Adult neural stem cells in the mammalian central nervous system

Neural stem cells (NSCs) are present not only during the embryonic development but also in the adult brain of all mammalian species, including humans. Stem cell niche architecture in vivo enables adult NSCs to continuously generate functional neurons in specific brain regions throughout life. The adult neurogenesis process is subject to dynamic regulation by various physiological, pathological and pharmacological stimuli. Multipotent adult NSCs also appear to be intrinsically plastic, amenable to genetic programing during normal differentiation, and to epigenetic reprograming during de-differentiation into pluripotency. Increasing evidence suggests that adult NSCs significantly contribute to specialized neural functions under physiological and pathological conditions. Fully understanding the biology of adult NSCs will provide crucial insights into both the etiology and potential therapeutic interventions of major brain disorders. Here, we review recent progress on adult NSCs of the mammalian central nervous system, including topics on their identity, niche, function, plasticity, and emerging roles in cancer and regenerative medicine.

[1]  D. Steindler,et al.  Human cortical glial tumors contain neural stem‐like cells expressing astroglial and neuronal markers in vitro , 2002, Glia.

[2]  Hirofumi Nakatomi,et al.  Regeneration of Hippocampal Pyramidal Neurons after Ischemic Brain Injury by Recruitment of Endogenous Neural Progenitors , 2002, Cell.

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

[4]  F. Gage,et al.  Cell fusion-independent differentiation of neural stem cells to the endothelial lineage , 2004, Nature.

[5]  G. Ming,et al.  G 9 a and Jhdm 2 a Regulate Embryonic Stem Cell Fusion-Induced Reprogramming of Adult Neural Stem Cells , 2008 .

[6]  F. Gage,et al.  FGF-2-Responsive Neuronal Progenitors Reside in Proliferative and Quiescent Regions of the Adult Rodent Brain , 1995, Molecular and Cellular Neuroscience.

[7]  S. Ge,et al.  GABA sets the tempo for activity-dependent adult neurogenesis , 2007, Trends in Neurosciences.

[8]  R. Jaenisch,et al.  Reprogramming Efficiency Following Somatic Cell Nuclear Transfer Is Influenced by the Differentiation and Methylation State of the Donor Nucleus , 2006, Stem cells.

[9]  O. Lindvall,et al.  Stem cells for the treatment of neurological disorders , 2006, Nature.

[10]  H. Gratzner,et al.  Monoclonal antibody to 5-bromo- and 5-iododeoxyuridine: A new reagent for detection of DNA replication. , 1982, Science.

[11]  S. Temple,et al.  LeX/ssea-1 Is Expressed by Adult Mouse CNS Stem Cells, Identifying Them as Nonependymal , 2002, Neuron.

[12]  Rene Hen,et al.  Adult hippocampal neurogenesis in depression , 2007, Nature Neuroscience.

[13]  Lia S. Campos β1 integrins and neural stem cells: making sense of the extracellular environment , 2005, BioEssays : news and reviews in molecular, cellular and developmental biology.

[14]  Fred H. Gage,et al.  Wnt signalling regulates adult hippocampal neurogenesis , 2005, Nature.

[15]  Nader Sanai,et al.  Cellular composition and cytoarchitecture of the adult human subventricular zone: A niche of neural stem cells , 2006, The Journal of comparative neurology.

[16]  V. Bonavita,et al.  The end of the central dogma of neurobiology: stem cells and neurogenesis in adult CNS , 2006, Neurological Sciences.

[17]  T. Palmer,et al.  Vascular niche for adult hippocampal neurogenesis , 2000, The Journal of comparative neurology.

[18]  Brent A. Reynolds,et al.  Multipotent CNS Stem Cells Are Present in the Adult Mammalian Spinal Cord and Ventricular Neuroaxis , 1996, The Journal of Neuroscience.

[19]  D. D.-B.,et al.  Degeneration and Regeneration of the Nervous System , 1930, Nature.

[20]  E. Gould,et al.  Neurogenesis in the adult is involved in the formation of trace memories , 2001, Nature.

