Glial Scar—a Promising Target for Improving Outcomes After CNS Injury

  • Yuanyuan He
  • Xiaoyan Liu
  • Zhongying ChenEmail author


After central nervous system (CNS) injury, a series of stress responses induce astrocytes activation. Reactive astrocytes, which are typically different from astrocytes in normal conditions in altered morphology and gene expression, combine with extracellular matrix (ECM) components to form a glial scar at the lesion site, which walls of the injured region from neighboring healthier tissue. However, as a physical and molecular barrier, glial scar can impede patients’ functional recovery in the late period of CNS injury. Thus, inhibiting glial scar formation in the chronic stage after CNS injury may be a promising target to improve outcomes. Since the therapeutic strategies targeting on mediating glial scar formation are regarded as an important part on improving functional recovery after CNS injury, in this review, we focus on the regulating effects of related signaling pathways and other molecules on glial scar, and the process of glial scar formation and the roles that it plays during the acute and chronic stages are also expounded in this article. We hope to get a comprehensive understanding of glial scar during CNS injury based on current researches and to open new perspectives for the therapies to promote functional recovery after CNS injury.


Glial scar Astrocyte Astrocyte reactivity CNS injury 



  1. Anderson MA et al (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature 532:195–200. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Asher RA, Morgenstern DA, Moon LD, Fawcett JW (2001) Chondroitin sulphate proteoglycans: inhibitory components of the glial scar. Prog Brain Res 132:611–619. CrossRefPubMedGoogle Scholar
  3. Bailey MS, Shipley MT (1993) Astrocyte subtypes in the rat olfactory bulb: morphological heterogeneity and differential laminar distribution. J Comp Neurol 328:501–526. CrossRefPubMedGoogle Scholar
  4. Bao Y et al (2012) CD36 is involved in astrocyte activation and astroglial scar formation. J Cereb Blood Flow Metab 32:1567–1577. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bardehle S et al (2013) Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Nat Neurosci 16:580–586. CrossRefPubMedGoogle Scholar
  6. Ben Haim L, Carrillo-de Sauvage MA, Ceyzeriat K, Escartin C (2015) Elusive roles for reactive astrocytes in neurodegenerative diseases. Front Cell Neurosci 9:278. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bhalala OG, Pan L, Sahni V, McGuire TL, Gruner K, Tourtellotte WG, Kessler JA (2012) microRNA-21 regulates astrocytic response following spinal cord injury. J Neurosci 32:17935–17947. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bialas AR, Stevens B (2013) TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci 16:1773–1782. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Blochet C, Buscemi L, Clement T, Gehri S, Badaut J, Hirt L (2018) Involvement of caveolin-1 in neurovascular unit remodeling after stroke: Effects on neovascularization and astrogliosis. J Cereb Blood Flow Metab 271678x18806893.
  10. Bonner JF, Connors TM, Silverman WF, Kowalski DP, Lemay MA, Fischer I (2011) Grafted neural progenitors integrate and restore synaptic connectivity across the injured spinal cord. J Neurosci 31:4675–4686. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Boyd JG, Gordon T (2003) Neurotrophic factors and their receptors in axonal regeneration and functional recovery after peripheral nerve injury. Mol Neurobiol 27:277–324. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Bradbury EJ, Carter LM (2011) Manipulating the glial scar: chondroitinase ABC as a therapy for spinal cord injury. Brain Res Bull 84:306–316. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Brambilla R et al (2005) Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 202:145–156. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Buffo A, Rolando C, Ceruti S (2010) Astrocytes in the damaged brain: molecular and cellular insights into their reactive response and healing potential. Biochem Pharmacol 79:77-89 PubMedCrossRefPubMedCentralGoogle Scholar
