Understanding the NG2 glial scar after spinal cord injury

Frontiers in Neurology

Volumn 7, Issue NOV, 2016, Pages

  Hackett, Amber R ^a   Lee, Jae K ^a  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

Astroglial scar; Axon regeneration; Oligodendrocyte progenitor cells; Oligodendrocytes; OPCs; Scar formation

Indexed keywords

CYTOKINE; PROTEOCHONDROITIN SULFATE;

ASTROGLIOGENESIS; CELL AGGREGATION; CELL FATE; CELL INFILTRATION; CELL PROLIFERATION; CENTRAL NERVOUS SYSTEM; GLIAL SCAR; HUMAN; HYPERTROPHY; INFLAMMATION; NERVE CELL DIFFERENTIATION; NERVE CELL PLASTICITY; NERVE FIBER REGENERATION; NERVE FUNCTION; NERVOUS SYSTEM DEVELOPMENT; NEUROPATHOLOGY; NONHUMAN; OLIGODENDROCYTE PROGENITOR; OLIGODENDROGENESIS; OLIGODENDROGLIA; PROTEIN ANALYSIS; PROTEIN EXPRESSION; REMYELINIZATION; REVIEW; SCAR FORMATION; SCHWANN CELL; SIGNAL TRANSDUCTION; SPINAL CORD INJURY; TISSUE REPAIR;

EID: 85006142014     PISSN: None     EISSN: 16642295     Source Type: Journal    
DOI: 10.3389/fneur.2016.00199     Document Type: Review

References (126)

1. Crowe MJ, Bresnahan JC, Shuman SL, Masters JN, Beattie MS. Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med (1997) 3:73-6. doi:10.1038/nm0197-73
2. McTigue DM, Wei P, Stokes BT. Proliferation of NG2-positive cells and altered oligodendrocyte numbers in the contused rat spinal cord. J Neurosci (2001) 21:3392-400.
3. Bunge RP, Puckett WR, Becerra JL, Marcillo A, Quencer RM. Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination. Adv Neurol (1993) 59:75-89.
4. Cao Q, Zhang YP, Iannotti C, Devries WH, Xu XM, Shields CB, et al. Functional and electrophysiological changes after graded traumatic spinal cord injury in adult rat. Exp Neurol (2005) 191(Suppl 1):S3-16. doi:10.1016/j.expneurol.2004.08.026
5. Guest JD, Hiester ED, Bunge RP. Demyelination and Schwann cell responses adjacent to injury epicenter cavities following chronic human spinal cord injury. Exp Neurol (2005) 192:384-93. doi:10.1016/j.expneurol.2004.11.033
6. Totoiu MO, Keirstead HS. Spinal cord injury is accompanied by chronic progressive demyelination. J Comp Neurol (2005) 486:373-83. doi:10.1002/cne.20517
7. Zai LJ, Wrathall JR. Cell proliferation and replacement following contusive spinal cord injury. Glia (2005) 50:247-57. doi:10.1002/glia.20176
8. Tripathi R, McTigue DM. Prominent oligodendrocyte genesis along the border of spinal contusion lesions. Glia (2007) 55:698-711. doi:10.1002/glia.20491
9. Sellers DL, Maris DO, Horner PJ. Postinjury niches induce temporal shifts in progenitor fates to direct lesion repair after spinal cord injury. J Neurosci (2009) 29:6722-33. doi:10.1523/JNEUROSCI.4538-08.2009
10. Barnabe-Heider F, Goritz C, Sabelstrom H, Takebayashi H, Pfrieger FW, Meletis K, et al. Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell (2010) 7:470-82. doi:10.1016/j.stem.2010.07.014
11. Powers BE, Sellers DL, Lovelett EA, Cheung W, Aalami SP, Zapertov N, et al. Remyelination reporter reveals prolonged refinement of spontaneously regenerated myelin. Proc Natl Acad Sci U S A (2013) 110:4075-80. doi:10.1073/pnas.1210293110
12. Crawford AH, Tripathi RB, Foerster S, Mckenzie I, Kougioumtzidou E, Grist M, et al. Pre-existing mature oligodendrocytes do not contribute to remyelination following toxin-induced spinal cord demyelination. Am J Pathol (2016) 186(3):511-6. doi:10.1016/j.ajpath.2015.11.005
13. Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, et al. PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci (2008) 11:1392-401. doi:10.1038/nn.2220
14. Lytle JM, Wrathall JR. Glial cell loss, proliferation and replacement in the contused murine spinal cord. Eur J Neurosci (2007) 25:1711-24. doi:10.1111/j.1460-9568.2007.05390.x
