The role of glial scar on axonal regeneration after spinal cord injury_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

LI Xing , LI Jiayin , XIAO Zhifeng ,  DAI Jianwu

Institute of Genetics and Development Biology, Chinese Academy of Sciences, Beijing, 100101, P.R.China;

Corresponding author：

DAI Jianwu, Email: jwdai@genetics.ac.cn

Keywords：

Spinal cord injury; glial scar; inhibitory molecules; axonal regeneration

DOI：

10.7507/1002-1892.201806093

Video：

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The ‘glial scar’ has been widely studied in the regeneration of spinal cord injury (SCI). For decades, mainstream scientific concept considers glial scar as a ‘physical barrier’ to impede axonal regeneration after SCI. Moreover, some extracellular molecules produced by glial scar are also regarded as axonal growth inhibitors. With the development of technology and the progress of research, multiple lines of new evidence challenge the pre-existing traditional notions in SCI repair, including the role of glial scar. This review briefly reviewed the history, advance, and controversy of glial scar research in SCI repair since 1930s, hoping to recognize the roles of glial scar and crack the international problem of SCI regeneration.

Citation： LI Xing, LI Jiayin, XIAO Zhifeng, DAI Jianwu. The role of glial scar on axonal regeneration after spinal cord injury. Chinese Journal of Reparative and Reconstructive Surgery, 2018, 32(8): 973-978. doi: 10.7507/1002-1892.201806093 Copy