  15. Burda JE, Sofroniew MV (2014) Reactive gliosis and the multicellular response to CNS damage and disease Neuron 81:229-248. PubMedPubMedCentralCrossRefGoogle Scholar
  16. Busch SA, Silver J (2007) The role of extracellular matrix in CNS regeneration. Curr Opin Neurobiol 17:120–127. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, Mucke L, Johnson MH, Sofroniew MV (1999) Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23:297–308PubMedCrossRefPubMedCentralGoogle Scholar
  18. Cai H et al. (2017) Hypoxia response element-regulated MMP-9 promotes neurological recovery via glial scar degradation and angiogenesis in delayed stroke. Mol Ther 25:1448-1459. PubMedPubMedCentralCrossRefGoogle Scholar
  19. Cekanaviciute E, Buckwalter MS (2016) Astrocytes: integrative regulators of neuroinflammation in stroke and other neurological diseases. Neurotherapeutics 13:685-701. PubMedPubMedCentralCrossRefGoogle Scholar
  20. Chen MH et al (2016) Lentiviral vector-mediated p27(kip1) expression facilitates recovery after spinal cord injury. Mol Neurobiol 53:6043–6056. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Chen M et al (2018) Leucine zipper-bearing kinase is a critical regulator of astrocyte reactivity in the adult mammalian CNS. Cell Rep 22:3587–3597. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Cua RC, Lau LW, Keough MB, Midha R, Apte SS, Yong VW (2013) Overcoming neurite-inhibitory chondroitin sulfate proteoglycans in the astrocyte matrix. Glia 61:972-984. PubMedCrossRefPubMedCentralGoogle Scholar
  23. Deckner M, Lindholm T, Cullheim S, Risling M (2000) Differential expression of tenascin-C, tenascin-R, tenascin/J1, and tenascin-X in spinal cord scar tissue and in the olfactory system. Exp Neurol 166:350–362. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Eng LF, Vanderhaeghen JJ, Bignami A, Gerstl B (1971) An acidic protein isolated from fibrous astrocytes. Brain Res 28:351–354PubMedPubMedCentralCrossRefGoogle Scholar
  25. Faiz M, Sachewsky N, Gascon S, Bang KW, Morshead CM, Nagy A (2015) Adult neural stem cells from the subventricular zone give rise to reactive astrocytes in the cortex after stroke. Cell Stem Cell 17:624–634. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24:2143–2155. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Fawcett JW, Asher RA (1999) The glial scar and central nervous system repair. Brain Res Bull 49:377–391PubMedCrossRefPubMedCentralGoogle Scholar
  28. Fawcett JW, Schwab ME, Montani L, Brazda N, Muller HW (2012) Defeating inhibition of regeneration by scar and myelin components. Handb Clin Neurol 109:503–522. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Filbin MT (2003) Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat Rev Neurosci 4:703-713. PubMedCrossRefPubMedCentralGoogle Scholar
  30. Fitch MT, Silver J (1997) Activated macrophages and the blood-brain barrier: inflammation after CNS injury leads to increases in putative inhibitory molecules. Exp Neurol 148:587–603. CrossRefPubMedGoogle Scholar
  31. Fitch MT, Doller C, Combs CK, Landreth GE, Silver J (1999) Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci 19:8182-8198PubMedPubMedCentralCrossRefGoogle Scholar
  32. Goldshmit Y, Galea MP, Wise G, Bartlett PF, Turnley AM (2004) Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. J Neurosci 24:10064-10073. PubMedCrossRefGoogle Scholar
  33. Goldshmit Y, Jona G, Schmukler E, Solomon S, Pinkas-Kramarski R, Ruban A (2018) Blood glutamate scavenger as a novel neuroprotective treatment in spinal cord injury. J Neurotrauma 35:2581–2590. CrossRefPubMedGoogle Scholar
  34. Hagino S et al. (2003) Slit and glypican-1 mRNAs are coexpressed in the reactive astrocytes of the injured adult brain. Glia 42:130-138. PubMedCrossRefGoogle Scholar
  35. He Z, Koprivica V (2004) The Nogo signaling pathway for regeneration block. Annu Rev Neurosci 27:341–368. CrossRefPubMedGoogle Scholar
  36. Herrmann JE et al. (2008) STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci 28:7231-7243. PubMedCrossRefGoogle Scholar
  37. Herrmann JE, Shah RR, Chan AF, Zheng B (2010) EphA4 deficient mice maintain astroglial-fibrotic scar formation after spinal cord injury. Exp Neurol 223:582–598. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Hira K et al. (2018) Astrocyte-derived exosomes treated with a semaphorin 3a inhibitor enhance stroke recovery via prostaglandin D2 Synthase. Stroke 49:2483-2494. PubMedCrossRefGoogle Scholar