15. Almad A, Sahinkaya FR, Mctigue DM. Oligodendrocyte fate after spinal cord injury. Neurotherapeutics (2011) 8:262-73. doi:10.1007/s13311-011-0033-5
16. Miron VE, Kuhlmann T, Antel JP. Cells of the oligodendroglial lineage, myelination, and remyelination. Biochim Biophys Acta (2011) 1812:184-93. doi:10.1016/j.bbadis.2010.09.010
17. Franklin RJ, Goldman SA. Glia disease and repair-remyelination. Cold Spring Harb Perspect Biol (2015) 7:a020594. doi:10.1101/cshperspect.a020594
18. Levine JM. Increased expression of the NG2 chondroitin-sulfate proteoglycan after brain injury. J Neurosci (1994) 14:4716-30.
19. Dou CL, Levine JM. Inhibition of neurite growth by the NG2 chondroitin sulfate proteoglycan. J Neurosci (1994) 14:7616-28.
20. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci (2004) 24:2143-55. doi:10.1523/JNEUROSCI.3547-03.2004
21. Wanner IB, Anderson MA, Song B, Levine J, Fernandez A, Gray-Thompson Z, et al. Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J Neurosci (2013) 33:12870-86. doi:10.1523/JNEUROSCI.2121-13.2013
22. Brambilla R, Bracchi-Ricard V, Hu WH, Frydel B, Bramwell A, Karmally S, et al. Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med (2005) 202:145-56. doi:10.1084/jem.20041918
23. Pineau I, Sun L, Bastien D, Lacroix S. Astrocytes initiate inflammation in the injured mouse spinal cord by promoting the entry of neutrophils and inflammatory monocytes in an IL-1 receptor/MyD88-dependent fashion. Brain Behav Immun (2010) 24:540-53. doi:10.1016/j.bbi.2009.11.007
24. Rhodes KE, Raivich G, Fawcett JW. The injury response of oligodendrocyte precursor cells is induced by platelets, macrophages and inflammation-associated cytokines. Neuroscience (2006) 140:87-100. doi:10.1016/j.neuroscience.2006.01.055
25. Sahinkaya FR, Milich LM, Mctigue DM. Changes in NG2 cells and oligodendrocytes in a new model of intraspinal hemorrhage. Exp Neurol (2014) 255:113-26. doi:10.1016/j.expneurol.2014.02.025
26. Silver J, Schwab ME, Popovich PG. Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb Perspect Biol (2014) 7:a020602. doi:10.1101/cshperspect.a020602
27. Hughes EG, Kang SH, Fukaya M, Bergles DE. Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain. Nat Neurosci (2013) 16:668-76. doi:10.1038/nn.3390
28. Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci (2004) 5:146-56. doi:10.1038/nrn1326
29. Cregg JM, Depaul MA, Filous AR, Lang BT, Tran A, Silver J. Functional regeneration beyond the glial scar. Exp Neurol (2014) 253:197-207. doi:10.1016/j.expneurol.2013.12.024
30. Evans TA, Barkauskas DS, Myers JT, Hare EG, You JQ, Ransohoff RM, et al. High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury. Exp Neurol (2014) 254:109-20. doi:10.1016/j.expneurol.2014.01.013
31. Zhu Y, Soderblom C, Krishnan V, Ashbaugh J, Bethea JR, Lee JK. Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury. Neurobiol Dis (2015) 74:114-25. doi:10.1016/j.nbd.2014.10.024
32. Goritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, Frisen J. A pericyte origin of spinal cord scar tissue. Science (2011) 333:238-42. doi:10.1126/science.1203165
33. Soderblom C, Luo X, Blumenthal E, Bray E, Lyapichev K, Ramos J, et al. Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury. J Neurosci (2013) 33:13882-7. doi:10.1523/JNEUROSCI.2524-13.2013
34. Buss A, Pech K, Kakulas BA, Martin D, Schoenen J, Noth J, et al. NG2 and phosphacan are present in the astroglial scar after human traumatic spinal cord injury. BMC Neurol (2009) 9:32. doi:10.1186/1471-2377-9-32
35. Levine JM, Stallcup WB. Plasticity of developing cerebellar cells in vitro studied with antibodies against the NG2 antigen. J Neurosci (1987) 7:2721-31.
