- Institute of Genetics and Development Biology, Chinese Academy of Sciences, Beijing, 100101,P.R.China;
Spinal cord injury (SCI), especially the complete SCI, usually results in complete paralysis below the level of the injury and seriously affects the patient’s quality of life. SCI repair is still a worldwide medical problem. In the last twenty years, Professor DAI Jianwu and his team pioneered complete SCI model by removing spinal tissue with varied lengths in rodents, canine, and non-human primates to verify therapeutic effect of different repair strategies. Moreover, they also started the first clinical study of functional collagen scaffold on patients with acute complete SCI on January 16th, 2015. This review mainly focusses on the possible mechanisms responsible for complete SCI. In common, recovery of some sensory and motor functions post complete SCI include the following three contributing reasons. ① Regeneration of long ascending and descending axons throughout the lesion site to re-connect the original targets; ② New neural circuits formed in the lesion site by newly generated neurons post injury, which effectively re-connect the transected stumps; ③ The combined effect of ① and ②. The numerous studies have confirmed that neural circuits rebuilt across the injury site by newborn neurons might be the main mechanisms for functional recovery of animals from rodents to dogs. In many SCI model, especially the complete spinal cord transection model, many studies have convincingly demonstrated that the quantity and length of regenerated long descending axons, particularly like CST fibers, are too few to across the lesion site that is millimeters in length to realize motor functional recovery. Hence, it is more feasible in guiding neuronal relays formation by bio-scaffolds implantation than directing long motor axons regeneration in improving motor function of animals with complete spinal cord transection. However, some other issues such as promoting more neuronal relays formation, debugging wrong connections, and maintaining adequate neural circuits for functional recovery are urgent problems to be addressed.
Citation: LI Jiayin, LI Xing, XIAO Zhifeng, DAI Jianwu. Review of the regeneration mechanism of complete spinal cord injury. Chinese Journal of Reparative and Reconstructive Surgery, 2018, 32(6): 641-649. doi: 10.7507/1002-1892.201805069 Copy
1. | Thuret S, Moon L, Gage FH. Therapeutic interventions after spinal cord injury. Nature Reviews Neuroscience, 2006, 7(8): 628-643. |
2. | Ahuja CS, Wilson JR, Nori S, et al. Traumatic spinal cord injury. Nat Rev Dis Primers, 2017, 3: 17018. |
3. | He Z, Koprivica V. The Nogo signaling pathway for regeneration block. Annu Rev Neurosci, 2004, 27: 341-368. |
4. | Filbin MT. Recapitulate development to promote axonal regeneration: good or bad approach? Philos Trans R Soc Lond B Biol Sci, 2006, 361(1473): 1565-1574. |
5. | Fitch MT, Silver J. CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Exp Neurol, 2008, 209(2): 294-301. |
6. | Kadoya K, Tsukada S, Lu P, et al. Combined intrinsic and extrinsic neuronal mechanisms facilitate bridging axonal regeneration one year after spinal cord injury. Neuron, 2009, 64(2): 165-172. |
7. | Giger RJ, Venkatesh K, Chivatakarn O, et al. Mechanisms of CNS myelin inhibition: evidence for distinct and neuronal cell type specific receptor systems. Restor Neurol Neurosci, 2008, 26(2-3): 97-115. |
8. | Sun F, He Z. Neuronal intrinsic barriers for axon regeneration in the adult CNS. Curr Opin Neurobiol, 2010, 20(4): 510-518. |
9. | Liu K, Tedeschi A, Park KK, et al. Neuronal intrinsic mechanisms of axon regeneration. Annu Rev Neurosci, 2011, 34: 131-152. |
10. | McCreedy DA, Sakiyama-Elbert SE. Combination therapies in the CNS: engineering the environment. Neurosci Lett, 2012, 519(2): 115-121. |
11. | Tedeschi A, Bradke F. Spatial and temporal arrangement of neuronal intrinsic and extrinsic mechanisms controlling axon regeneration. Curr Opin Neurobiol, 2017, 42: 118-127. |