  39. Hochstim C, Deneen B, Lukaszewicz A, Zhou Q, Anderson DJ (2008) Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code. Cell 133:510–522. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Hung KS et al. (2005) Calpain inhibitor inhibits p35-p25-Cdk5 activation, decreases tau hyperphosphorylation, and improves neurological function after spinal cord hemisection in rats. J Neuropathol Exp Neurol 64:15-26. CrossRefGoogle Scholar
  41. Hurwitz AA, Berman JW, Rashbaum WK, Lyman WD (1993) Human fetal astrocytes induce the expression of blood-brain barrier specific proteins by autologous endothelial cells. Brain Res 625:238–243PubMedCrossRefGoogle Scholar
  42. Iglesias J, Morales L, Barreto GE (2017) Metabolic and inflammatory adaptation of reactive astrocytes: role of PPARs. Mol Neurobiol 54:2518–2538. CrossRefPubMedGoogle Scholar
  43. Jeffrey KL, Camps M, Rommel C, Mackay CR (2007) Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov 6:391–403. CrossRefPubMedGoogle Scholar
  44. Jeong SR et al (2012) Hepatocyte growth factor reduces astrocytic scar formation and promotes axonal growth beyond glial scars after spinal cord injury. Exp Neurol 233:312–322. CrossRefPubMedGoogle Scholar
  45. Jin Y et al (2011) Transplantation of human glial restricted progenitors and derived astrocytes into a contusion model of spinal cord injury. J Neurotrauma 28:579–594. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Kaltschmidt B, Widera D, Kaltschmidt C (2005) Signaling via NF-kappaB in the nervous system. Biochim Biophys Acta 1745:287-299. CrossRefGoogle Scholar
  47. Karamouzian S, Nematollahi-Mahani SN, Nakhaee N, Eskandary H (2012) Clinical safety and primary efficacy of bone marrow mesenchymal cell transplantation in subacute spinal cord injured patients. Clin Neurol Neurosurg 114:935–939. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Karimi-Abdolrezaee S, Billakanti R (2012) Reactive astrogliosis after spinal cord injury-beneficial and detrimental effects. Molecular Neurobiol 46:251–264. CrossRefGoogle Scholar
  49. Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Morshead CM, Fehlings MG (2006) Delayed transplantation of adult neural precursor cells promotes remyelination and functional neurological recovery after spinal cord injury. J Neurosci 26:3377–3389. CrossRefPubMedPubMedCentralGoogle Scholar
  50. Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Schut D, Fehlings MG (2010) Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. J Neurosci 30:1657–1676. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Karova K, Wainwright JV, Machova-Urdzikova L, Pisal RV, Schmidt M, Jendelova P, Jhanwar-Uniyal M (2019) Transplantation of neural precursors generated from spinal progenitor cells reduces inflammation in spinal cord injury via NF-kappaB pathway inhibition. J Neuroinflammation 16:12. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Keough MB, Rogers JA, Zhang P, Jensen SK, Stephenson EL, Chen T, Hurlbert MG, Lau LW, Rawji KS, Plemel JR, Koch M, Ling CC, Yong VW (2016) An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination 7:11312 doi:
  53. Khaing ZZ, Milman BD, Vanscoy JE, Seidlits SK, Grill RJ, Schmidt CE (2011) High molecular weight hyaluronic acid limits astrocyte activation and scar formation after spinal cord injury. J Neural Eng 8:046033. CrossRefPubMedGoogle Scholar
  54. Kitamura K, Nagoshi N, Tsuji O, Matsumoto M, Okano H, Nakamura M (2019) Application of hepatocyte growth factor for acute spinal cord injury: the road from basic studies to human treatment International. J. Mol. Sci. 20. PubMedCentralCrossRefPubMedGoogle Scholar
  55. Lawrenson ID et al (2002) Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3-expressing 293T and melanoma cells by CrkII and Rho-mediated signalling. J Cell Sci 115:1059–1072PubMedGoogle Scholar
  56. Lee SI, Zhang W, Ravi M, Weschenfelder M, Bastmeyer M, Levine JM (2013) Atypical protein kinase C and Par3 are required for proteoglycan-induced axon growth inhibition. J Neurosci 33:2541-2554. PubMedCrossRefGoogle Scholar