36. Stallcup WB, Beasley L. Bipotential glial precursor cells of the optic nerve express the NG2 proteoglycan. J Neurosci (1987) 7:2737-44.
37. Nishiyama A, Lin XH, Giese N, Heldin CH, Stallcup WB. Co-localization of NG2 proteoglycan and PDGF alpha-receptor on O2A progenitor cells in the developing rat brain. J Neurosci Res (1996) 43:299-314. doi:10.1002/(SICI)1097-4547(19960201)43:3<299::AID-JNR5>3.0.CO;2-E
38. Jones LL, Yamaguchi Y, Stallcup WB, Tuszynski MH. NG2 is a major chondroitin sulfate proteoglycan produced after spinal cord injury and is expressed by macrophages and oligodendrocyte progenitors. J Neurosci (2002) 22:2792-803.
39. McTigue DM, Tripathi R, Wei P. NG2 colocalizes with axons and is expressed by a mixed cell population in spinal cord lesions. J Neuropathol Exp Neurol (2006) 65:406-20. doi:10.1097/01.jnen.0000218447.32320.52
40. Levine J. The reactions and role of NG2 glia in spinal cord injury. Brain Res (2015) 1638(Pt B):199-208. doi:10.1016/j.brainres.2015.07.026
41. Dimou L, Simon C, Kirchhoff F, Takebayashi H, Gotz M. Progeny of Olig2-expressing progenitors in the gray and white matter of the adult mouse cerebral cortex. J Neurosci (2008) 28:10434-42. doi:10.1523/JNEUROSCI.2831-08.2008
42. Buffo A, Vosko MR, Erturk D, Hamann GF, Jucker M, Rowitch D, et al. Expression pattern of the transcription factor Olig2 in response to brain injuries: implications for neuronal repair. Proc Natl Acad Sci U S A (2005) 102:18183-8. doi:10.1073/pnas.0506535102
43. Lytle JM, Chittajallu R, Wrathall JR, Gallo V. NG2 cell response in the CNP-EGFP mouse after contusive spinal cord injury. Glia (2009) 57:270-85. doi:10.1002/glia.20755
44. Bu J, Akhtar N, Nishiyama A. Transient expression of the NG2 proteoglycan by a subpopulation of activated macrophages in an excitotoxic hippocampal lesion. Glia (2001) 34:296-310. doi:10.1002/glia.1063
45. Zhang SC. Defining glial cells during CNS development. Nat Rev Neurosci (2001) 2:840-3. doi:10.1038/35097593
46. Pozniak CD, Langseth AJ, Dijkgraaf GJ, Choe Y, Werb Z, Pleasure SJ. Sox10 directs neural stem cells toward the oligodendrocyte lineage by decreasing suppressor of fused expression. Proc Natl Acad Sci U S A (2010) 107:21795-800. doi:10.1073/pnas.1016485107
47. Kang SH, Fukaya M, Yang JK, Rothstein JD, Bergles DE. NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron (2010) 68:668-81. doi:10.1016/j.neuron.2010.09.009
48. Zhu X, Hill RA, Dietrich D, Komitova M, Suzuki R, Nishiyama A. Age-dependent fate and lineage restriction of single NG2 cells. Development (2011) 138:745-53. doi:10.1242/dev.047951
49. Hackett AR, Lee DH, Dawood A, Rodriguez M, Funk L, Tsoulfas P, et al. STAT3 and SOCS3 regulate NG2 cell proliferation and differentiation after contusive spinal cord injury. Neurobiol Dis (2016) 89:10-22. doi:10.1016/j.nbd.2016.01.017
50. Honsa P, Pivonkova H, Dzamba D, Filipova M, Anderova M. Polydendrocytes display large lineage plasticity following focal cerebral ischemia. PLoS One (2012) 7:e36816. doi:10.1371/journal.pone.0036816