1.	Ahuja CS, Nori S, Tetreault L, et al. Traumatic spinal cord injury-repair and regeneration. Neurosurgery, 2017, 80(3S): S9-S22.
2.	Fitch MT, Silver J. CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Exp Neurol, 2008, 209(2): 294-301.
3.	Tuszynski MH, Steward O. Concepts and methods for the study of axonal regeneration in the CNS. Neuron, 2012, 74(5): 777-791.
4.	Sofroniew MV. Dissecting spinal cord regeneration. Nature, 2018, 557(7705): 343-350.
5.	Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci, 2006, 7(8): 617-627.
6.	O’Shea TM, Burda JE, Sofroniew MV. Cell biology of spinal cord injury and repair. J Clin Invest, 2017, 127(9): 3259-3270.
7.	Sabelström H, Stenudd M, Frisén J. Neural stem cells in the adult spinal cord. Exp Neurol, 2014, 260: 44-49.
8.	Raff MC, Miller RH, Noble M. A glial progenitor-cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture-medium. Nature, 1983, 303(5916): 390-396.
9.	Zhu XQ, Bergles DE, Nishiyama A. NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development, 2008, 135(1): 145-157.
10.	Zhu XQ, Hill RA, Dietrich D, et al. Age-dependent fate and lineage restriction of single NG2 cells. Development, 2011, 138(4): 745-753.
11.	Robins SC, Trudel E, Rotondi O, et al. Evidence for NG2-glia derived, adult-born functional neurons in the hypothalamus. PLoS One, 2013, 8(10): e78236.
12.	Guo F, Maeda Y, Ma J, et al. Pyramidal neurons are generated from oligodendroglial progenitor cells in adult piriform cortex. J Neurosci, 2010, 30(36): 12036-12049.
13.	Kang SH, Fukaya M, Yang JK, et al. NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron, 2010, 68(4): 668-681.
14.	Hackett AR, Yahn SL, Lyapichev K, et al. Injury type-dependent differentiation of NG2 glia into heterogeneous astrocytes. Exp Neurol, 2018, 308: 72-79.
15.	Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature, 2017, 541(7638): 481-487.
16.	Mathews A, Ohsawa K, Buckland ME, et al. Microglioma in a child-a further case in support of the microglioma entity and distinction from histiocytic sarcoma. Clin Neuropathol, 2016, 35(5): 302-313.
17.	Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol, 2013, 39(1): 3-18.
18.	Joers V, Tansey MG, Mulas G, et al. Microglial phenotypes in Parkinson’s disease and animal models of the disease. Prog Neurobiol, 2017, 155: 57-75.
19.	Shechter R, Schwartz M. Harnessing monocyte-derived macrophages to control central nervous system pathologies: no longer ‘if’ but ‘how’. J Pathol, 2013, 229(2): 332-346.
20.	Gensel JC, Zhang B. Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res, 2015, 1619: 1-11.
21.	Michell-Robinson MA, Touil H, Healy LM, et al. Roles of microglia in brain development, tissue maintenance and repair. Brain, 2015, 138(Pt 5): 1138-1159.
22.	Santiago Ramón y Cajal, Raoul M. May, Javier DeFelipe, et al. Cajal’s Degeneration and Regeneration of the Nervous System. Oxford: Oxford Univ. Press, 1992: 465.
23.	Clemente CD, Windle WF. Regeneration of severed nerve fibers in the spinal cord of the adult cat. J Comp Neurol, 1954, 101(3): 691-731.
24.	Arteta JL. Research on the regeneration of the spinal cord in the cat submitted to the action of pyrogenous substances (5 OR 3895) of bacterial origin. J Comp Neurol, 1956, 105(2): 171-184.
25.	Matthews MA, St Onge MF, Faciane CL, et al. Spinal cord transection: a quantitative analysis of elements of the connective tissue matrix formed within the site of lesion following administration of piromen, cytoxan or trypsin. Neuropathol Appl Neurobiol, 1979, 5(3): 161-180.
26.	He Z, Koprivica V. The Nogo signaling pathway for regeneration block. Annu Rev Neurosci, 2004, 27: 341-368.