  57. Li ZW et al (2011) Inhibiting epidermal growth factor receptor attenuates reactive astrogliosis and improves functional outcome after spinal cord injury in rats. Neurochem Int 58:812–819. CrossRefPubMedGoogle Scholar
  58. Li ZW, Li JJ, Wang L, Zhang JP, Wu JJ, Mao XQ, Shi GF, Wang Q, Wang F, Zou J (2014) Epidermal growth factor receptor inhibitor ameliorates excessive astrogliosis and improves the regeneration microenvironment and functional recovery in adult rats following spinal cord injury. J Neuroinflammation 11:71–16. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Li D, Tong L, Kawano H, Liu N, Yan HJ, Zhao L, Li HP (2016a) Regulation and role of ERK phosphorylation in glial cells following a nigrostriatal pathway injury. Brain Res 1648:90–100. CrossRefPubMedGoogle Scholar
  60. Li G et al (2016b) Mdivi-1 inhibits astrocyte activation and astroglial scar formation and enhances axonal regeneration after spinal cord injury in rats. Front Cell Neurosci 10:241. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Li D et al (2017) Interactions between Sirt1 and MAPKs regulate astrocyte activation induced by brain injury in vitro and in vivo. J Neuroinflammation 14:67. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Lian H et al. (2015) NFkappaB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron 85: 101-115. PubMedCrossRefGoogle Scholar
  63. Liddelow SA et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Lindenau J, Noack H, Asayama K, Wolf G (1998) Enhanced cellular glutathione peroxidase immunoreactivity in activated astrocytes and in microglia during excitotoxin induced neurodegeneration. Glia 24:252-256PubMedCrossRefGoogle Scholar
  65. Liu B, Neufeld AH (2004) Activation of epidermal growth factor receptor causes astrocytes to form cribriform structures. Glia 46:153-168 PubMedCrossRefGoogle Scholar
  66. Liu B, Chen H, Johns TG, Neufeld AH (2006) Epidermal growth factor receptor activation: an upstream signal for transition of quiescent astrocytes into reactive astrocytes after neural injury. J Neurosci 26:7532-7540. PubMedCrossRefGoogle Scholar
  67. Liu R, Wang W, Wang S, Xie W, Li H, Ning B (2018) microRNA-21 regulates astrocytic reaction post-acute phase of spinal cord injury through modulating TGF-beta signaling. Aging 10:1474–1488. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Liu W et al (2019) Exosomes derived from bone mesenchymal stem cells repair traumatic spinal cord injury by suppressing the activation of A1 neurotoxic reactive astrocytes. J Neurotrauma 36:469–484. CrossRefPubMedGoogle Scholar
  69. Maria Ferri AL, Bersano A, Lisini D, Boncoraglio G, Frigerio S, Parati E (2016) Mesenchymal stem cells for ischemic stroke: progress and possibilities. Curr Med Chem 23:1598–1608. CrossRefPubMedGoogle Scholar
  70. Mattson MP, Meffert MK (2006) Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ 13:852–860. CrossRefPubMedGoogle Scholar
  71. McKeon RJ, Schreiber RC, Rudge JS, Silver J (1991) Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J Neurosci 11:3398-3411PubMedPubMedCentralCrossRefGoogle Scholar
  72. McKeon RJ, Hoke A, Silver J (1995) Injury-induced proteoglycans inhibit the potential for laminin-mediated axon growth on astrocytic scars. Exp Neurol 136:32–43. CrossRefPubMedGoogle Scholar
  73. McKillop WM, Dragan M, Schedl A, Brown A (2013) Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury. Glia 61:164-177. PubMedPubMedCentralCrossRefGoogle Scholar
  74. Menet V, Prieto M, Privat A, Gimenez y Ribotta M (2003) Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Proc Natl Acad Sci USA 100:8999-9004. CrossRefGoogle Scholar
  75. Miao H, Burnett E, Kinch M, Simon E, Wang B (2000) Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol 2, 62:–69. CrossRefGoogle Scholar
  76. Mizuno H, Warita H, Aoki M, Itoyama Y (2008) Accumulation of chondroitin sulfate proteoglycans in the microenvironment of spinal motor neurons in amyotrophic lateral sclerosis transgenic rats. J Neuroscience R 86:2512–2523. CrossRefGoogle Scholar
  77. Moon LD, Asher RA, Rhodes KE, Fawcett JW (2001) Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nat Neurosci 4:465-466. PubMedCrossRefGoogle Scholar