51. Tatsumi K, Takebayashi H, Manabe T, Tanaka KF, Makinodan M, Yamauchi T, et al. Genetic fate mapping of Olig2 progenitors in the injured adult cerebral cortex reveals preferential differentiation into astrocytes. J Neurosci Res (2008) 86:3494-502. doi:10.1002/jnr.21862
52. Birey F, Aguirre A. Age-dependent netrin-1 signaling regulates NG2+ glial cell spatial homeostasis in normal adult gray matter. J Neurosci (2015) 35:6946-51. doi:10.1523/JNEUROSCI.0356-15.2015
53. Keirstead HS, Levine JM, Blakemore WF. Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord. Glia (1998) 22:161-70. doi:10.1002/(SICI)1098-1136(199802)22:2<161::AID-GLIA7>3.0.CO;2-A
54. Hill RA, Patel KD, Goncalves CM, Grutzendler J, Nishiyama A. Modulation of oligodendrocyte generation during a critical temporal window after NG2 cell division. Nat Neurosci (2014) 17:1518-27. doi:10.1038/nn.3815
55. Gibson EM, Purger D, Mount CW, Goldstein AK, Lin GL, Wood LS, et al. Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science (2014) 344:1252304. doi:10.1126/science.1252304
56. Wolswijk G, Noble M. Cooperation between PDGF and FGF converts slowly dividing O-2Aadult progenitor cells to rapidly dividing cells with characteristics of O-2Aperinatal progenitor cells. J Cell Biol (1992) 118:889-900. doi:10.1083/jcb.118.4.889
57. Tripathi RB, McTigue DM. Chronically increased ciliary neurotrophic factor and fibroblast growth factor-2 expression after spinal contusion in rats. J Comp Neurol (2008) 510:129-44. doi:10.1002/cne.21787
58. Zai LJ, Yoo S, Wrathall JR. Increased growth factor expression and cell proliferation after contusive spinal cord injury. Brain Res (2005) 1052:147-55. doi:10.1016/j.brainres.2005.05.071
59. Whittaker MT, Zai LJ, Lee HJ, Pajoohesh-Ganji A, Wu J, Sharp A, et al. GGF2 (Nrg1-beta3) treatment enhances NG2+ cell response and improves functional recovery after spinal cord injury. Glia (2012) 60:281-94. doi:10.1002/glia.21262
60. Fernandez-Martos CM, Gonzalez-Fernandez C, Gonzalez P, Maqueda A, Arenas E, Rodriguez FJ. Differential expression of Wnts after spinal cord contusion injury in adult rats. PLoS One (2011) 6:e27000. doi:10.1371/journal.pone.0027000
61. Furusho M, Roulois AJ, Franklin RJ, Bansal R. Fibroblast growth factor signaling in oligodendrocyte-lineage cells facilitates recovery of chronically demyelinated lesions but is redundant in acute lesions. Glia (2015) 63:1714-28. doi:10.1002/glia.22838
62. Kasai M, Jikoh T, Fukumitsu H, Furukawa S. FGF-2-responsive and spinal cord-resident cells improve locomotor function after spinal cord injury. J Neurotrauma (2014) 31:1584-98. doi:10.1089/neu.2009.1108
63. Canoll PD, Musacchio JM, Hardy R, Reynolds R, Marchionni MA, Salzer JL. GGF/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors. Neuron (1996) 17:229-43. doi:10.1016/S0896-6273(00)80155-5
64. Cannella B, Hoban CJ, Gao YL, Garcia-Arenas R, Lawson D, Marchionni M, et al. The neuregulin, glial growth factor 2, diminishes autoimmune demyelination and enhances remyelination in a chronic relapsing model for multiple sclerosis. Proc Natl Acad Sci U S A (1998) 95:10100-5. doi:10.1073/pnas.95.17.10100
65. Fancy SP, Baranzini SE, Zhao C, Yuk DI, Irvine KA, Kaing S, et al. Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes Dev (2009) 23:1571-85. doi:10.1101/gad.1806309
