Deciphering glial scar after spinal cord injury
- Burns & Trauma Vol. 9, Issue 1, (2021)
- 作者机构：
1. Jiangsu Province Hospital of Chinese Medicine
2. Medical College of Nantong University
3. Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education
4. Nantong University
- 作者简介：
- 基金信息：
DOI：10.1093/burnst/tkab035
CLC：Published：2021，
Published Online：8 November 2021，
扫 描 看 全 文
Yu Zhang, Shuhai Yang, Chang Liu, Xiaoxiao Han, Xiaosong Gu, Songlin Zhou, Deciphering glial scar after spinal cord injury, Burns & Trauma, Volume 9, 2021, tkab035, https://doi.org/10.1093/burnst/tkab035
摘要
Abstract
Spinal cord injury (SCI) often leads to permanent disability
which is mainly caused by the loss of functional recovery. In this review
we aimed to investigate why the healing process is interrupted. One of the reasons for this interruption is the formation of a glial scar around the severely damaged tissue
which is usually covered by reactive glia
macrophages and fibroblasts. Aiming to clarify this issue
we summarize the latest research findings pertaining to scar formation
tissue repair
and the divergent roles of blood-derived monocytes/macrophages
ependymal cells
fibroblasts
microglia
oligodendrocyte progenitor cells (OPCs)
neuron-glial antigen 2 (NG2) and astrocytes during the process of scar formation
and further analyse the contribution of these cells to scar formation. In addition
we recapitulate the development of therapeutic treatments targeting glial scar components. Altogether
we aim to present a comprehensive decoding of the glial scar and explore potential therapeutic strategies for improving functional recovery after SCI.
关键词
Keywords
Spinal cord injuryGlial scarAxon regenerationTherapeutic strategy
references
1.Courtine G, Sofroniew MV. Spinal cord repair: advances in biology and technology. Nat Med. 2019;25:898–908.
2.He Y, Liu X, Chen Z. Glial scar-a promising target for improving outcomes after CNS injury. J Mol Neurosci. 2020;70:340–52.
3.Yu B, Yao C, Wang Y, Mao S, Wang Y, Wu R, et al. The landscape of gene expression and molecular regulation following spinal cord Hemisection in rats. Front Mol Neurosci. 2019;12:287.
4.Adams KL, Gallo V. The diversity and disparity of the glial scar. Nat Neurosci. 2018;21:9–15.
5.Sami A, Selzer ME, Li S. Advances in the Signaling pathways downstream of glial-scar axon growth inhibitors. Front Cell Neurosci. 2020;14:174.
6.Fang Y, Huang X, Wan Y, Tian H, Tian Y, Wang W, et al. Deficiency of TREK-1 potassium channel exacerbates secondary injury following spinal cord injury in mice. J Neurochem. 2017;141:236–46.
7.Lytle JM, Wrathall JR. Glial cell loss, proliferation and replacement in the contused murine spinal cord. Eur J Neurosci. 2007;25:1711–24.
8.Ropper AE, Ropper AH. Acute spinal cord compression. N Engl J Med. 2017;376:1358–69.
9.Zhang N, Yin Y, Xu SJ, Wu YP, Chen WS. Inflammation & apoptosis in spinal cord injury. Indian J Med Res. 2012;135:287–96.
10.Gao K, Shen Z, Yuan Y, Han D, Song C, Guo Y, et al. Simvastatin inhibits neural cell apoptosis and promotes locomotor recovery via activation of Wnt/β-catenin signaling pathway after spinal cord injury. J Neurochem. 2016;138:139–49.
11.He M, Ding Y, Chu C, Tang J, Xiao Q, Luo ZG. Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury. Proc Natl Acad Sci U S A. 2016;113:11324–9.
12.Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.
13.Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, De Zen F, et al. Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A. 2014;111:16836–41.
14.Cardoso BR, Hare DJ, Bush AI, Roberts BR. Glutathione peroxidase 4: a new player in neurodegeneration? Mol Psychiatry. 2017;22:328–35.