  78. Mori T, Tan J, Arendash GW, Koyama N, Nojima Y, Town T (2008) Overexpression of human S100B exacerbates brain damage and periinfarct gliosis after permanent focal ischemia. Stroke 39:2114–2121. CrossRefPubMedPubMedCentralGoogle Scholar
  79. Muroyama Y, Fujiwara Y, Orkin SH, Rowitch DH (2005) Specification of astrocytes by bHLH protein SCL in a restricted region of the neural tube. Nature 438:360–363. CrossRefPubMedGoogle Scholar
  80. Norsted Gregory E, Delaney A, Abdelmoaty S, Bas DB, Codeluppi S, Wigerblad G, Svensson CI (2013) Pentoxifylline and propentofylline prevent proliferation and activation of the mammalian target of rapamycin and mitogen activated protein kinase in cultured spinal astrocytes. J Neuroscience Res 91:300–312. CrossRefGoogle Scholar
  81. O’Shea TM, Burda JE, Sofroniew MV (2017) Cell biology of spinal cord injury and repair. J Clin Invest 127:3259-3270. PubMedCrossRefPubMedCentralGoogle Scholar
  82. Okada S et al (2006) Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nature Med 12:829–834. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Pendleton JC, Shamblott MJ, Gary DS, Belegu V, Hurtado A, Malone ML, JW MD (2013) Chondroitin sulfate proteoglycans inhibit oligodendrocyte myelination through PTPsigma. Exp Neurol 247:113–121. CrossRefPubMedPubMedCentralGoogle Scholar
  84. Poyhonen S, Er S, Domanskyi A, Airavaara M (2019) Effects of neurotrophic factors in glial cells in the central nervous system: expression and properties in neurodegeneration and injury. Front Physiol 10:486. CrossRefPubMedPubMedCentralGoogle Scholar
  85. Profyris C, Cheema SS, Zang D, Azari MF, Boyle K, Petratos S (2004) Degenerative and regenerative mechanisms governing spinal cord injury. Neurobiol Dis 15:415–436. CrossRefPubMedPubMedCentralGoogle Scholar
  86. Qu WS, Tian DS, Guo ZB, Fang J, Zhang Q, Yu ZY, Xie MJ, Zhang HQ, Lü JG, Wang W (2012) Inhibition of EGFR/MAPK signaling reduces microglial inflammatory response and the associated secondary damage in rats after spinal cord injury. J Neuroinflammation 9:178.
  87. Ray SK, Matzelle DD, Wilford GG, Hogan EL, Banik NL (2001) Inhibition of calpain-mediated apoptosis by E-64 d-reduced immediate early gene (IEG) expression and reactive astrogliosis in the lesion and penumbra following spinal cord injury in rats. Brain Res 916:115-126. PubMedCrossRefPubMedCentralGoogle Scholar
  88. Reier PJ, Houle JD (1988) The glial scar: its bearing on axonal elongation and transplantation approaches to CNS repair. Adv Neurol 47:87–138PubMedPubMedCentralGoogle Scholar
  89. Rolls A, Shechter R, Schwartz M (2009) The bright side of the glial scar in CNS repair. Nat Rev Neurosci 10:235–241. CrossRefPubMedGoogle Scholar
  90. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16:675–686PubMedCrossRefPubMedCentralGoogle Scholar
  91. Saito F et al (2012) Administration of cultured autologous bone marrow stromal cells into cerebrospinal fluid in spinal injury patients: a pilot study. Restor Neurol Neurosci 30:127–136. CrossRefPubMedPubMedCentralGoogle Scholar
  92. Santra M, Reed CC, Iozzo RV (2002) Decorin binds to a narrow region of the epidermal growth factor (EGF) receptor, partially overlapping but distinct from the EGF-binding epitope. J Biol Chem 277:35671-35681. PubMedCrossRefPubMedCentralGoogle Scholar
  93. Schachtrup C, Ryu JK, Mammadzada K, Khan AS, Carlton PM (2015) Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-beta signaling and astrocyte functions. Nat Neurosci 18:1077-1080. PubMedPubMedCentralCrossRefGoogle Scholar
  94. Seifert G, Schilling K, Steinhauser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat Rev Neurosci 7:194–206. CrossRefPubMedPubMedCentralGoogle Scholar
  95. Sicotte M, Tsatas O, Jeong SY, Cai CQ, He Z, David S (2003) Immunization with myelin or recombinant Nogo-66/MAG in alum promotes axon regeneration and sprouting after corticospinal tract lesions in the spinal cord. Mol Cell Neurosci 23:251–263PubMedCrossRefPubMedCentralGoogle Scholar
  96. Siebert JR, Stelzner DJ, Osterhout DJ (2011) Chondroitinase treatment following spinal contusion injury increases migration of oligodendrocyte progenitor cells. Exp Neurol. 231:19-29. PubMedCrossRefPubMedCentralGoogle Scholar
