The bright side of the glial scar in CNS repair

Following CNS injury, in an apparently counterintuitive response, scar tissue formation inhibits axonal growth, imposing a major barrier to regeneration. Accordingly, scar-modulating treatments have become a leading therapeutic goal in the field of spinal cord injury. However, increasing evidence suggests a beneficial role for this scar tissue as part of the endogenous local immune regulation and repair process. How can these opposing effects be reconciled? Perhaps it is all a matter of timing.

[1]  V. Gallo,et al.  The proteoglycan chondroitin sulfate is present in a subpopulation of cultured astrocytes and in their precursors. , 1987, Developmental biology.

[2]  Reier Pj,et al.  The glial scar: its bearing on axonal elongation and transplantation approaches to CNS repair. , 1988 .

[3]  P. Caroni,et al.  Antibody against myelin associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter , 1988, Neuron.

[4]  P. Reier,et al.  The glial scar: its bearing on axonal elongation and transplantation approaches to CNS repair. , 1988, Advances in neurology.

[5]  E. Benveniste,et al.  Tumor necrosis factor-alpha production by astrocytes. Induction by lipopolysaccharide, IFN-gamma, and IL-1 beta. , 1990, Journal of immunology.

[6]  D. Steindler,et al.  Molecular and cellular characterization of the glial roof plate of the spinal cord and optic tectum: a possible role for a proteoglycan in the development of an axon barrier. , 1990, Developmental biology.

[7]  J. Silver,et al.  Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[8]  H. M. Geller,et al.  An inhibitor of neurite outgrowth produced by astrocytes. , 1994, Journal of cell science.

[9]  J. Silver,et al.  Exogenous glycosaminoglycans induce complete inversion of retinal ganglion cell bodies and their axons within the retinal neuroepithelium. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[10]  M. Bennett,et al.  Retinal ganglion cell survival in vitro maintained by a chondroitin sulfate proteoglycan from the superior colliculus carrying the HNK‐1 epitope , 1994, Journal of neuroscience research.

[11]  M. Filbin,et al.  A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration , 1994, Neuron.

[12]  A L Pearlman,et al.  Thalamocortical axons extend along a chondroitin sulfate proteoglycan- enriched pathway coincident with the neocortical subplate and distinct from the efferent path , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  N. Nishiyama,et al.  Neurotrophic factor gene expression in astrocytes during development and following injury , 1994, Brain Research Bulletin.

[14]  M. Schachner,et al.  Isolation of a neural chondroitin sulfate proteoglycan with neurite outgrowth promoting properties , 1994, The Journal of cell biology.

[15]  L. Mckerracher,et al.  Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth , 1994, Neuron.

[16]  D. Steindler,et al.  Cell and molecular analysis of the developing and adult mouse subventricular zone of the cerebral hemispheres , 1995, The Journal of comparative neurology.

[17]  A. Oohira,et al.  Chondroitin Sulphate Proteoglycans in the Rat Brain: Candidates for Axon Barriers of Sensory Neurons and the Possible Modification by Laminin of their Actions , 1995, The European journal of neuroscience.

[18]  J. Fawcett,et al.  Increased axon regeneration in astrocytes grown in the presence of proteoglycan synthesis inhibitors. , 1995, Journal of cell science.

[19]  Jerry Silver,et al.  Activated Macrophages and the Blood–Brain Barrier: Inflammation after CNS Injury Leads to Increases in Putative Inhibitory Molecules , 1997, Experimental Neurology.

[20]  J. Houlé,et al.  Activated Macrophage/Microglial Cells Can Promote the Regeneration of Sensory Axons into the Injured Spinal Cord , 1997, Experimental Neurology.

[21]  P. Dijkhuizen,et al.  NT‐3 delivered by an adenoviral vector induces injured dorsal root axons to regenerate into the spinal cord of adult rats , 1998, Journal of neuroscience research.

[22]  H. Müller,et al.  The CNS lesion scar: new vistas on an old regeneration barrier , 1998, Cell and Tissue Research.

[23]  N. Nishiyama,et al.  A Culture Model of Reactive Astrocytes: Increased Nerve Growth Factor Synthesis and Reexpression of Cytokine Responsiveness , 1998, Journal of neurochemistry.