15.Imai H, Matsuoka M, Kumagai T, Sakamoto T, Koumura T. Lipid peroxidation-dependent cell death regulated by GPx4 and Ferroptosis. Curr Top Microbiol Immunol. 2017;403:143–70.
16.Zhang Y, Sun C, Zhao C, Hao J, Zhang Y, Fan B, et al. Ferroptosis inhibitor SRS 16-86 attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury. Brain Res. 1706;2019:48–57.
17.Hao J, Li B, Duan HQ, Zhao CX, Zhang Y, Sun C, et al. Mechanisms underlying the promotion of functional recovery by deferoxamine after spinal cord injury in rats. Neural Regen Res. 2017;12:959–68.
18.Maher P, van Leyen K, Dey PN, Honrath B, Dolga A, Methner A. The role of ca(2+) in cell death caused by oxidative glutamate toxicity and ferroptosis. Cell Calcium. 2018;70:47–55.
19.Hsu H, Shu HB, Pan MG, Goeddel DV. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell. 1996;84:299–308.
20.Grech AP, Gardam S, Chan T, Quinn R, Gonzales R, Basten A, et al. Tumor necrosis factor receptor 2 (TNFR2) signaling is negatively regulated by a novel, carboxyl-terminal TNFR-associated factor 2 (TRAF2)-binding site. J Biol Chem. 2005;280:31572–81.
21.Brenner D, Blaser H, Mak TW. Regulation of tumour necrosis factor signalling: live or let die. Nat Rev Immunol. 2015;15:362–74.
22.Fitch MT, Doller C, Combs CK, Landreth GE, Silver J. 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. 1999;19:8182–98.
23.Li Y, He X, Kawaguchi R, Zhang Y, Wang Q, Monavarfeshani A, et al. Microglia-organized scar-free spinal cord repair in neonatal mice. Nature. 2020;587:613–8.
24.Milich LM, Ryan CB, Lee JK. The origin, fate, and contribution of macrophages to spinal cord injury pathology. Acta Neuropathol. 2019;137:785–97.
25.Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci. 2009;29:13435–44.
26.Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci. 2013;16:273–80.
27.Askew K, Li K, Olmos-Alonso A, Garcia-Moreno F, Liang Y, Richardson P, et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep. 2017;18:391–405.
28.Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38:79–91.
29.Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR, 3rd, Lafaille JJ, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. 2013;155:1596–609.
30.Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, et al. Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. Brain. 2016;139:1265–81.
31.Bellver-Landete V, Bretheau F, Mailhot B, Vallières N, Lessard M, Janelle ME, et al. Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat Commun. 2019;10:518.
32.Li Y, He X, Kawaguchi R, Zhang Y, Wang Q, Monavarfeshani A, et al. Microglia-organized scar-free spinal cord repair in neonatal mice. Nature. 2020;587:613–18.
33.Kobashi S, Terashima T, Katagi M, et al. Transplantation of M2-Deviated Microglia Promotes Recovery of Motor Function after Spinal Cord Injury in Mice. Mol Ther. 2020;28:254–65.
34.Bartus K, Burnside ER, Galino J, James ND, Bennett DLH, Bradbury EJ. ErbB receptor signaling directly controls oligodendrocyte progenitor cell transformation and spontaneous remyelination after spinal cord injury. Glia. 2019;67:1036–46.
35.Dou CL, Levine JM. Inhibition of neurite growth by the NG2 chondroitin sulfate proteoglycan. J Neurosci. 1994;14:7616–28.
36.Schäfer MKE, Tegeder I. NG2/CSPG4 and progranulin in the posttraumatic glial scar. Matrix Biol. 2018;68-69:571–88.
37.Hackett AR, Lee JK. Understanding the NG2 glial scar after spinal cord injury. Front Neurol. 2016;7:199.
38.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.
39.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.
40.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.