12. | Selvarajah S, Hammond ER, Haider AH, et al. The burden of acute traumatic spinal cord injury among adults in the united states: an update. J Neurotrauma, 2014, 31(3): 228-238. |
13. | Wilson JR, Forgione N, Fehlings MG. Emerging therapies for acute traumatic spinal cord injury. Canadian Medical Association Journal, 2013, 185(6): 485-492. |
14. | Dvorak MF, Noonan VK, Fallah N, et al. The influence of time from injury to surgery on motor recovery and length of hospital stay in acute traumatic spinal cord injury: an observational Canadian cohort study. J Neurotrauma, 2015, 32(9): 645-654. |
15. | Giger RJ, Hollis ER 2nd, Tuszynski MH. Guidance molecules in axon regeneration. Cold Spring Harb Perspect Biol, 2010, 2(7): a001867. |
16. | Kwon BK, Oxland TR, Tetzlaff W. Animal models used in spinal cord regeneration research. Spine (Phila Pa 1976), 2002, 27(14): 1504-1510. |
17. | Akhtar AZ, Pippin JJ, Sandusky CB. Animal models in spinal cord injury: a review. Rev Neurosci, 2008, 19(1): 47-60. |
18. | Han Q, Jin W, Xiao Z, et al. The promotion of neural regeneration in an extreme rat spinal cord injury model using a collagen scaffold containing a collagen binding neuroprotective protein and an EGFR neutralizing antibody. Biomaterials, 2010, 31(35): 9212-9220. |
19. | Jeffery ND, Lakatos A, Franklin RJ. Autologous olfactory glial cell transplantation is reliable and safe in naturally occurring canine spinal cord injury. J Neurotrauma, 2005, 22(11): 1282-1293. |
20. | Han S, Li X, Xiao Z, et al. Complete canine spinal cord transection model: a large animal model for the translational research of spinal cord regeneration. Sci China Life Sci, 2018, 61(1): 115-117. |
21. | Raineteau O, Schwab ME. Plasticity of motor systems after incomplete spinal cord injury. Nat Rev Neurosci, 2001, 2(4): 263-273. |
22. | Courtine G, Song B, Roy RR, et al. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat Med, 2008, 14(1): 69-74. |
23. | Rosenzweig ES, Courtine G, Jindrich DL, et al. Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nat Neurosci, 2010, 13(12): 1505-1510. |
24. | Li X, Han J, Zhao Y, et al. Functionalized collagen scaffold neutralizing the myelin-inhibitory molecules promoted neurites outgrowth in vitro and facilitated spinal cord regeneration in vivo. ACS Appl Mater Interfaces, 2015, 7(25): 13960-13971. |
25. | Li X, Han J, Zhao Y, et al. Functionalized collagen scaffold implantation and cAMP administration collectively facilitate spinal cord regeneration. Acta Biomater, 2016, 30: 233-245. |
26. | Fan C, Li X, Xiao Z, et al. A modified collagen scaffold facilitates endogenous neurogenesis for acute spinal cord injury repair. Acta Biomater, 2017, 51: 304-316. |
27. | Xu B, Zhao Y, Xiao Z, et al. A Dual Functional Scaffold Tethered with EGFR Antibody Promotes Neural Stem Cell Retention and Neuronal Differentiation for Spinal Cord Injury Repair. Adv Healthc Mater, 2017, 6(9): 12. |
28. | Wang N, Xiao Z, Zhao Y, et al. Collagen scaffold combined with human umbilical cord-derived mesenchymal stem cells promote functional recovery after scar resection in rats with chronic spinal cord injury. J Tissue Eng Regen Med, 2018, 12(2): e1154-e1163. |
29. | Li, X, Liu SM, Zhao YN, et al. Training neural stem cells on functional collagen scaffolds for severe spinal cord injury repair. Advanced Functional Materials, 2016, 26(32): 5835-5847. |
30. | Zhao Y, Xiao Z, Chen B, et al. The neuronal differentiation microenvironment is essential for spinal cord injury repair. Organogenesis, 2017, 13(3): 63-70. |
31. | Han S, Wang B, Jin W, et al. The collagen scaffold with collagen binding BDNF enhances functional recovery by facilitating peripheral nerve infiltrating and ingrowth in canine complete spinal cord transection. Spinal Cord, 2014, 52(12): 867-873. |
32. | Han S, Wang B, Jin W, et al. The linear-ordered collagen scaffold-BDNF complex significantly promotes functional recovery after completely transected spinal cord injury in canine. Biomaterials, 2015, 41: 89-96. |