27.	Schwab ME, Strittmatter SM. Nogo limits neural plasticity and recovery from injury. Curr Opin Neurobiol, 2014, 27: 53-60.
28.	Geoffroy CG, Zheng B. Myelin-associated inhibitors in axonal growth after CNS injury. Curr Opin Neurobiol, 2014, 27: 31-38.
29.	McKeon RJ, Schreiber RC, Rudge JS, 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. J Neurosci, 1991, 11(11): 3398-3411.
30.	Bradbury EJ, Moon LD, Popat RJ, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature, 2002, 416(6881): 636-640.
31.	García-Alías G, Barkhuysen S, Buckle M, et al. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat Neurosci, 2009, 12(9): 1145-1151.
32.	Barritt AW, Davies M, Marchand F, et al. Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury. J Neurosci, 2006, 26(42): 10856-10867.
33.	Lee H, McKeon RJ, Bellamkonda RV. Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury. Proc Natl Acad Sci U S A, 2010, 107(8): 3340-3345.
34.	Bowes C, Massey JM, Burish M, et al. Chondroitinase ABC promotes selective reactivation of somatosensory cortex in squirrel monkeys after a cervical dorsal column lesion. Proc Natl Acad Sci U S A, 2012, 109(7): 2595-2600.
35.	Zhao RR, Fawcett JW. Combination treatment with chondroitinase ABC in spinal cord injury—breaking the barrier. Neurosci Bull, 2013, 29(4): 477-483.
36.	Lang BT, Cregg JM, DePaul MA, et al. Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury. Nature, 2015, 518(7539): 404-408.
37.	Lu P, Jones LL, Tuszynski MH. Axon regeneration through scars and into sites of chronic spinal cord injury. Exp Neurol, 2007, 203(1): 8-21.
38.	Jones LL, Sajed D, Tuszynski MH. Axonal regeneration through regions of chondroitin sulfate proteoglycan deposition after spinal cord injury: a balance of permissiveness and inhibition. J Neurosci, 2003, 23(28): 9276-9288.
39.	Yang Z, Suzuki R, Daniels SB, et al. NG2 glial cells provide a favorable substrate for growing axons. J Neurosci, 2006, 26(14): 3829-3839.
40.	Anderson MA, Burda JE, Ren Y, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature, 2016, 532(7598): 195-200.
41.	de Castro R Jr, Tajrishi R, Claros J, et al. Differential responses of spinal axons to transection: influence of the NG2 proteoglycan. Exp Neurol, 2005, 192(2): 299-309.
42.	Schäfer MKE, Tegeder I. NG2/CSPG4 and progranulin in the posttraumatic glial scar. Matrix Biol, 2018, 68-69: 571-588.
43.	Silver J. The glial scar is more than just astrocytes. Exp Neurol, 2016, 286: 147-149.
44.	Li X, Yang B, Xiao Z, et al. Comparison of subacute and chronic scar tissues after complete spinal cord transection. Exp Neurol, 2018, 306: 132-137.
45.	Hara M, Kobayakawa K, Ohkawa Y, et al. Interaction of reactive astrocytes with type I collagen induces astrocytic scar formation through the integrin-N-cadherin pathway after spinal cord injury. Nat Med, 2017, 23(7): 818-828.
46.	Hara M, Kobayakawa K, Ohkawa Y, et al. Interaction of reactive astrocytes with type Ⅰ collagen induces astrocytic scar formation through the integrin-N-cadherin pathway after spinal cord injury. Nat Med, 2017, 23(7): 818-828.
47.	Donnelly DJ, Popovich PG. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol, 2008, 209(2): 378-388.
48.	Xiao Z, Tang F, Tang J, et al. One-year clinical study of NeuroRegen scaffold implantation following scar resection in complete chronic spinal cord injury patients. Sci China Life Sci, 2016, 59(7): 647-655.
49.	Zhao Y, Tang F, Xiao Z, et al. Clinical Study of NeuroRegen Scaffold Combined With Human Mesenchymal Stem Cells for the Repair of Chronic Complete Spinal Cord Injury. Cell Transplant, 2017, 26(5): 891-900.