[21]  T. Shimazaki,et al.  [Mammalian neural stem cells]. , 2008, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[22]  F. Gage,et al.  In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. , 2007, Cell stem cell.

[23]  F. Gage,et al.  Activity-dependent regulation of neuronal plasticity and self repair. , 2000, Progress in brain research.

[24]  Shulan Tian,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[25]  Wulfram Gerstner,et al.  Spike-timing dependent plasticity , 2010, Scholarpedia.

[26]  Ryoichiro Kageyama,et al.  Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain , 2008, Nature Neuroscience.

[27]  R. Duman,et al.  Regulation of adult neurogenesis by psychotropic drugs and stress. , 2001, The Journal of pharmacology and experimental therapeutics.

[28]  Afra H. Wang,et al.  Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus , 2007, Nature Neuroscience.

[29]  G. Ming,et al.  Activity‐dependent Extrinsic Regulation of Adult Olfactory Bulb and Hippocampal Neurogenesis , 2009, Annals of the New York Academy of Sciences.

[30]  Dawen Zhao,et al.  Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. , 2005, Cancer cell.

[31]  E. Kandel The Molecular Biology of Memory Storage: A Dialogue Between Genes and Synapses , 2001, Science.

[32]  S. Lipton,et al.  Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease , 2007, Nature Medicine.

[33]  J. Utikal,et al.  Reprogramming of Neural Progenitor Cells into Induced Pluripotent Stem Cells in the Absence of Exogenous Sox2 Expression , 2008, Stem cells.

[34]  A. Joyner,et al.  In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog , 2005, Nature.

[35]  Claes Nordborg,et al.  Human Neuroblasts Migrate to the Olfactory Bulb via a Lateral Ventricular Extension , 2007, Science.

[36]  S. Bauer Cytokine Control of Adult Neural Stem Cells , 2009, Annals of the New York Academy of Sciences.

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

[38]  T. Ben-Hur,et al.  The changing face of neural stem cell therapy in neurologic diseases. , 2008, Archives of neurology.

[39]  R. Bradshaw,et al.  Trophic stimulation of cultured neurons from neonatal rat brain by epidermal growth factor. , 1987, Science.

[40]  Marcos J. Araúzo-Bravo,et al.  Oct4-Induced Pluripotency in Adult Neural Stem Cells , 2009, Cell.

[41]  M. Bonaguidi,et al.  Noggin Expands Neural Stem Cells in the Adult Hippocampus , 2008, The Journal of Neuroscience.

[42]  F. Gage,et al.  Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons , 2002, Nature Neuroscience.

[43]  J. Hinds,et al.  Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. , 1977, Science.

[44]  R. Sidman,et al.  Neural Stem Cells Rescue nervous Purkinje Neurons by Restoring Molecular Homeostasis of Tissue Plasminogen Activator and Downstream Targets , 2006, The Journal of Neuroscience.

[45]  J. Hugnot,et al.  NG2 and Olig2 Expression Provides Evidence for Phenotypic Deregulation of Cultured Central Nervous System and Peripheral Nervous System Neural Precursor Cells , 2007, Stem cells.

[46]  J. García-Verdugo,et al.  Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus , 2004, The Journal of comparative neurology.

[47]  J. García-Verdugo,et al.  Neural stem cells confer unique pinwheel architecture to the ventricular surface in neurogenic regions of the adult brain. , 2008, Cell stem cell.

[48]  Linheng Li,et al.  Stem cell niche: structure and function. , 2005, Annual review of cell and developmental biology.

[49]  R. J. McDonald,et al.  A role for adult neurogenesis in spatial long-term memory , 2005, Neuroscience.

[50]  Arturo Alvarez-Buylla,et al.  Mosaic Organization of Neural Stem Cells in the Adult Brain , 2007, Science.

[51]  A. Álvarez-Buylla,et al.  For the Long Run Maintaining Germinal Niches in the Adult Brain , 2004, Neuron.