  97. Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5:146–156. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Sivasankaran R, Pei J, Wang KC, Zhang YP, Shields CB, Xu XM, He Z (2004) PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration. Nat Neurosci 7:261–268. CrossRefPubMedPubMedCentralGoogle Scholar
  99. Smith GM, Strunz C (2005) Growth factor and cytokine regulation of chondroitin sulfate proteoglycans by astrocytes. Glia 52:209-218. PubMedCrossRefPubMedCentralGoogle Scholar
  100. Sofroniew MV (2005) Reactive astrocytes in neural repair and protection. Neuroscientist. 11:400-407. PubMedCrossRefPubMedCentralGoogle Scholar
  101. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647. CrossRefPubMedPubMedCentralGoogle Scholar
  102. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35. CrossRefGoogle Scholar
  103. Stichel CC et al. (1999) Inhibition of collagen IV deposition promotes regeneration of injured CNS axons. Eur J Neurosci 11:632-646PubMedCrossRefPubMedCentralGoogle Scholar
  104. Su Z et al. (2011) Reactive astrocytes inhibit the survival and differentiation of oligodendrocyte precursor cells by secreted TNF-alpha Journal of neurotrauma 28:1089-1100. PubMedCrossRefPubMedCentralGoogle Scholar
  105. Terenghi G (1999) Peripheral nerve regeneration and neurotrophic factors. J Anat 194(Pt 1):1–14. CrossRefPubMedPubMedCentralGoogle Scholar
  106. Tysseling-Mattiace VM et al. (2008) Self-assembling nanofibers inhibit glial scar formation and promote axon elongation after spinal cord injury. J Neurosci 28:3814-3823. PubMedCrossRefGoogle Scholar
  107. Vermeiren C, Najimi M, Vanhoutte N, Tilleux S, de Hemptinne I, Maloteaux JM, Hermans E (2005) Acute up-regulation of glutamate uptake mediated by mGluR5a in reactive astrocytes. Journal Neurochem 94:405–416. CrossRefGoogle Scholar
  108. Wang Y, Cheng X, He Q, Zheng Y, Kim DH, Whittemore SR, Cao QL (2011) Astrocytes from the contused spinal cord inhibit oligodendrocyte differentiation of adult oligodendrocyte precursor cells by increasing the expression of bone morphogenetic proteins. J Neurosci 31:6053-6058. PubMedCrossRefGoogle Scholar
  109. Wang SM, Hsu JC, Ko CY, Chiu NE, Kan WM, Lai MD, Wang JM (2016) Astrocytic CCAAT/enhancer-binding protein delta contributes to glial scar formation and impairs functional recovery after spinal cord injury. Mol Neurobiol 53:5912-5927. PubMedPubMedCentralCrossRefGoogle Scholar
  110. Wehrle R, Camand E, Chedotal A, Sotelo C, Dusart I (2005) Expression of netrin-1, slit-1 and slit-3 but not of slit-2 after cerebellar and spinal cord lesions. Eur J Neurosci 22:2134-2144. PubMedCrossRefGoogle Scholar
  111. Wilhelmsson U et al. (2006) Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci USA. 103:17513-17518. CrossRefGoogle Scholar
  112. Yamaguchi Y, Mann DM, Ruoslahti E (1990) Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 346:281–284. CrossRefPubMedGoogle Scholar
  113. Yamane K et al (2018) Collagen-binding hepatocyte growth factor (HGF) alone or with a gelatin-furfurylamine hydrogel enhances functional recovery in mice after spinal cord injury. Scientific Rep 8:917. CrossRefGoogle Scholar
  114. Yang X, Geng K, Zhang J, Zhang Y, Shao J, Xia W (2017) Sirt3 mediates the inhibitory effect of adjudin on astrocyte activation and glial scar formation following ischemic stroke. Front Pharmacol 8:943. CrossRefPubMedPubMedCentralGoogle Scholar
  115. Yiu G, He Z (2003) Signaling mechanisms of the myelin inhibitors of axon regeneration. Curr Opin Neurobiol 13:545–551PubMedCrossRefGoogle Scholar
  116. Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, Barres BA (2012) Genomic analysis of reactive astrogliosis. J Neurosci 32:6391-6410. PubMedCrossRefGoogle Scholar
  117. Zhang R et al. (2018) RGMa mediates reactive astrogliosis and glial scar formation through TGFbeta1/Smad2/3 signaling after stroke. Cell Death Differ 25:1503-1516. CrossRefGoogle Scholar
  118. Zhu Z et al. (2007) Inhibiting cell cycle progression reduces reactive astrogliosis initiated by scratch injury in vitro and by cerebral ischemia in vivo. Glia 55:546-558. PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of PharmacyXuyi People’s HospitalXuyiPeople’s Republic of China

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