1. Ahuja CS, Nori S, Tetreault L, et al. Traumatic spinal cord injury-repair and regeneration. Neurosurgery, 2017, 80(3S): S9-S22.
2. Fitch MT, Silver J. CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Exp Neurol, 2008, 209(2): 294-301.
3. Tuszynski MH, Steward O. Concepts and methods for the study of axonal regeneration in the CNS. Neuron, 2012, 74(5): 777-791.
4. Sofroniew MV. Dissecting spinal cord regeneration. Nature, 2018, 557(7705): 343-350.
5. Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci, 2006, 7(8): 617-627.
6. O’Shea TM, Burda JE, Sofroniew MV. Cell biology of spinal cord injury and repair. J Clin Invest, 2017, 127(9): 3259-3270.
7. Sabelström H, Stenudd M, Frisén J. Neural stem cells in the adult spinal cord. Exp Neurol, 2014, 260: 44-49.
8. Raff MC, Miller RH, Noble M. A glial progenitor-cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture-medium. Nature, 1983, 303(5916): 390-396.
9. Zhu XQ, Bergles DE, Nishiyama A. NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development, 2008, 135(1): 145-157.
10. Zhu XQ, Hill RA, Dietrich D, et al. Age-dependent fate and lineage restriction of single NG2 cells. Development, 2011, 138(4): 745-753.
11. Robins SC, Trudel E, Rotondi O, et al. Evidence for NG2-glia derived, adult-born functional neurons in the hypothalamus. PLoS One, 2013, 8(10): e78236.
12. Guo F, Maeda Y, Ma J, et al. Pyramidal neurons are generated from oligodendroglial progenitor cells in adult piriform cortex. J Neurosci, 2010, 30(36): 12036-12049.
13. Kang SH, Fukaya M, Yang JK, et al. NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron, 2010, 68(4): 668-681.
14. Hackett AR, Yahn SL, Lyapichev K, et al. Injury type-dependent differentiation of NG2 glia into heterogeneous astrocytes. Exp Neurol, 2018, 308: 72-79.
15. Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature, 2017, 541(7638): 481-487.
16. Mathews A, Ohsawa K, Buckland ME, et al. Microglioma in a child-a further case in support of the microglioma entity and distinction from histiocytic sarcoma. Clin Neuropathol, 2016, 35(5): 302-313.
17. Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol, 2013, 39(1): 3-18.
18. Joers V, Tansey MG, Mulas G, et al. Microglial phenotypes in Parkinson’s disease and animal models of the disease. Prog Neurobiol, 2017, 155: 57-75.
19. Shechter R, Schwartz M. Harnessing monocyte-derived macrophages to control central nervous system pathologies: no longer ‘if’ but ‘how’. J Pathol, 2013, 229(2): 332-346.
20. Gensel JC, Zhang B. Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res, 2015, 1619: 1-11.
21. Michell-Robinson MA, Touil H, Healy LM, et al. Roles of microglia in brain development, tissue maintenance and repair. Brain, 2015, 138(Pt 5): 1138-1159.
22. Santiago Ramón y Cajal, Raoul M. May, Javier DeFelipe, et al. Cajal’s Degeneration and Regeneration of the Nervous System. Oxford: Oxford Univ. Press, 1992: 465.
23. Clemente CD, Windle WF. Regeneration of severed nerve fibers in the spinal cord of the adult cat. J Comp Neurol, 1954, 101(3): 691-731.
24. Arteta JL. Research on the regeneration of the spinal cord in the cat submitted to the action of pyrogenous substances (5 OR 3895) of bacterial origin. J Comp Neurol, 1956, 105(2): 171-184.
25. Matthews MA, St Onge MF, Faciane CL, et al. Spinal cord transection: a quantitative analysis of elements of the connective tissue matrix formed within the site of lesion following administration of piromen, cytoxan or trypsin. Neuropathol Appl Neurobiol, 1979, 5(3): 161-180.
26. He Z, Koprivica V. The Nogo signaling pathway for regeneration block. Annu Rev Neurosci, 2004, 27: 341-368.
27. Schwab ME, Strittmatter SM. Nogo limits neural plasticity and recovery from injury. Curr Opin Neurobiol, 2014, 27: 53-60.
28. Geoffroy CG, Zheng B. Myelin-associated inhibitors in axonal growth after CNS injury. Curr Opin Neurobiol, 2014, 27: 31-38.
29. McKeon RJ, Schreiber RC, Rudge JS, 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. J Neurosci, 1991, 11(11): 3398-3411.
30. Bradbury EJ, Moon LD, Popat RJ, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature, 2002, 416(6881): 636-640.
31. García-Alías G, Barkhuysen S, Buckle M, et al. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat Neurosci, 2009, 12(9): 1145-1151.
32. Barritt AW, Davies M, Marchand F, et al. Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury. J Neurosci, 2006, 26(42): 10856-10867.
33. Lee H, McKeon RJ, Bellamkonda RV. Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury. Proc Natl Acad Sci U S A, 2010, 107(8): 3340-3345.
34. Bowes C, Massey JM, Burish M, et al. Chondroitinase ABC promotes selective reactivation of somatosensory cortex in squirrel monkeys after a cervical dorsal column lesion. Proc Natl Acad Sci U S A, 2012, 109(7): 2595-2600.
35. Zhao RR, Fawcett JW. Combination treatment with chondroitinase ABC in spinal cord injury—breaking the barrier. Neurosci Bull, 2013, 29(4): 477-483.
36. Lang BT, Cregg JM, DePaul MA, et al. Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury. Nature, 2015, 518(7539): 404-408.
37. Lu P, Jones LL, Tuszynski MH. Axon regeneration through scars and into sites of chronic spinal cord injury. Exp Neurol, 2007, 203(1): 8-21.
38. Jones LL, Sajed D, Tuszynski MH. Axonal regeneration through regions of chondroitin sulfate proteoglycan deposition after spinal cord injury: a balance of permissiveness and inhibition. J Neurosci, 2003, 23(28): 9276-9288.
39. Yang Z, Suzuki R, Daniels SB, et al. NG2 glial cells provide a favorable substrate for growing axons. J Neurosci, 2006, 26(14): 3829-3839.
40. Anderson MA, Burda JE, Ren Y, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature, 2016, 532(7598): 195-200.
41. de Castro R Jr, Tajrishi R, Claros J, et al. Differential responses of spinal axons to transection: influence of the NG2 proteoglycan. Exp Neurol, 2005, 192(2): 299-309.
42. Schäfer MKE, Tegeder I. NG2/CSPG4 and progranulin in the posttraumatic glial scar. Matrix Biol, 2018, 68-69: 571-588.
43. Silver J. The glial scar is more than just astrocytes. Exp Neurol, 2016, 286: 147-149.
44. Li X, Yang B, Xiao Z, et al. Comparison of subacute and chronic scar tissues after complete spinal cord transection. Exp Neurol, 2018, 306: 132-137.
45. Hara M, Kobayakawa K, Ohkawa Y, et al. Interaction of reactive astrocytes with type I collagen induces astrocytic scar formation through the integrin-N-cadherin pathway after spinal cord injury. Nat Med, 2017, 23(7): 818-828.
46. Hara M, Kobayakawa K, Ohkawa Y, et al. Interaction of reactive astrocytes with type Ⅰ collagen induces astrocytic scar formation through the integrin-N-cadherin pathway after spinal cord injury. Nat Med, 2017, 23(7): 818-828.
47. Donnelly DJ, Popovich PG. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol, 2008, 209(2): 378-388.
48. Xiao Z, Tang F, Tang J, et al. One-year clinical study of NeuroRegen scaffold implantation following scar resection in complete chronic spinal cord injury patients. Sci China Life Sci, 2016, 59(7): 647-655.
49. Zhao Y, Tang F, Xiao Z, et al. Clinical Study of NeuroRegen Scaffold Combined With Human Mesenchymal Stem Cells for the Repair of Chronic Complete Spinal Cord Injury. Cell Transplant, 2017, 26(5): 891-900.

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