66. Rodriguez JP, Coulter M, Miotke J, Meyer RL, Takemaru K, Levine JM. Abrogation of beta-catenin signaling in oligodendrocyte precursor cells reduces glial scarring and promotes axon regeneration after CNS injury. J Neurosci (2014) 34:10285-97. doi:10.1523/JNEUROSCI.4915-13.2014
67. Mayer M, Bhakoo K, Noble M. Ciliary neurotrophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro. Development (1994) 120:143-53.
68. Barres BA, Burne JF, Holtmann B, Thoenen H, Sendtner M, Raff MC. Ciliary neurotrophic factor enhances the rate of oligodendrocyte generation. Mol Cell Neurosci (1996) 8:146-56. doi:10.1006/mcne.1996.0053
69. Ishibashi T, Lee PR, Fields RD. Leukemia inhibitory factor regulates the timing of oligodendrocyte development and myelination in the postnatal optic nerve. J Neurosci Res (2009) 87:3343-55. doi:10.1002/jnr.22173
70. Kuhlmann T, Remington L, Cognet I, Bourbonniere L, Zehntner S, Guilhot F, et al. Continued administration of ciliary neurotrophic factor protects mice from inflammatory pathology in experimental autoimmune encephalomyelitis. Am J Pathol (2006) 169:584-98. doi:10.2353/ajpath.2006.051086
71. Steelman AJ, Zhou Y, Koito H, Kim S, Payne HR, Lu QR, et al. Activation of oligodendroglial Stat3 is required for efficient remyelination. Neurobiol Dis (2016) 91:336-46. doi:10.1016/j.nbd.2016.03.023
72. Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP. TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci (2001) 4:1116-22. doi:10.1038/nn738
73. Madsen PM, Motti D, Karmally S, Szymkowski DE, Lambertsen KL, Bethea JR, et al. Oligodendroglial TNFR2 mediates membrane TNF-dependent repair in experimental autoimmune encephalomyelitis by promoting oligodendrocyte differentiation and remyelination. J Neurosci (2016) 36:5128-43. doi:10.1523/JNEUROSCI.0211-16.2016
74. Novrup HG, Bracchi-Ricard V, Ellman DG, Ricard J, Jain A, Runko E, et al. Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice. J Neuroinflammation (2014) 11:159. doi:10.1186/s12974-014-0159-6
75. Molofsky AV, Deneen B. Astrocyte development: a guide for the perplexed. Glia (2015) 63:1320-9. doi:10.1002/glia.22836
76. Bergles DE, Richardson WD. Oligodendrocyte development and plasticity. Cold Spring Harb Perspect Biol (2016) 8:a020453. doi:10.1101/cshperspect.a020453
77. 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) 303:390-6. doi:10.1038/303390a0
78. Zhu X, Bergles DE, Nishiyama A. NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development (2008) 135:145-57. doi:10.1242/dev.004895
79. Zhu X, Hill RA, Nishiyama A. NG2 cells generate oligodendrocytes and gray matter astrocytes in the spinal cord. Neuron Glia Biol (2008) 4:19-26. doi:10.1017/S1740925X09000015
80. Komitova M, Serwanski DR, Lu QR, Nishiyama A. NG2 cells are not a major source of reactive astrocytes after neocortical stab wound injury. Glia (2011) 59:800-9. doi:10.1002/glia.21152
81. Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, et al. Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science (1997) 278:477-83. doi:10.1126/science.278.5337.477
