Stem cell repair of central nervous system injury

Neural stem cells (NSCs) have great potential as a therapeutic tool for the repair of a number of CNS disorders. NSCs can either be isolated from embryonic and adult brain tissue or be induced from both mouse and human ES cells. These cells proliferate in vitro through many passages without losing their multipotentiality. Following engraftment into the adult CNS, NSCs differentiate mainly into glia, except in neurogenic areas. After engraftment into the injured and diseased CNS, their differentiation is further retarded. In vitro manipulation of NSC fate prior to transplantation and/or modification of the host environment may be necessary to control the terminal lineage of the transplanted cells to obtain functionally significant numbers of neurons. NSCs and a few types of glial precursors have shown the capability to differentiate into oligodendrocytes and to remyeliate the demyelinated axons in the CNS, but the functional extent of remyelination achieved by these transplants is limited. Manipulation of endogenous neural precursors may be an alternative therapy or a complimentary therapy to stem cell transplantation for neurodegenerative disease and CNS injury. However, this at present is challenging and so far has been unsuccessful. Understanding mechanisms of NSC differentiation in the context of the injured CNS will be critical to achieving these therapeutic strategies. © 2002 Wiley‐Liss, Inc.

[1]  I. Duncan,et al.  Myelination Following Transplantation of EGF-Responsive Neural Stem Cells into a Myelin-Deficient Environment , 1997, Experimental Neurology.

[2]  R. Sidman,et al.  Engraftable human neural stem cells respond to development cues, replace neurons, and express foreign genes , 1998, Nature Biotechnology.

[3]  P. Horner,et al.  Adult Spinal Cord Stem Cells Generate Neurons after Transplantation in the Adult Dentate Gyrus , 2000, The Journal of Neuroscience.

[4]  S. Dunnett,et al.  The morphological development of neurons derived from EGF‐ and FGF‐2‐driven human CNS precursors depends on their site of integration in the neonatal rat brain , 2000, The European journal of neuroscience.

[5]  J. D. Macklis,et al.  Embryonic Neurons Transplanted to Regions of Targeted Photolytic Cell Death in Adult Mouse Somatosensory Cortex Re-form Specific Callosal Projections , 1996, Experimental Neurology.

[6]  G. Wolswijk.  Chronic Stage Multiple Sclerosis Lesions Contain a Relatively Quiescent Population of Oligodendrocyte Precursor Cells , 1998, The Journal of Neuroscience.

[7]  G. Wolswijk,et al.  Oligodendrocyte‐type‐2 astrocyte (O‐2A) progenitor cells derived from adult rat spinal cord: In vitro characteristics and response to PDGF, bFGF and NT‐3 , 1996, Glia.

[8]  J. Goldman,et al.  Endogenous Progenitors Remyelinate Demyelinated Axons in the Adult CNS , 1997, Neuron.

[9]  Johannes Schwarz,et al.  Long-Term Proliferation and Dopaminergic Differentiation of Human Mesencephalic Neural Precursor Cells , 2001, Experimental Neurology.

[10]  J. Mcdonald,et al.  Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord , 1999, Nature Medicine.

[11]  Daniel A. Lim,et al.  Subventricular Zone Astrocytes Are Neural Stem Cells in the Adult Mammalian Brain , 1999, Cell.

[12]  Jonas Frisén,et al.  Identification of a Neural Stem Cell in the Adult Mammalian Central Nervous System , 1999, Cell.

[13]  Bruce G. Jenkins,et al.  Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  D. Lenartz,et al.  Differentiation of green fluorescent protein-labeled embryonic stem cell-derived neural precursor cells into Thy-1-positive neurons and glia after transplantation into adult rat striatum. , 2000, Journal of neurosurgery.

[15]  Marius Wernig,et al.  In vitro differentiation of transplantable neural precursors from human embryonic stem cells , 2001, Nature Biotechnology.

[16]  D. Anderson,et al.  Stem Cells and Pattern Formation in the Nervous System The Possible versus the Actual , 2001, Neuron.

[17]  M. Barrot,et al.  Opiates inhibit neurogenesis in the adult rat hippocampus. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[18]  W. Blakemore.  Transplanted cultured type‐1 astrocytes can be used to reconstitute the glia limitans of the CNS: the structure which prevents Schwann cells from myelinating CNS axons , 1992, Neuropathology and applied neurobiology.