[52]  J. Rubenstein,et al.  Pax6 Is Required for Making Specific Subpopulations of Granule and Periglomerular Neurons in the Olfactory Bulb , 2005, The Journal of Neuroscience.

[53]  F. Gage,et al.  Expression and function of orphan nuclear receptor TLX in adult neural stem cells , 2004, Nature.

[54]  Bruno Di Stefano,et al.  Efficient genetic reprogramming of unmodified somatic neural progenitors uncovers the essential requirement of Oct4 and Klf4. , 2009, Stem cells and development.

[55]  O. Lindvall,et al.  Neurogenesis after ischaemic brain insults , 2003, Current Opinion in Neurobiology.

[56]  J. Altman,et al.  Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats , 1965, The Journal of comparative neurology.

[57]  Arturo Alvarez-Buylla,et al.  EGF Converts Transit-Amplifying Neurogenic Precursors in the Adult Brain into Multipotent Stem Cells , 2002, Neuron.

[58]  R. Hen,et al.  Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants , 2003, Science.

[59]  P. Rakic DNA Synthesis and Cell Division in the Adult Primate Brain a , 1985, Annals of the New York Academy of Sciences.

[60]  F. Gage,et al.  Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation. , 2006, Stem cells and development.

[61]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[62]  P. Rakić Limits of neurogenesis in primates. , 1985, Science.

[63]  S. Ge,et al.  A Critical Period for Enhanced Synaptic Plasticity in Newly Generated Neurons of the Adult Brain , 2007, Neuron.

[64]  O. Lindvall,et al.  Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke , 2009, Nature Neuroscience.

[65]  J. García-Verdugo,et al.  Composition and organization of the SCZ: a large germinal layer containing neural stem cells in the adult mammalian brain. , 2006, Cerebral cortex.

[66]  David J. Anderson,et al.  Deregulation of Dorsoventral Patterning by FGF Confers Trilineage Differentiation Capacity on CNS Stem Cells In Vitro , 2003, Neuron.

[67]  P. Taupin The therapeutic potential of adult neural stem cells. , 2006, Current opinion in molecular therapeutics.

[68]  C. Y. Brazel,et al.  Sox2 expression defines a heterogeneous population of neurosphere‐forming cells in the adult murine brain , 2005, Aging cell.

[69]  H. Schwegler,et al.  Neurogenesis in the Dentate Gyrus Depends on Ciliary Neurotrophic Factor and Signal Transducer and Activator of Transcription 3 Signaling , 2009, Stem cells.

[70]  S. Weiss,et al.  Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. , 1996, Developmental biology.

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

[72]  T. Palmer,et al.  Fibroblast Growth Factor-2 Activates a Latent Neurogenic Program in Neural Stem Cells from Diverse Regions of the Adult CNS , 1999, The Journal of Neuroscience.

[73]  J. Altman Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb , 1969, The Journal of comparative neurology.

[74]  E. Kandel,et al.  An Animal Model of a Behavioral Intervention for Depression , 2008, Neuron.

[75]  B. Roysam,et al.  Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. , 2008, Cell stem cell.

[76]  G. Ming,et al.  Neuronal Activity–Induced Gadd45b Promotes Epigenetic DNA Demethylation and Adult Neurogenesis , 2009, Science.

[77]  F. Gage,et al.  More hippocampal neurons in adult mice living in an enriched environment , 1997, Nature.

[78]  L. Brain The Nervous System , 1963, Nature.

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

[80]  Daniel J. Hoeppner,et al.  Notch signalling regulates stem cell numbers in vitro and in vivo , 2006, Nature.

[81]  Perry F. Bartlett,et al.  Purification of a pluripotent neural stem cell from the adult mouse brain , 2001, Nature.

[82]  D. Farkas,et al.  Isolation of cancer stem cells from adult glioblastoma multiforme , 2004, Oncogene.

[83]  Hideyuki Okano,et al.  New Neurons Follow the Flow of Cerebrospinal Fluid in the Adult Brain , 2006, Science.

[84]  Ugo Orfanelli,et al.  Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma , 2004, Cancer Research.