33. | Han S, Xiao Z, Li X, et al. Human placenta-derived mesenchymal stem cells loaded on linear ordered collagen scaffold improves functional recovery after completely transected spinal cord injury in canine. Sci China Life Sci, 2018, 61(1): 2-13. |
34. | Yin W, Li X, Zhao Y, et al. Taxol-modified collagen scaffold implantation promotes functional recovery after long-distance spinal cord complete transection in canines. Biomater Sci, 2018, 6(5): 1099-1108. |
35. | Li X, Tan J, Xiao Z, et al. Transplantation of hUCMSCs seeded collagen scaffolds reduces scar formation and promotes functional recovery in canines with chronic spinal cord injury. Sci Rep, 2017, 7: 43559. |
36. | Li X, Zhao Y, Cheng S, et al. Cetuximab modified collagen scaffold directs neurogenesis of injury-activated endogenous neural stem cells for acute spinal cord injury repair. Biomaterials, 2017, 137: 73-86. |
37. | Lu P, Wang Y, Graham L, et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell, 2012, 150(6): 1264-1273. |
38. | Jenkins AD, Kratochvil P, Stepto RFT, et al. Glossary of basic terms in polymer science. Pure and Applied Chemistry, 1996, 68(12): 2287-2311. |
39. | Williams DF. On the mechanisms of biocompatibility. Biomaterials, 2008, 29(20): 2941-2953. |
40. | Xiao ZF, Chen B, Dai JW. Building the regenerative microenvironment with functional Biomaterials for spinal cord injury repair. Journal of Spine, 2016, S7: 005. |
41. | 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. |
42. | 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. |
43. | Fan J, Xiao Z, Zhang H, et al. Linear ordered collagen scaffolds loaded with collagen-binding neurotrophin-3 promote axonal regeneration and partial functional recovery after complete spinal cord transection. J Neurotrauma, 2010, 27(9): 1671-1683. |
44. | Ibarra A, Hernández E, Lomeli J, et al. Cyclosporin-A enhances non-functional axonal growing after complete spinal cord transection. Brain Res, 2007, 1149: 200-209. |
45. | Guest JD, Herrera L, Margitich I, et al. Xenografts of expanded primate olfactory ensheathing glia support transient behavioral recovery that is independent of serotonergic or corticospinal axonal regeneration in nude rats following spinal cord transection. Exp Neurol, 2008, 212(2): 261-274. |
46. | Yang CC, Shih YH, Ko MH, et al. Transplantation of human umbilical mesenchymal stem cells from Wharton’s jelly after complete transection of the rat spinal cord. PLoS One, 2008, 3(10): e3336. |
47. | Abematsu M, Tsujimura K, Yamano M, et al. Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury. J Clin Invest, 2010, 120(9): 3255-3266. |
48. | Guo X, Zahir T, Mothe A, et al. The effect of growth factors and soluble Nogo-66 receptor protein on transplanted neural stem/progenitor survival and axonal regeneration after complete transection of rat spinal cord. Cell Transplant, 2012, 21(6): 1177-1197. |
49. | Lu P, Blesch A, Graham L, et al. Motor axonal regeneration after partial and complete spinal cord transection. J Neurosci, 2012, 32(24): 8208-8218. |
50. | Hou S, Tom VJ, Graham L, et al. Partial restoration of cardiovascular function by embryonic neural stem cell grafts after complete spinal cord transection. J Neurosci, 2013, 33(43): 17138-17149. |
51. | Lu P, Woodruff G, Wang Y, et al. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron, 2014, 83(4): 789-796. |
52. | Du BL, Xiong Y, Zeng CG, et al. Transplantation of artificial neural construct partly improved spinal tissue repair and functional recovery in rats with spinal cord transection. Brain Res, 2011, 1400: 87-98. |
53. | Gao M, Lu P, Bednark B, et al. Templated agarose scaffolds for the support of motor axon regeneration into sites of complete spinal cord transection. Biomaterials, 2013, 34(5): 1529-1536. |
54. | Yang Z, Zhang A, Duan H, et al. NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury. Proc Natl Acad Sci U S A, 2015, 112(43): 13354-13359. |
55. | Li X, Li M, Sun J, et al. Radially aligned electrospun fibers with continuous gradient of SDF1α for the guidance of neural stem cells. Small, 2016, 12(36): 5009-5018. |