[19]  R. Franklin,et al.  Transplanted type-1 astrocytes facilitate repair of demyelinating lesions by host oligodendrocytes in adult rat spinal cord , 1991, Journal of neurocytology.

[20]  M. Rao,et al.  Glial-restricted precursors are derived from multipotent neuroepithelial stem cells. , 1997, Developmental biology.

[21]  Mitotically active cells that generate neurons and astrocytes are present in multiple regions of the adult mouse hippocampus , 2000, The Journal of comparative neurology.

[22]  R. Sidman,et al.  Segregation of Human Neural Stem Cells in the Developing Primate Forebrain , 2001, Science.

[23]  B. Barres,et al.  Purification and Characterization of Adult Oligodendrocyte Precursor Cells from the Rat Optic Nerve , 1998, The Journal of Neuroscience.

[24]  Monte A. Gates,et al.  Site-Specific Migration and Neuronal Differentiation of Human Neural Progenitor Cells after Transplantation in the Adult Rat Brain , 1999, The Journal of Neuroscience.

[25]  Charles G. Gross,et al.  Neurogenesis in the adult brain: death of a dogma , 2000, Nature Reviews Neuroscience.

[26]  D. Baas,et al.  Oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells express glutamine synthetase: developmental and cell type-specific regulation , 1998, Molecular Psychiatry.

[27]  R. McKay,et al.  Transplanted CNS stem cells form functional synapses in vivo , 2000, The European journal of neuroscience.

[28]  E. Parati,et al.  Isolation and intracerebral grafting of nontransformed multipotential embryonic human CNS stem cells. , 1999, Journal of neurotrauma.

[29]  M. Luskin,et al.  Region-specific differentiation of neural tube-derived neuronal restricted progenitor cells after heterotopic transplantation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[30]  E. Jauniaux,et al.  Human Neural Precursor Cells Express Low Levels of Telomerase in Vitro and Show Diminishing Cell Proliferation with Extensive Axonal Outgrowth following Transplantation , 2000, Experimental Neurology.

[31]  R. Franklin,et al.  Local recruitment of remyelinating cells in the repair of demyelination in the central nervous system , 1997, Journal of neuroscience research.

[32]  M. Rao,et al.  Isolation of Lineage-Restricted Neuronal Precursors from Multipotent Neuroepithelial Stem Cells , 1997, Neuron.

[33]  Quantitative insight into proliferation and differentiation of oligodendrocyte type 2 astrocyte progenitor cells in vitro. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[34]  M. Perricaudet,et al.  Transplantation to the rat brain of human neural progenitors that were genetically modified using adenoviruses , 1995, Nature Genetics.

[35]  D. Min,et al.  Upregulation of phospholipase D in astrocytes in response to transient forebrain ischemia , 2000, Glia.

[36]  J. Levine,et al.  Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord , 1998, Glia.

[37]  G. Wolswijk.  Oligodendrocyte precursor cells in chronic multiple sclerosis lesions , 1997, Multiple sclerosis.

[38]  F. Gage,et al.  Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[39]  F. Gage,et al.  Neurogenesis in the adult human hippocampus , 1998, Nature Medicine.

[40]  L. Olson,et al.  Ethical issues in brain-cell transplantation , 1991, Trends in Neurosciences.

[41]  J. D. Macklis,et al.  Transplanted Neuroblasts Differentiate Appropriately into Projection Neurons with Correct Neurotransmitter and Receptor Phenotype in Neocortex Undergoing Targeted Projection Neuron Degeneration , 2000, The Journal of Neuroscience.

[42]  R. Franklin,et al.  Glial-cell transplantation and plasticity in the O-2A lineage — implications for CNS repair , 1995, Trends in Neurosciences.

[43]  J. Frisén,et al.  Get to know your stem cells , 2000, Current Opinion in Neurobiology.

[44]  Benjamin E. Reubinoff,et al.  Neural progenitors from human embryonic stem cells , 2001, Nature Biotechnology.

[45]  C. Lois,et al.  Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[46]  S. Dunnett,et al.  Survival and Differentiation of Rat and Human Epidermal Growth Factor-Responsive Precursor Cells Following Grafting into the Lesioned Adult Central Nervous System , 1996, Experimental Neurology.

[47]  E. Snyder,et al.  Establishment and Properties of Neural Stem Cell Clones: Plasticity In Vitro and In Vivo , 1999, Brain pathology.