[85]  A. Scheibel,et al.  Degeneration and regeneration of the nervous system , 1960 .

[86]  F. DiMeco,et al.  Erratum: Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma (Cancer Research (October 2004) 64 (7011-7021) , 2004 .

[87]  Q. Lan,et al.  Differentiation profile of brain tumor stem cells: a comparative study with neural stem cells , 2006, Cell Research.

[88]  M. Sofroniew,et al.  GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain , 2004, Nature Neuroscience.

[89]  M. Moskowitz,et al.  FGF-2 regulation of neurogenesis in adult hippocampus after brain injury , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[90]  A. Shetty,et al.  Concise Review: Prospects of Stem Cell Therapy for Temporal Lobe Epilepsy , 2007, Stem cells.

[91]  F. Gage,et al.  Experience-Specific Functional Modification of the Dentate Gyrus through Adult Neurogenesis: A Critical Period during an Immature Stage , 2007, The Journal of Neuroscience.

[92]  D. Chen,et al.  Induction of Neurogenesis in Nonconventional Neurogenic Regions of the Adult Central Nervous System by Niche Astrocyte‐Produced Signals , 2008, Stem cells.

[93]  M. Götz,et al.  Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior , 2008, Proceedings of the National Academy of Sciences.

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

[95]  Brent A. Reynolds,et al.  Neural stem cells in the adult mammalian forebrain: A relatively quiescent subpopulation of subependymal cells , 1994, Neuron.

[96]  Hongjun Song,et al.  Adult neurogenesis in the mammalian central nervous system. , 2005, Annual review of neuroscience.

[97]  V. Nurcombe,et al.  Developmental regulation of neural response to FGF-1 and FGF-2 by heparan sulfate proteoglycan. , 1993, Science.

[98]  Arturo Alvarez-Buylla,et al.  A unified hypothesis on the lineage of neural stem cells , 2001, Nature Reviews Neuroscience.

[99]  F. Gage,et al.  Mechanisms and Functional Implications of Adult Neurogenesis , 2008, Cell.

[100]  Christelle Rochefort,et al.  Enriched Odor Exposure Increases the Number of Newborn Neurons in the Adult Olfactory Bulb and Improves Odor Memory , 2002, The Journal of Neuroscience.

[101]  C. Svendsen,et al.  Combining Growth Factors, Stem Cells, and Gene Therapy for the Aging Brain , 2004, Annals of the New York Academy of Sciences.

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

[103]  R. DePinho,et al.  Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. , 2002, Cancer cell.

[104]  Hongjun Song,et al.  Adult neural stem cells and repair of the adult central nervous system. , 2003, Journal of hematotherapy & stem cell research.

[105]  Fred H. Gage,et al.  Astroglia induce neurogenesis from adult neural stem cells , 2002, Nature.

[106]  G. Bourne Cell Research , 1957, Nature.

[107]  P. D. Lewis Mitotic Activity in the Primate Subependymal Layer and the Genesis of Gliomas , 1968, Nature.

[108]  I. Fariñas,et al.  Pigment epithelium–derived factor is a niche signal for neural stem cell renewal , 2006, Nature Neuroscience.

[109]  I. Bayazitov,et al.  A perivascular niche for brain tumor stem cells. , 2007, Cancer Cell.

[110]  E. Kandel The Molecular Biology of Memory Storage: A Dialog Between Genes and Synapses , 2004, Bioscience reports.

[111]  R. McKay,et al.  Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus , 2001, The Journal of comparative neurology.

[112]  Xin Duan,et al.  Disrupted-In-Schizophrenia 1 Regulates Integration of Newly Generated Neurons in the Adult Brain , 2007, Cell.

[113]  R. Henkelman,et al.  Identification of human brain tumour initiating cells , 2004, Nature.

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

[115]  Fred H. Gage,et al.  A role for adult TLX-positive neural stem cells in learning and behaviour , 2008, Nature.

[116]  Takashi Aoi,et al.  Generation of Pluripotent Stem Cells from Adult Mouse Liver and Stomach Cells , 2008, Science.