56. | Ganz J, Shor E, Guo S, et al. Implantation of 3D constructs embedded with oral mucosa-derived cells induces functional recovery in rats with complete spinal cord transection. Front Neurosci, 2017, 11: 589. |
57. | Tuszynski MH, Steward O. Concepts and methods for the study of axonal regeneration in the CNS. Neuron, 2012, 74(5): 777-791. |
58. | Deng L, Ruan Y, Chen C, et al. Characterization of dendritic morphology and neurotransmitter phenotype of thoracic descending propriospinal neurons after complete spinal cord transection and GDNF treatment. Exp Neurol, 2016, 277: 103-114. |
59. | Kadoya K, Lu P, Nguyen K, et al. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med, 2016, 22(5): 479-487. |
60. | Khankan RR, Griffis KG, Haggerty-Skeans JR, et al. Olfactory ensheathing cell transplantation after a complete spinal cord transection mediates neuroprotective and immunomodulatory mechanisms to facilitate regeneration. J Neurosci, 2016, 36(23): 6269-6286. |
61. | Knudsen EB, Moxon KA. Restoration of hindlimb movements after complete spinal cord injury using brain-controlled functional electrical stimulation. Front Neurosci, 2017, 11: 715. |
62. | Lee YS, Wu S, Arinzeh TL, et al. Enhanced noradrenergic axon regeneration into schwann cell-filled PVDF-TrFE conduits after complete spinal cord transection. Biotechnol Bioeng, 2017, 114(2): 444-456. |
63. | Ren S, Liu ZH, Wu Q, et al. Polyethylene glycol-induced motor recovery after total spinal transection in rats. CNS Neurosci Ther, 2017, 23(8): 680-685. |
64. | Tian T, Yu Z, Zhang N, et al. Modified acellular nerve-delivering PMSCs improve functional recovery in rats after complete spinal cord transection. Biomater Sci, 2017, 5(12): 2480-2492. |
65. | Yang C, Li X, Sun L, et al. Potential of human dental stem cells in repairing the complete transection of rat spinal cord. J Neural Eng, 2017, 14(2): 026005. |
66. | Coumans JV, Lin TT, Dai HN, et al. Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins. J Neurosci, 2001, 21(23): 9334-9344. |
67. | Kim JE, Li S, GrandPré T, et al. Axon regeneration in young adult mice lacking Nogo-A/B. Neuron, 2003, 38(2): 187-199. |
68. | Simonen M, Pedersen V, Weinmann O, et al. Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron, 2003, 38(2): 201-211. |
69. | Zheng B, Ho C, Li S, et al. Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron, 2003, 38(2): 213-224. |
70. | Lee JK, Chan AF, Luu SM, et al. Reassessment of corticospinal tract regeneration in Nogo-deficient mice. J Neurosci, 2009, 29(27): 8649-8654. |
71. | Zukor K, Belin S, Wang C, et al. Short hairpin RNA against PTEN enhances regenerative growth of corticospinal tract axons after spinal cord injury. J Neurosci, 2013, 33(39): 15350-15361. |
72. | Lewandowski G, Steward O. AAVshRNA-mediated suppression of PTEN in adult rats in combination with salmon fibrin administration enables regenerative growth of corticospinal axons and enhances recovery of voluntary motor function after cervical spinal cord injury. J Neurosci, 2014, 34(30): 9951-9962. |
73. | Danilov CA, Steward O. Conditional genetic deletion of PTEN after a spinal cord injury enhances regenerative growth of CST axons and motor function recovery in mice. Experimental Neurology, 2015, 266: 147-160. |
74. | Du K, Zheng S, Zhang Q, et al. Pten deletion promotes regrowth of corticospinal tract axons 1 year after spinal cord injury. J Neurosci, 2015, 35(26): 9754-9763. |
75. | Jin D, Liu Y, Sun F, et al. Restoration of skilled locomotion by sprouting corticospinal axons induced by co-deletion of PTEN and SOCS3. Nat Commun, 2015, 6: 8074. |
76. | Geoffroy CG, Lorenzana AO, Kwan JP, et al. Effects of PTEN and Nogo codeletion on corticospinal axon sprouting and regeneration in mice. J Neurosci, 2015, 35(16): 6413-6428. |
77. | Fabes J, Anderson P, Brennan C, et al. Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord. Eur J Neurosci, 2007, 26(9): 2496-2505. |