[24]  S. Nesathurai,et al.  Steroids and spinal cord injury: revisiting the NASCIS 2 and NASCIS 3 trials. , 1998, The Journal of trauma.

[25]  M. Schwartz,et al.  Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats , 1998, Nature Medicine.

[26]  M. Jurynec,et al.  The Chondroitin Sulfate Proteoglycans Neurocan and Phosphacan Are Expressed by Reactive Astrocytes in the Chronic CNS Glial Scar , 1999, The Journal of Neuroscience.

[27]  Phillip G. Popovich,et al.  Depletion of Hematogenous Macrophages Promotes Partial Hindlimb Recovery and Neuroanatomical Repair after Experimental Spinal Cord Injury , 1999, Experimental Neurology.

[28]  S. R. Thornton,et al.  Comparing Astrocytic Cell Lines that Are Inhibitory or Permissive for Axon Growth: the Major Axon-Inhibitory Proteoglycan Is NG2 , 1999, The Journal of Neuroscience.

[29]  Eva Syková,et al.  Diffusion barriers evoked in the rat cortex by reactive astrogliosis , 1999, Glia.

[30]  Clive N Svendsen,et al.  Leukocyte Infiltration, Neuronal Degeneration, and Neurite Outgrowth after Ablation of Scar-Forming, Reactive Astrocytes in Adult Transgenic Mice , 1999, Neuron.

[31]  A. Aruffo,et al.  Characterization of the Heparan Sulfate and Chondroitin Sulfate Assembly Sites in CD44* , 1999, The Journal of Biological Chemistry.

[32]  Irun R. Cohen,et al.  Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy , 1999, Nature Medicine.

[33]  B. Gusterson,et al.  Inducible ablation of astrocytes shows that these cells are required for neuronal survival in the adult brain , 2001, Glia.

[34]  H. Dai,et al.  Axonal Regeneration and Functional Recovery after Complete Spinal Cord Transection in Rats by Delayed Treatment with Transplants and Neurotrophins , 2001, The Journal of Neuroscience.

[35]  R. Swanson,et al.  Astrocytes protect neurons from nitric oxide toxicity by a glutathione‐dependent mechanism , 2001, Journal of neurochemistry.

[36]  J. Fawcett,et al.  Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC , 2001, Nature Neuroscience.

[37]  M. Garry,et al.  Functional Regeneration of Chronically Injured Sensory Afferents into Adult Spinal Cord after Neurotrophin Gene Therapy , 2001, The Journal of Neuroscience.

[38]  C. ffrench-Constant,et al.  Knockout mice reveal a contribution of the extracellular matrix molecule tenascin-C to neural precursor proliferation and migration. , 2001, Development.

[39]  James W. Fawcett,et al.  Chondroitinase ABC promotes functional recovery after spinal cord injury , 2002, Nature.

[40]  B. Ellezam,et al.  Rho Signaling Pathway Targeted to Promote Spinal Cord Repair , 2002, The Journal of Neuroscience.

[41]  I. Vorisek,et al.  Water ADC, extracellular space volume, and tortuosity in the rat cortex after traumatic injury , 2002, Magnetic resonance in medicine.

[42]  A. Basbaum,et al.  Regeneration of Sensory Axons within the Injured Spinal Cord Induced by Intraganglionic cAMP Elevation , 2002, Neuron.

[43]  J. Schwab,et al.  The Rho/ROCK pathway mediates neurite growth-inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar , 2003, Molecular and Cellular Neuroscience.

[44]  A. Faissner,et al.  Oversulfated Dermatan Sulfate Exhibits Neurite Outgrowth-promoting Activity toward Embryonic Mouse Hippocampal Neurons , 2003, Journal of Biological Chemistry.

[45]  J. Steeves,et al.  Suppression of Rho-kinase activity promotes axonal growth on inhibitory CNS substrates , 2003, Molecular and Cellular Neuroscience.

[46]  J. Fawcett,et al.  Inhibiting cell proliferation during formation of the glial scar: effects on axon regeneration in the CNS , 2003, Neuroscience.

[47]  M. Tuszynski,et al.  The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury , 2003, Experimental Neurology.