41.Bei F, Lee HHC, Liu X, Gunner G, Jin H, Ma L, et al. Restoration of visual function by enhancing conduction in regenerated axons. Cell. 2016;164:219–32.
42.Hara M, Kobayakawa K, Ohkawa Y, Kumamaru H, Yokota K, Saito T, 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;23:818–28.
43.Hayakawa K, Esposito E, Wang X, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016;535:551–55.
44.Ren Y, Ao Y, O'Shea TM, Burda JE, Bernstein AM, Brumm AJ, et al. Ependymal cell contribution to scar formation after spinal cord injury is minimal, local and dependent on direct ependymal injury. Sci Rep. 2017;7:41122.
45.Li L, Ni L, Heary RF, Elkabes S. Astroglial TLR9 antagonism promotes chemotaxis and alternative activation of macrophages via modulation of astrocyte-derived signals: implications for spinal cord injury. J Neuroinflammation. 2020;17:73.
46.Yang J, Zhang L, Yu C, Yang XF, Wang H. Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res. 2014;2:1.
47.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.
48.Donnelly DJ, Longbrake EE, Shawler TM, Kigerl KA, Lai W, Tovar CA, et al. Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages. J Neurosci. 2011;31:9910–22.
49.Wang X, Cao K, Sun X, Chen Y, Duan Z, Sun L, et al. Macrophages in spinal cord injury: phenotypic and functional change from exposure to myelin debris. Glia. 2015;63:635–51.
50.Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci. 2013;16:1211–8.
51.Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front Physiol. 2018;9:419.
52.Noble LJ, Donovan F, Igarashi T, Goussev S, Werb Z. Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci. 2002;22:7526–35.
53.Lindborg JA, Mack M, Zigmond RE. Neutrophils are critical for myelin removal in a peripheral nerve injury model of Wallerian degeneration. J Neurosci. 2017;37:10258–77.
54.Torres-Espín A, Forero J, Fenrich KK, Lucas-Osma AM, Krajacic A, Schmidt E, et al. Eliciting inflammation enables successful rehabilitative training in chronic spinal cord injury. Brain. 2018;141:1946–62.
55.Tai W, Xu XM, Zhang CL. Regeneration through in vivo cell fate reprogramming for neural repair. Front Cell Neurosci. 2020;14:107.
56.Barnabé-Heider F, Göritz C, Sabelström 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.
57.Mothe AJ, Tator CH. Proliferation, migration, and differentiation of endogenous ependymal region stem/progenitor cells following minimal spinal cord injury in the adult rat. Neuroscience. 2005;131:177–87.
58.Li X, Floriddia EM, Toskas K, Fernandes KJL, Guérout N, Barnabé-Heider F. Regenerative potential of ependymal cells for spinal cord injuries over time. EBioMedicine. 2016;13:55–65.
59.Ma Y, Deng M, Zhao XQ, Liu M. Alternatively polarized macrophages regulate the growth and differentiation of ependymal stem cells through the SIRT2 pathway. Exp Neurobiol. 2020;29:150–63.
60.Llorens-Bobadilla E, Chell JM, Le Merre P, Wu Y, Zamboni M, Bergenstråhle J, et al. A latent lineage potential in resident neural stem cells enables spinal cord repair. Science. 2020;370:eabb8795.
61.Bradbury EJ, Burnside ER. Moving beyond the glial scar for spinal cord repair. Nat Commun. 2019;10:3879.
62.Dias DO, Kim H, Holl D, Werne Solnestam B, Lundeberg J, Carlén M, et al. Reducing Pericyte-derived scarring promotes recovery after spinal cord injury. Cell. 2018;173:153–165.e122.
63.Anderson MA, Burda JE, Ren Y, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature. 2016;532:195–200.
64.Bellver-Landete V, Bretheau F, Mailhot B, Vallières N, Lessard M, Janelle ME, et al. Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat Commun. 2019;10:518.
65.McKeon RJ, Schreiber RC, Rudge JS, Silver J. 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;11:3398–411.
66.Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature. 2002;416:636–40.