[48]  Scott R. Whittemore,et al.  Pluripotent Stem Cells Engrafted into the Normal or Lesioned Adult Rat Spinal Cord Are Restricted to a Glial Lineage , 2001, Experimental Neurology.

[49]  W. Blakemore,et al.  The role of oligodendrocytes and oligodendrocyte progenitors in CNS remyelination. , 1999, Advances in experimental medicine and biology.

[50]  R. Bakay,et al.  Neuronal progenitor cells of the neonatal subventricular zone differentiate and disperse following transplantation into the adult rat striatum. , 1998, Cell transplantation.

[51]  Masahiro Yamaguchi,et al.  Generation of Dopaminergic Neurons in the Adult Brain from Mesencephalic Precursor Cells Labeled with a nestin-GFP Transgene , 2001, The Journal of Neuroscience.

[52]  H. Keirstead,et al.  Identification of Post‐mitotic Oligodendrocytes Incapable of Remyelination within the Demyelinated Adult Spinal Cord , 1997, Journal of neuropathology and experimental neurology.

[53]  I. Duncan,et al.  Self‐renewing canine oligodendroglial progenitor expanded as oligospheres , 1998, Journal of neuroscience research.

[54]  D. van der Kooy,et al.  Adult Mammalian Forebrain Ependymal and Subependymal Cells Demonstrate Proliferative Potential, but only Subependymal Cells Have Neural Stem Cell Characteristics , 1999, The Journal of Neuroscience.

[55]  S. Whittemore,et al.  Mitogen and substrate differentially affect the lineage restriction of adult rat subventricular zone neural precursor cell populations. , 1999, Experimental cell research.

[56]  T. Holekamp,et al.  Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[57]  F. Gage,et al.  Stem cells of the central nervous system. , 1998, Current opinion in neurobiology.

[58]  Patrik Brundin,et al.  Immunological aspects of grafting in the mammalian central nervous system. A review and speculative synthesis , 1988, Brain Research Reviews.

[59]  A. Álvarez-Buylla,et al.  Stem cells in the adult mammalian central nervous system , 1999, Current Opinion in Neurobiology.

[60]  S. Geuna,et al.  Adult stem cells and neurogenesis: Historical roots and state of the art , 2001, The Anatomical record.

[61]  A. Tessler,et al.  Characterization and intraspinal grafting of EGF/bFGF-dependent neurospheres derived from embryonic rat spinal cord , 2000, Brain Research.

[62]  C. Andressen,et al.  Nestin‐Specific Green Fluorescent Protein Expression in Embryonic Stem Cell‐Derived Neural Precursor Cells Used for Transplantation , 2001, Stem cells.

[63]  B. Stokes,et al.  Proliferation of NG2-Positive Cells and Altered Oligodendrocyte Numbers in the Contused Rat Spinal Cord , 2001, The Journal of Neuroscience.

[64]  S. Dunnett,et al.  Long-Term Survival of Human Central Nervous System Progenitor Cells Transplanted into a Rat Model of Parkinson's Disease , 1997, Experimental Neurology.

[65]  A. Trounson,et al.  Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro , 2000, Nature Biotechnology.

[66]  Kozo Nakamura,et al.  Proliferation of Parenchymal Neural Progenitors in Response to Injury in the Adult Rat Spinal Cord , 2001, Experimental Neurology.

[67]  J. Kocsis,et al.  Transplantation of Clonal Neural Precursor Cells Derived from Adult Human Brain Establishes Functional Peripheral Myelin in the Rat Spinal Cord , 2001, Experimental Neurology.

[68]  F. Gage,et al.  Proliferation and Differentiation of Progenitor Cells Throughout the Intact Adult Rat Spinal Cord , 2000, The Journal of Neuroscience.

[69]  R. Franklin,et al.  Transplanting oligodendrocyte progenitors into the adult CNS , 1997, Journal of anatomy.

[70]  I. Duncan,et al.  Adult brain retains the potential to generate oligodendroglial progenitors with extensive myelination capacity. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[71]  M. Rao,et al.  Precursor cells for transplantation. , 2000, Progress in brain research.

[72]  S. Whittemore,et al.  Chapter 4 Immortalized neural cell lines for CNS transplantation , 2000 .

[73]  K. Mizuseki,et al.  Induction of Midbrain Dopaminergic Neurons from ES Cells by Stromal Cell–Derived Inducing Activity , 2000, Neuron.