[48]  Vincenzo Crunelli,et al.  An astrocyte bridge from synapse to blood flow , 2003, Nature Neuroscience.

[49]  S. Davies,et al.  Changes in distribution, cell associations, and protein expression levels of NG2, neurocan, phosphacan, brevican, versican V2, and tenascin‐C during acute to chronic maturation of spinal cord scar tissue , 2003, Journal of neuroscience research.

[50]  Barbara Grimpe,et al.  A Novel DNA Enzyme Reduces Glycosaminoglycan Chains in the Glial Scar and Allows Microtransplanted Dorsal Root Ganglia Axons to Regenerate beyond Lesions in the Spinal Cord , 2004, The Journal of Neuroscience.

[51]  C. ffrench-Constant,et al.  The extracellular matrix glycoprotein Tenascin‐C is expressed by oligodendrocyte precursor cells and required for the regulation of maturation rate, survival and responsiveness to platelet‐derived growth factor , 2004, The European journal of neuroscience.

[52]  V. Litvak,et al.  A disaccharide derived from chondroitin sulphate proteoglycan promotes central nervous system repair in rats and mice † , 2004, The European journal of neuroscience.

[53]  Jerry Silver,et al.  Regeneration beyond the glial scar , 2004, Nature Reviews Neuroscience.

[54]  T. Muramatsu,et al.  Requirement of chondroitin sulfate/dermatan sulfate recognition in midkine-dependent migration of macrophages , 2001, Glycoconjugate Journal.

[55]  Ngan B. Doan,et al.  Reactive Astrocytes Protect Tissue and Preserve Function after Spinal Cord Injury , 2004, The Journal of Neuroscience.

[56]  A. Blight,et al.  Chondroitinase ABCI improves locomotion and bladder function following contusion injury of the rat spinal cord. , 2005, Journal of neurotrauma.

[57]  M. Schwartz,et al.  Does Inflammation in an Autoimmune Disease Differ from Inflammation in Neurodegenerative Diseases? Possible Implications for Therapy , 2006, Journal of Neuroimmune Pharmacology.

[58]  M. Sofroniew,et al.  Reactive Astrocytes in Neural Repair and Protection , 2005, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

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

[60]  J. Fawcett.  Overcoming inhibition in the damaged spinal cord. , 2006, Journal of neurotrauma.

[61]  Yaniv Ziv,et al.  Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood , 2006, Nature Neuroscience.

[62]  M. Schwartz,et al.  A sulfated disaccharide derived from chondroitin sulfate proteoglycan protects against inflammation‐associated neurodegeneration , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[63]  Hideyuki Okano,et al.  Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury , 2006, Nature Medicine.

[64]  M. Sofroniew,et al.  Essential protective roles of reactive astrocytes in traumatic brain injury. , 2006, Brain : a journal of neurology.

[65]  D. Steindler,et al.  Derivation and large-scale expansion of multipotent astroglial neural progenitors from adult human brain , 2006, Development.

[66]  J. Julien,et al.  Bone Marrow-Derived Microglia Play a Critical Role in Restricting Senile Plaque Formation in Alzheimer's Disease , 2006, Neuron.

[67]  Kanako Hirano,et al.  Identification of Neurite Outgrowth-promoting Domains of Neuroglycan C, a Brain-specific Chondroitin Sulfate Proteoglycan, and Involvement of Phosphatidylinositol 3-Kinase and Protein Kinase C Signaling Pathways in Neuritogenesis* , 2006, Journal of Biological Chemistry.

[68]  Yaniv Ziv,et al.  Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury , 2006, Proceedings of the National Academy of Sciences.

[69]  K. Nakanishi,et al.  Identification and Functions of Chondroitin Sulfate in the Milieu of Neural Stem Cells* , 2006, Journal of Biological Chemistry.

[70]  C. Nandini,et al.  Role of the sulfation pattern of chondroitin sulfate in its biological activities and in the binding of growth factors. , 2006, Advances in pharmacology.

[71]  Zhigang He,et al.  Glial inhibition of CNS axon regeneration , 2006, Nature Reviews Neuroscience.