[117]  Cynthia Hawkins,et al.  Identification of a cancer stem cell in human brain tumors. , 2003, Cancer research.

[118]  Bob S Carter,et al.  Adult-Born and Preexisting Olfactory Granule Neurons Undergo Distinct Experience-Dependent Modifications of their Olfactory Responses In Vivo , 2005, The Journal of Neuroscience.

[119]  M. Götz,et al.  Neuronal fate determinants of adult olfactory bulb neurogenesis , 2005, Nature Neuroscience.

[120]  Hongjun Song,et al.  Neurogenesis in the adult brain: new strategies for central nervous system diseases. , 2004, Annual review of pharmacology and toxicology.

[121]  G. Fan,et al.  CD133+ neural stem cells in the ependyma of mammalian postnatal forebrain , 2008, Proceedings of the National Academy of Sciences.

[122]  Fred H. Gage,et al.  The Adult Rat Hippocampus Contains Primordial Neural Stem Cells , 1997, Molecular and Cellular Neuroscience.

[123]  F. Gage,et al.  Directed differentiation of hippocampal stem/progenitor cells in the adult brain , 2008, Nature Neuroscience.

[124]  Gerald C. Chu,et al.  P53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation , 2008, Nature.

[125]  Arturo Alvarez-Buylla,et al.  Chain Migration of Neuronal Precursors , 1996, Science.

[126]  G. Ming,et al.  G9a and Jhdm2a Regulate Embryonic Stem Cell Fusion‐Induced Reprogramming of Adult Neural Stem Cells , 2008, Stem cells.

[127]  Sean J. Morrison,et al.  Stem Cells and Niches: Mechanisms That Promote Stem Cell Maintenance throughout Life , 2008, Cell.

[128]  F. Gage,et al.  Is neurogenesis reparative after status epilepticus? , 2007, Epilepsia.

[129]  Y. Dan,et al.  Spike timing-dependent plasticity: from synapse to perception. , 2006, Physiological reviews.

[130]  S. Weiss,et al.  Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. , 1992, Science.

[131]  D. van der Kooy,et al.  Transforming Growth Factor-α Null and Senescent Mice Show Decreased Neural Progenitor Cell Proliferation in the Forebrain Subependyma , 1997, The Journal of Neuroscience.

[132]  T. Palmer,et al.  Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[133]  S. Weiss,et al.  Identity crisis for adult periventricular neural stem cells: subventricular zone astrocytes, ependymal cells or both? , 2009, Nature Reviews Neuroscience.

[134]  B. Luikart,et al.  TrkB Regulates Hippocampal Neurogenesis and Governs Sensitivity to Antidepressive Treatment , 2008, Neuron.

[135]  Loic Deleyrolle,et al.  Enumeration of Neural Stem and Progenitor Cells in the Neural Colony‐Forming Cell Assay , 2008, Stem cells.

[136]  P. Dirks,et al.  Brain tumor stem cells: bringing order to the chaos of brain cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[137]  U. Lendahl,et al.  Generalized potential of adult neural stem cells. , 2000, Science.

[138]  H. Schmidt,et al.  The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior , 2007, Behavioural pharmacology.

[139]  Xinyu Zhao,et al.  Neural Stem Cells and Neurogenic Niche in the Adult Brain , 2008 .

[140]  Xin Duan,et al.  Development of neural stem cell in the adult brain , 2008, Current Opinion in Neurobiology.

[141]  G. Ming,et al.  Glial influences on neural stem cell development: cellular niches for adult neurogenesis , 2005, Current Opinion in Neurobiology.

[142]  J. García-Verdugo,et al.  A specialized vascular niche for adult neural stem cells. , 2008, Cell stem cell.

[143]  D. Kooy,et al.  Hematopoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations , 2002, Nature Medicine.

[144]  S. Bauer,et al.  Leukemia Inhibitory Factor Promotes Neural Stem Cell Self-Renewal in the Adult Brain , 2006, The Journal of Neuroscience.