82. Rajan P, McKay RD. Multiple routes to astrocytic differentiation in the CNS. J Neurosci (1998) 18:3620-9.
83. Fukuda S, Kondo T, Takebayashi H, Taga T. Negative regulatory effect of an oligodendrocytic bHLH factor OLIG2 on the astrocytic differentiation pathway. Cell Death Differ (2004) 11:196-202. doi:10.1038/sj.cdd.4401332
84. Setoguchi T, Kondo T. Nuclear export of OLIG2 in neural stem cells is essential for ciliary neurotrophic factor-induced astrocyte differentiation. J Cell Biol (2004) 166:963-8. doi:10.1083/jcb.200404104
85. Mabie PC, Mehler MF, Marmur R, Papavasiliou A, Song Q, Kessler JA. Bone morphogenetic proteins induce astroglial differentiation of oligodendroglial-astroglial progenitor cells. J Neurosci (1997) 17:4112-20.
86. Hampton DW, Asher RA, Kondo T, Steeves JD, Ramer MS, Fawcett JW. A potential role for bone morphogenetic protein signalling in glial cell fate determination following adult central nervous system injury in vivo. Eur J Neurosci (2007) 26:3024-35. doi:10.1111/j.1460-9568.2007.05940.x
87. Wang Y, Cheng X, He Q, Zheng Y, Kim DH, Whittemore SR, et al. Astrocytes from the contused spinal cord inhibit oligodendrocyte differentiation of adult oligodendrocyte precursor cells by increasing the expression of bone morphogenetic proteins. J Neurosci (2011) 31:6053-8. doi:10.1523/JNEUROSCI.5524-09.2011
88. Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, et al. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science (1999) 284:479-82.
89. Bugga L, Gadient RA, Kwan K, Stewart CL, Patterson PH. Analysis of neuronal and glial phenotypes in brains of mice deficient in leukemia inhibitory factor. J Neurobiol (1998) 36:509-24.
90. Nakashima K, Wiese S, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, et al. Developmental requirement of gp130 signaling in neuronal survival and astrocyte differentiation. J Neurosci (1999) 19:5429-34.
91. Zhu X, Zuo H, Maher BJ, Serwanski DR, Loturco JJ, Lu QR, et al. Olig2-dependent developmental fate switch of NG2 cells. Development (2012) 139:2299-307. doi:10.1242/dev.078873
92. Bresnahan JC. An electron-microscopic analysis of axonal alterations following blunt contusion of the spinal cord of the rhesus monkey (Macaca mulatta). J Neurol Sci (1978) 37:59-82. doi:10.1016/0022-510X(78)90228-9
93. Bunge MB, Holets VR, Bates ML, Clarke TS, Watson BD. Characterization of photochemically induced spinal cord injury in the rat by light and electron microscopy. Exp Neurol (1994) 127:76-93. doi:10.1006/exnr.1994.1082
94. Zawadzka M, Rivers LE, Fancy SP, Zhao C, Tripathi R, Jamen F, et al. CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell (2010) 6:578-90. doi:10.1016/j.stem.2010.04.002
95. Bartus K, Galino J, James ND, Hernandez-Miranda LR, Dawes JM, Fricker FR, et al. Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury. Brain (2016) 139(Pt 5):1394-416. doi:10.1093/brain/aww039
96. Doucette R. PNS-CNS transitional zone of the first cranial nerve. J Comp Neurol (1991) 312:451-66. doi:10.1002/cne.903120311
97. Jones LL, Margolis RU, Tuszynski MH. The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury. Exp Neurol (2003) 182:399-411. doi:10.1016/S0014-4886(03)00087-6
98. McKeon RJ, Jurynec MJ, Buck CR. The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar. J Neurosci (1999) 19:10778-88.