[72]  J. Levine,et al.  Antibodies against the NG2 Proteoglycan Promote the Regeneration of Sensory Axons within the Dorsal Columns of the Spinal Cord , 2006, The Journal of Neuroscience.

[73]  J. Briscoe,et al.  Morphogens and the Control of Cell Proliferation and Patterning in the Spinal Cord , 2007, Cell cycle.

[74]  Michal Schwartz,et al.  Selective ablation of bone marrow‐derived dendritic cells increases amyloid plaques in a mouse Alzheimer's disease model , 2007, The European journal of neuroscience.

[75]  Daishi Tian,et al.  Attenuation of astrogliosis by suppressing of microglial proliferation with the cell cycle inhibitor olomoucine in rat spinal cord injury model , 2007, Brain Research.

[76]  Yaniv Ziv,et al.  Toll-like receptors modulate adult hippocampal neurogenesis , 2007, Nature Cell Biology.

[77]  M. Götz,et al.  Chondroitin sulfate glycosaminoglycans control proliferation, radial glia cell differentiation and neurogenesis in neural stem/progenitor cells , 2007, Development.

[78]  G. Chadi,et al.  Responses of reactive astrocytes containing S100β protein and fibroblast growth factor‐2 in the border and in the adjacent preserved tissue after a contusion injury of the spinal cord in rats: implications for wound repair and neuroregeneration , 2007, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[79]  D. Steindler,et al.  Astrocytic stem cells in the adult brain. , 2007, Neurosurgery clinics of North America.

[80]  S. Rivest,et al.  Neuroprotective role of the innate immune system by microglia , 2007, Neuroscience.

[81]  H. Dai,et al.  Delayed transplantation with exogenous neurotrophin administration enhances plasticity of corticofugal projections after spinal cord injury. , 2007, Journal of neurotrauma.

[82]  K. Nakanishi,et al.  Reduction of Brain Injury in Neonatal Hypoxic—Ischemic Rats by Intracerebroventricular Injection of Neural Stem/Progenitor Cells Together With Chondroitinase ABC , 2008, Reproductive Sciences.

[83]  D. Howland,et al.  Chondroitinase ABC improves basic and skilled locomotion in spinal cord injured cats , 2008, Experimental Neurology.

[84]  J. Kipnis,et al.  Immunity and cognition: what do age-related dementia, HIV-dementia and 'chemo-brain' have in common? , 2008, Trends in immunology.

[85]  L. Jakeman,et al.  TGF-α increases astrocyte invasion and promotes axonal growth into the lesion following spinal cord injury in mice , 2008, Experimental Neurology.

[86]  J. Houlé,et al.  Intraspinal microinjection of chondroitinase ABC following injury promotes axonal regeneration out of a peripheral nerve graft bridge , 2008, Experimental Neurology.

[87]  T. Langmann,et al.  Chondroitin sulfate disaccharide stimulates microglia to adopt a novel regulatory phenotype , 2008, Journal of leukocyte biology.

[88]  Michal Schwartz,et al.  America , 2012 .

[89]  K. Horn,et al.  Another Barrier to Regeneration in the CNS: Activated Macrophages Induce Extensive Retraction of Dystrophic Axons through Direct Physical Interactions , 2008, The Journal of Neuroscience.

[90]  P. Caroni,et al.  Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. , 2008, Neuron.

[91]  A. Faissner,et al.  Expression of Multiple Chondroitin/Dermatan Sulfotransferases in the Neurogenic Regions of the Embryonic and Adult Central Nervous System Implies That Complex Chondroitin Sulfates Have a Role in Neural Stem Cell Maintenance , 2008, Stem cells.

[92]  J. Kipnis,et al.  Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype , 2008, The Journal of Immunology.

[93]  K. Nakanishi,et al.  A highly sulfated chondroitin sulfate preparation, CS‐E, prevents excitatory amino acid‐induced neuronal cell death , 2008, Journal of neurochemistry.

[94]  S. Akira,et al.  STAT3 is a Critical Regulator of Astrogliosis and Scar Formation after Spinal Cord Injury , 2008, The Journal of Neuroscience.

[95]  M. Schwartz,et al.  Toll-like receptor 4 restricts retinal progenitor cell proliferation , 2008, The Journal of cell biology.