[74]  A. Crang,et al.  Behavioural consequences of oligodendrocyte progenitor cell transplantation into experimental demyelinating lesions in the rat spinal cord , 1999, The European journal of neuroscience.

[75]  R. McKay,et al.  Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats , 1998, Nature Biotechnology.

[76]  T. Ben-Hur,et al.  Polysialylated Neural Cell Adhesion Molecule-Positive CNS Precursors Generate Both Oligodendrocytes and Schwann Cells to Remyelinate the CNS after Transplantation , 1999, The Journal of Neuroscience.

[77]  R. McKay,et al.  Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. , 1996, Genes & development.

[78]  Elizabeth Gould,et al.  Stress and hippocampal neurogenesis , 1999, Biological Psychiatry.

[79]  David J. Anderson,et al.  Neural Crest Stem Cells Undergo Cell-Intrinsic Developmental Changes in Sensitivity to Instructive Differentiation Signals , 2001, Neuron.

[80]  R. McKay.  Mammalian deconstruction for stem cell reconstruction , 2000, Nature Medicine.

[81]  A. Groves,et al.  Lineage-restricted neural precursors can be isolated from both the mouse neural tube and cultured ES cells. , 1999, Developmental biology.

[82]  R. McKay,et al.  Embryonic stem cell-derived glial precursors: a source of myelinating transplants. , 1999, Science.

[83]  R. McKay,et al.  Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats , 1998, Nature Neuroscience.

[84]  Blair R. Leavitt,et al.  Induction of neurogenesis in the neocortex of adult mice , 2000, Nature.

[85]  M. Rao,et al.  Gliogenesis in the central nervous system , 2000, Glia.

[86]  F. Gage,et al.  Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo , 1996, Nature.

[87]  E Gould,et al.  Hippocampal neurogenesis in adult Old World primates. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[88]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[89]  R. McKay,et al.  Reply to “Survival of expanded dopaminergic precursors is critical for clinical trials” , 1998, Nature Neuroscience.

[90]  E. Gould,et al.  Learning enhances adult neurogenesis in the hippocampal formation , 1999, Nature Neuroscience.

[91]  L. Parada,et al.  Brain remodeling due to neuronal and astrocytic proliferation after controlled cortical injury in mice , 2001, Journal of neuroscience research.

[92]  J. García-Verdugo,et al.  Adult‐derived neural precursors transplanted into multiple regions in the adult brain , 1999, Annals of neurology.

[93]  R. McKay,et al.  In vitro generation and transplantation of precursor‐derived human dopamine neurons , 2001, Journal of neuroscience research.

[94]  B. Trapp,et al.  NG2-Positive Oligodendrocyte Progenitor Cells in Adult Human Brain and Multiple Sclerosis Lesions , 2000, The Journal of Neuroscience.

[95]  A. Björklund,et al.  Cell replacement therapies for central nervous system disorders , 2000, Nature Neuroscience.

[96]  R. Reynolds,et al.  Activation and Proliferation of Endogenous Oligodendrocyte Precursor Cells during Ethidium Bromide-Induced Demyelination , 1999, Experimental Neurology.

[97]  M. Schachner,et al.  Transplantation of neural precursor cells into the dysmyelinated CNS of mutant mice deficient in the myelin‐associated glycoprotein and Fyn tyrosine kinase , 2001, The European journal of neuroscience.

[98]  R. Franklin,et al.  Transplantation options for therapeutic central nervous system remyelination. , 2000, Cell transplantation.

[99]  R. Franklin,et al.  The role of astrocytes in the remyelination of glia-free areas of demyelination. , 1993, Advances in neurology.

[100]  C. Gross,et al.  Neurogenesis in the neocortex of adult primates. , 1999, Science.

[101]  F. Gage,et al.  Mammalian neural stem cells. , 2000, Science.

[102]  F. Gage,et al.  Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus , 1999, Nature Neuroscience.

[103]  P. Tresco,et al.  Embryonic-Derived Glial-Restricted Precursor Cells (GRP Cells) Can Differentiate into Astrocytes and Oligodendrocytes in Vivo , 2001, Experimental Neurology.

[104]  M. Noble,et al.  A tripotential glial precursor cell is present in the developing spinal cord. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[105]  Richard Reynolds,et al.  The oligodendrocyte precursor cell in health and disease , 2001, Trends in Neurosciences.