99. Asher RA, Morgenstern DA, Fidler PS, Adcock KH, Oohira A, Braistead JE, et al. Neurocan is upregulated in injured brain and in cytokine-treated astrocytes. J Neurosci (2000) 20:2427-38.
100. Asher RA, Morgenstern DA, Shearer MC, Adcock KH, Pesheva P, Fawcett JW. Versican is upregulated in CNS injury and is a product of oligodendrocyte lineage cells. J Neurosci (2002) 22:2225-36.
101. Crespo D, Asher RA, Lin R, Rhodes KE, Fawcett JW. How does chondroitinase promote functional recovery in the damaged CNS? Exp Neurol (2007) 206:159-71. doi:10.1016/j.expneurol.2007.05.001
102. Asher RA, Morgenstern DA, Properzi F, Nishiyama A, Levine JM, Fawcett JW. Two separate metalloproteinase activities are responsible for the shedding and processing of the NG2 proteoglycan in vitro. Mol Cell Neurosci (2005) 29:82-96. doi:10.1016/j.mcn.2005.02.001
103. Tan AM, Colletti M, Rorai AT, Skene JH, Levine JM. Antibodies against the NG2 proteoglycan promote the regeneration of sensory axons within the dorsal columns of the spinal cord. J Neurosci (2006) 26:4729-39. doi:10.1523/JNEUROSCI.3900-05.2006
104. Petrosyan HA, Hunanyan AS, Alessi V, Schnell L, Levine J, Arvanian VL. Neutralization of inhibitory molecule NG2 improves synaptic transmission, retrograde transport, and locomotor function after spinal cord injury in adult rats. J Neurosci (2013) 33:4032-43. doi:10.1523/JNEUROSCI.4702-12.2013
105. Lee JK, Chow R, Xie F, Chow SY, Tolentino KE, Zheng B. Combined genetic attenuation of myelin and semaphorin-mediated growth inhibition is insufficient to promote serotonergic axon regeneration. J Neurosci (2010) 30:10899-904. doi:10.1523/JNEUROSCI.2269-10.2010
106. Zukor K, Belin S, Wang C, Keelan N, Wang X, He Z. Short hairpin RNA against PTEN enhances regenerative growth of corticospinal tract axons after spinal cord injury. J Neurosci (2013) 33:15350-61. doi:10.1523/JNEUROSCI.2510-13.2013
107. Anderson MA, Burda JE, Ren Y, Ao Y, O'shea TM, Kawaguchi R, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature (2016) 532:195-200. doi:10.1038/nature17623
108. Yang Z, Suzuki R, Daniels SB, Brunquell CB, Sala CJ, Nishiyama A. NG2 glial cells provide a favorable substrate for growing axons. J Neurosci (2006) 26:3829-39. doi:10.1523/JNEUROSCI.4247-05.2006
109. 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) 23:9276-88.