67.Lang BT, Cregg JM, DePaul MA, Tran AP, Xu K, Dyck SM, et al. Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury. Nature. 2015;518:404–8.
68.Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–7.
69.Silver J. The glial scar is more than just astrocytes. Exp Neurol. 2016;286:147–9.
70.Li X, Yang B, Xiao Z, Zhao Y, Han S, Yin Y, et al. Comparison of subacute and chronic scar tissues after complete spinal cord transection. Exp Neurol. 2018;306:132–7.
71.Zhao Y, Tang F, Xiao Z, Han G, Wang N, Yin N, 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;26:891–900.
72.Deng LX, Walker C, Xu XM. Schwann cell transplantation and descending propriospinal regeneration after spinal cord injury. Brain Res. 1619;2015:104–14.
73.Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W. Cell transplantation therapy for spinal cord injury. Nat Neurosci. 2017;20:637–47.
74.Priest CA, Manley NC, Denham J, Wirth ED, 3rd, Lebkowski JS. Preclinical safety of human embryonic stem cell-derived oligodendrocyte progenitors supporting clinical trials in spinal cord injury. Regen Med. 2015;10:939–58.
75.Mitsui T, Shumsky JS, Lepore AC, Murray M, Fischer I. Transplantation of neuronal and glial restricted precursors into contused spinal cord improves bladder and motor functions, decreases thermal hypersensitivity, and modifies intraspinal circuitry. J Neurosci. 2005;25:9624–36.
76.Bonner JF, Blesch A, Neuhuber B, Fischer I. Promoting directional axon growth from neural progenitors grafted into the injured spinal cord. J Neurosci Res. 2010;88:1182–92.
77.Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell. 2012;150:1264–73.
78.Lu P, Woodruff G, Wang Y, Graham L, Hunt M, Wu D, et al. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron. 2014;83:789–96.
79.Kadoya K, Lu P, Nguyen K, Lee-Kubli C, Kumamaru H, Yao L, et al. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med. 2016;22:479–87.
80.Brock JH, Graham L, Staufenberg E, Im S, Tuszynski MH. Rodent neural progenitor cells support functional recovery after cervical spinal cord contusion. J Neurotrauma. 2018;35:1069–78.
81.Rosenzweig ES, Brock JH, Lu P, Kumamaru H, Salegio EA, Kadoya K, et al. Restorative effects of human neural stem cell grafts on the primate spinal cord. Nat Med. 2018;24:484–90.
82.Poplawski GHD, Kawaguchi R, Van Niekerk E, Lu P, Mehta N, Canete P, et al. Injured adult neurons regress to an embryonic transcriptional growth state. Nature. 2020;581:77–82.
83.Anderson MA, O'Shea TM, Burda JE, Ao Y, Barlatey SL, Bernstein AM, et al. Required growth facilitators propel axon regeneration across complete spinal cord injury. Nature. 2018;561:396–400.
84.Letourneau PC. Cell-to-substratum adhesion and guidance of axonal elongation. Dev Biol. 1975;44:92–101.
85.Gundersen RW. Response of sensory neurites and growth cones to patterned substrata of laminin and fibronectin in vitro. Dev Biol. 1987;121:423–31.
86.Asher RA, Morgenstern DA, Moon LD, Fawcett JW. Chondroitin sulphate proteoglycans: inhibitory components of the glial scar. Prog Brain Res. 2001;132:611–9.
87.Zhao RR, Fawcett JW. Combination treatment with chondroitinase ABC in spinal cord injury--breaking the barrier. Neurosci Bull. 2013;29:477–83.
88.Hu HZ, Granger N, Pai SB, Bellamkonda RV, Jeffery ND. Therapeutic efficacy of microtube-embedded chondroitinase ABC in a canine clinical model of spinal cord injury. Brain. 2018;141:1017–27.
89.Shinozaki M, Iwanami A, Fujiyoshi K, Tashiro S, Kitamura K, Shibata S, et al. Combined treatment with chondroitinase ABC and treadmill rehabilitation for chronic severe spinal cord injury in adult rats. Neurosci Res. 2016;113:37–47.
