerful electron microscope, the team identified the tube, and showed it contained stem cells as well as cells which were gradually turning into nerve cells as they travelled along.

    The researchers said the addition of new nerve cells in the olfactory bulb in humans helped the system respond to different stimuli throughout a person's life.

    Brain repair

    Experts said the findings could be important for future research into brain cell repair in patients with neurodegenerative diseases such as Alzheimer's disease and Multiple Sclerosis and, importantly, that studies in mice would be applicable to humans.

    Dr Mark Baxter, Wellcome Trust senior research fellow at Oxford University, said: "This study is exciting because it reveals a group of brain cells in the adult human brain that are continuously regenerating.

    "This opens another direction by which we may discover ways to repair human brains that are damaged from injury or diseases, and underscores the importance of animal research in guiding biomedical research in humans."

    Professor Sebastian Brandner, head of the division of neuropathology at the Institute of Neurology, University College London, said it has been known for decades that such cells were present in mice and rats.

    "Understanding stem cell biology is essential to study brain repair in neurodegenerative diseases such as Alzheimer's and it is even possible that stem cells are the source of some brain tumours."

    Source: BBC News Copywrite BBC MMVII (22/02/07)

    Firm's stem cell discovery could mean cures, profits
    An Athens company's new technique for mass-producing neural stem cells holds the promise of a cure or a better life for people who suffer from devastating medical conditions, according to the researcher who founded the company as well as some who suffer from those crippling neurological conditions.

    The discovery also could mean hundreds of millions of dollars of annual income for the business, called Aruna Biomedical.

    University of Georgia stem cell researcher Steven Stice's company announced the new technique last month, touching off a tug-of-war between investors in Wisconsin, where much of the country's stem cell research is concentrated, and Georgia, where Stice's company began.

    Stice, known around the world for his work with cloning and stem cells, has said he has no intention of leaving UGA. But the company's future depends on investors, and where those investors want the company to be will play a big part in the decision, he said.

    The details of how Stice's company is making stem cells by the billions are secret. Stice does say, though, that the keys are in how researchers choose the cells to begin with and the materials used to grow them.

    But it's not hard to grasp the company's commercial potential.

    It's very expensive for a researcher to set up a lab to work with human stem cells, but Stice, working with graduate student Soo Shin, has found a way to eliminate much of that cost, as well as cut out the time researchers must spend growing the cells.

    Some stem cells can develop into many or all kinds of human tissue - heart, lungs, nerves or skin, for example.

    But the stem cells Aruna is producing are more limited. They can only develop into neural cells - brain, spine and nerve cells.

    By making stem cells available, in large quantities at low cost, many more researchers can now work with neural stem cells.

    Stice estimates that literally thousands of researchers will want to buy the kits Aruna Biomedical plans to start selling this year. The kits include not only a supply of the neural stem cells, but materials that will allow researchers who buy them to grow more - up to a point. As the cells multiply over months, over time they differentiate and no longer have the uniform characteristics that make them useful in research, he said.

    The researcher then has to get a new supply, but at $500 to $1,000 per batch, researchers should be able to afford to keep their labs supplied.

    Business consultants have told Stice the market for the cells could be $200 million or more a year for the neural stem cell kits.

    Stice and researchers who work with him hope soon to be able to market other kinds of products. One possibility is large-scale production of another kind of stem cell that can develop into heart tissues.

    The business potential pales in comparison to the medical hope the new mass-production of stem cells may hold, said James Shepherd, chairman of the board of Atlanta's Shepherd Center, a catastrophic care hospital for patients with spinal cord and brain injuries or multiple sclerosis.

    Brain or spinal cord tissue won't regenerate like most kinds of human tissue - wounds don't heal, and brains can't grow new brain cells the way our skin can grow new cells to heal a cut, Shepherd explained.

    But stem cells offer the hope that medical workers may be able to grow new spinal cord tissue to repair a damaged spine, or grow healthy cells to replace the damaged neural cells of someone afflicted with Parkinson's Disease, even Alzheimer's, he said.

    "This breakthrough (will) get these cells into the hands of many more people than would otherwise have them. The timeline for a breakthrough probably gets reduced substantially. It could lead to cures or significant improvements in condition for people with multiple sclerosis, brain injuries and other conditions", he said.

    "Ten years ago, I would have told you there is no cure in my lifetime," Shepherd said. "But the ability to mass-produce neural stem cells has changed his mind", he said.

    Now, there's "significant hope," he said.

    On the business side, state and economic development professionals at UGA and other state research universities have for years worked to turn discoveries like Stice's into start-up companies like Aruna, with mixed success.

    But often, they've lost companies to other states as the businesses begin to prove their commercial potential.

    Whether companies move or stay where they started often depends on what investors want or need, said Clifton Baile, a professor and Georgia Research Alliance Eminent Scholar at UGA.

    Baile also founded or co-founded several start-up companies based on his own research, including Insectigen, a company developing "biopesticides" to protect crops against insects that eat or otherwise damage them.

    "This is a business world," he said.

    But Georgia may have created a better atmosphere for biotech to develop into an industry over the past decade, Baile said.

    "I think I can say 'yes,' but it's a soft 'yes,' " Baile said about the willingness of Georgia investors to back new biotechnology companies.

    At UGA, researchers now have an easier time getting the help they need to commercialise promising research, he said.

    The Georgia Research Alliance, a private corporation that spent about $28 million in public funds last year to stimulate research-based economic development, also has become increasingly effective in helping research become business, he said.

    Source: Athens Banner-Herald © 2007 (22/02/07)

    Biomed firm commercialises stem-cell sales
    A U.S. biomedical company said Thursday it reached an agreement to commercialise the distribution of neural stem cells by the billions.

    'We`re going to be able to distribute a cell that has the ability to produce all the different cell types in the nervous system,' Aruna Biomedical Inc. Chief Executive Steven Stice told the Atlanta Journal-Constitution.

    Stice developed neural progenitor cell technology at the University of Georgia, where he is also a professor and director of its Regenerative Bioscience Center.

    His arrangement with the university`s research foundation calls for Aruna to market the cells, with the university getting a cut.

    'We are offering a product that may accelerate the pace of neurological research for tens of thousands of scientists,' he said, 'and thereby may provide patients with possible therapies and treatments for debilitating neurological diseases and spinal cord injuries much sooner than imagined.'

    Aruna anticipates launching human neural progenitor cells in a few months and other advances soon afterward.

    Source: United Press International Copyright 2007 by United Press International (26/01/07)

    © Multiple Sclerosis Resource Centre

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