110. Williams RR, Henao M, Pearse DD, Bunge MB. Permissive Schwann cell graft/spinal cord interfaces for axon regeneration. Cell Transplant (2015) 24:115-31. doi:10.3727/096368913X674657
111. de Castro R Jr, Tajrishi R, Claros J, Stallcup WB. Differential responses of spinal axons to transection: influence of the NG2 proteoglycan. Exp Neurol (2005) 192:299-309. doi:10.1016/j.expneurol.2004.11.027
112. Filous AR, Tran A, Howell CJ, Busch SA, Evans TA, Stallcup WB, et al. Entrapment via synaptic-like connections between NG2 proteoglycan+ cells and dystrophic axons in the lesion plays a role in regeneration failure after spinal cord injury. J Neurosci (2014) 34:16369-84. doi:10.1523/JNEUROSCI.1309-14.2014
113. Han SB, Kim H, Skuba A, Tessler A, Ferguson T, Son YJ. Sensory axon regeneration: a review from an in vivo imaging perspective. Exp Neurobiol (2012) 21:83-93. doi:10.5607/en.2012.21.3.83
114. Son YJ. Synapsing with NG2 cells (polydendrocytes), unappreciated barrier to axon regeneration? Neural Regen Res (2015) 10:346-8. doi:10.4103/1673-5374.153672
115. Bergles DE, Roberts JD, Somogyi P, Jahr CE. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature (2000) 405:187-91. doi:10.1038/35012083
116. Busch SA, Horn KP, Cuascut FX, Hawthorne AL, Bai L, Miller RH, et al. Adult NG2+ cells are permissive to neurite outgrowth and stabilize sensory axons during macrophage-induced axonal dieback after spinal cord injury. J Neurosci (2010) 30:255-65. doi:10.1523/JNEUROSCI.3705-09.2010
117. Di Maio A, Skuba A, Himes BT, Bhagat SL, Hyun JK, Tessler A, et al. In vivo imaging of dorsal root regeneration: rapid immobilization and presynaptic differentiation at the CNS/PNS border. J Neurosci (2011) 31:4569-82. doi:10.1523/JNEUROSCI.4638-10.2011
118. Lau LT, Yu AC. Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury. J Neurotrauma (2001) 18:351-9. doi:10.1089/08977150151071035
119. Brambilla R, Persaud T, Hu X, Karmally S, Shestopalov VI, Dvoriantchikova G, et al. Transgenic inhibition of astroglial NF-kappa B improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J Immunol (2009) 182:2628-40. doi:10.4049/jimmunol.0802954
120. Brambilla R, Morton PD, Ashbaugh JJ, Karmally S, Lambertsen KL, Bethea JR. Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination. Glia (2014) 62:452-67. doi:10.1002/glia.22616
121. Choi SS, Lee HJ, Lim I, Satoh J, Kim SU. Human astrocytes: secretome profiles of cytokines and chemokines. PLoS One (2014) 9:e92325. doi:10.1371/journal.pone.0092325
122. Kim RY, Hoffman AS, Itoh N, Ao Y, Spence R, Sofroniew MV, et al. Astrocyte CCL2 sustains immune cell infiltration in chronic experimental autoimmune encephalomyelitis. J Neuroimmunol (2014) 274:53-61. doi:10.1016/j.jneuroim.2014.06.009
123. Mills Ko E, Ma JH, Guo F, Miers L, Lee E, Bannerman P, et al. Deletion of astroglial CXCL10 delays clinical onset but does not affect progressive axon loss in a murine autoimmune multiple sclerosis model. J Neuroinflammation (2014) 11:105. doi:10.1186/1742-2094-11-105
124. Kang Z, Wang C, Zepp J, Wu L, Sun K, Zhao J, et al. Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells. Nat Neurosci (2013) 16:1401-8. doi:10.1038/nn.3505
125. Tirotta E, Ransohoff RM, Lane TE. CXCR2 signaling protects oligodendrocyte progenitor cells from IFN-gamma/CXCL10-mediated apoptosis. Glia (2011) 59:1518-28. doi:10.1002/glia.21195
126. Moyon S, Dubessy AL, Aigrot MS, Trotter M, Huang JK, Dauphinot L, et al. Demyelination causes adult CNS progenitors to revert to an immature state and express immune cues that support their migration. J Neurosci (2015) 35:4-20. doi:10.1523/JNEUROSCI.0849-14.2015