90.Janzadeh A, Sarveazad A, Yousefifard M, Dameni S, Samani FS, Mokhtarian K, et al. Combine effect of Chondroitinase ABC and low level laser (660nm) on spinal cord injury model in adult male rats. Neuropeptides. 2017;65:90–9.
91.Bartus K, James ND, Didangelos A, Bosch KD, Verhaagen J, Yáñez-Muñoz RJ, et al. Large-scale chondroitin sulfate proteoglycan digestion with chondroitinase gene therapy leads to reduced pathology and modulates macrophage phenotype following spinal cord contusion injury. J Neurosci. 2014;34:4822–36.
92.Burnside ER, De Winter F, Didangelos A, James ND, Andreica EC, Layard-Horsfall H, et al. Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury. Brain. 2018;141:2362–81.
93.Gilmore SA. A study of neurological and morphological changes following x-irradiation of spinal cords of neonatal rats. J Ark Med Soc. 1963;59:375.
94.Miki T, Yokoyama T, Sumitani K, Wang ZY, Yang W, Kusaka T, et al. The effect of prenatal X-irradiation on the developing cerebral cortex of rats. II: a quantitative assessment of glial cells in the somatosensory cortex. Int J Dev Neurosci. 2007;25:293–7.
95.Philippo H, Winter EA, van der Kogel AJ, Huiskamp R. Recovery capacity of glial progenitors after in vivo fission-neutron or X irradiation: age dependence, fractionation and low-dose-rate irradiations. Radiat Res. 2005;163:636–43.
96.Kalderon N, Fuks Z. Severed corticospinal axons recover electrophysiologic control of muscle activity after x-ray therapy in lesioned adult spinal cord. Proc Natl Acad Sci U S A. 1996;93:11185–90.
97.Ning G, Chen R, Li Y, Wu Q, Wu Q, Li Y, et al. X-irradiation for inhibiting glial scar formation in injured spinal cord. Neural Regen Res. 2013;8:1582–9.
98.Mokalled MH, Patra C, Dickson AL, Endo T, Stainier DY, Poss KD. Injury-induced ctgfa directs glial bridging and spinal cord regeneration in zebrafish. Science. 2016;354:630–4.
99.Dulin JN, Adler AF, Kumamaru H, Poplawski GHD, Lee-Kubli C, Strobl H, et al. Injured adult motor and sensory axons regenerate into appropriate organotypic domains of neural progenitor grafts. Nat Commun. 2018;9:84.
100.Kumamaru H, Lu P, Rosenzweig ES, Kadoya K, Tuszynski MH. Regenerating corticospinal axons innervate phenotypically appropriate neurons within neural stem cell grafts. Cell Rep. 2019;26:2329–2339.e2324.
101.Qian H, Kang X, Hu J, Zhang D, Liang Z, Meng F, et al. Reversing a model of Parkinson's disease with in situ converted nigral neurons. Nature. 2020;582:550–6.
102.Gaudet AD, Fonken LK. Glial cells shape pathology and repair after spinal cord injury. Neurotherapeutics. 2018;15:554–77.
103.Suzuki H, Sakai T. Current concepts of stem cell therapy for chronic spinal cord injury. Int J Mol Sci. 2021;22:7435.
104.Wang X, Allen WE, Wright MA, et al. Three-dimensional intact-tissue sequencing of single-cell transcriptional states. Science. 2018;361:eaat5691.
0
Views
0
下载量
0
CSCD
- L-PDFDownload
- Meta-XMLDownload
- BibTeXDownload
- EndnoteDownload
- RefMan Download
- NoteExpressDownload
- NoteFirstDownload
Publicity Resources
Related Articles
Related Author
Related Institution
- Technical support is provided by Beijing Founder electronics co., LTD 京ICP备09064830号-19
京公网安备11010802024621 - It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
- Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.