78. | Omoto S, Ueno M, Mochio S, et al. Corticospinal tract fibers cross the ephrin-B3-negative part of the midline of the spinal cord after brain injury. Neurosci Res, 2011, 69(3): 187-195. |
79. | Blackmore MG, Wang Z, Lerch JK, et al. Krüppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract. Proc Natl Acad Sci U S A, 2012, 109(19): 7517-7522. |
80. | Lang C, Bradley PM, Jacobi A, et al. STAT3 promotes corticospinal remodelling and functional recovery after spinal cord injury. EMBO Rep, 2013, 14(10): 931-937. |
81. | Wang X, Hu J, She Y, et al. Cortical PKC inhibition promotes axonal regeneration of the corticospinal tract and forelimb functional recovery after cervical dorsal spinal hemisection in adult rats. Cereb Cortex, 2014, 24(11): 3069-3079. |
82. | Wang Z, Reynolds A, Kirry A, et al. Overexpression of Sox11 promotes corticospinal tract regeneration after spinal injury while interfering with functional recovery. J Neurosci, 2015, 35(7): 3139-3145. |
83. | Al-Ali H, Ding Y, Slepak T, et al. The mTOR substrate S6 kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential grug target for central nervous system injury. J Neurosci, 2017, 37(30): 7079-7095. |
84. | Lu P, Kadoya K, Tuszynski MH. Axonal growth and connectivity from neural stem cell grafts in models of spinal cord injury. Curr Opin Neurobiol, 2014, 27: 103-109. |
85. | Bonner JF, Connors TM, Silverman WF, et al. Grafted neural progenitors integrate and restore synaptic connectivity across the injured spinal cord. J Neurosci, 2011, 31(12): 4675-4686. |
86. | Cusimano M, Biziato D, Brambilla E, et al. Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. Brain, 2012, 135(Pt 2): 447-460. |
87. | Mothe AJ, Tator CH. Review of transplantation of neural stem/progenitor cells for spinal cord injury. Int J Dev Neurosci, 2013, 31(7): 701-713. |
88. | Meletis K, Barnabé-Heider F, Carlén M, et al. Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biol, 2008, 6(7): e182. |
89. | Hamilton LK, Truong MK, Bednarczyk MR, et al. Cellular organization of the central canal ependymal zone, a niche of latent neural stem cells in the adult mammalian spinal cord. Neuroscience, 2009, 164(3): 1044-1056. |
90. | McDonough A, Martínez-Cerdeño V. Endogenous proliferation after spinal cord injury in animal models. Stem Cells Int, 2012, 2012: 387513. |
91. | Lacroix S, Hamilton LK, Vaugeois A, et al. Central canal ependymal cells proliferate extensively in response to traumatic spinal cord injury but not demyelinating lesions. PLoS One, 2014, 9(1): e85916. |
92. | 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(1): 177-187. |
93. | Sabelström H, Stenudd M, Frisén J. Neural stem cells in the adult spinal cord. Exp Neurol, 2014, 260: 44-49. |
94. | Barnabé-Heider F, Göritz C, Sabelström H, et al. Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell, 2010, 7(4): 470-482. |
95. | Karimi-Abdolrezaee S, Billakanti R. Reactive astrogliosis after spinal cord injury-beneficial and detrimental effects. Mol Neurobiol, 2012, 46(2): 251-264. |
96. | 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. |
97. | Li X, Dai J . Bridging the gap with functional collagen scaffolds: tuning endogenous neural stem cells for severe spinal cord injury repair. Biomater Sci, 2018, 6(2): 265-271. |
98. | Chen B, Xiao ZF, Zhao YN, et al. Functional biomaterial-based regenerative microenvironment for spinal cord injury repair. National Science Review, 2017, 4(4): 530-532. |
99. | Mar FM, Bonni A, Sousa MM. Cell intrinsic control of axon regeneration. EMBO Rep, 2014, 15(3): 254-263. |
100. | Kaplan A, Ong Tone S, Fournier AE. Extrinsic and intrinsic regulation of axon regeneration at a crossroads. Front Mol Neurosci, 2015, 8: 27. |
101. | Weng YL, Joseph J, An R, et al. Epigenetic regulation of axonal regenerative capacity. Epigenomics, 2016, 8(10): 1429-1442. |
102. | Hilton BJ, Bradke F. Can injured adult CNS axons regenerate by recapitulating development? Development, 2017, 144(19): 3417-3429. |
103. | Grégoire CA, Goldenstein BL, Floriddia EM, et al. Endogenous neural stem cell responses to stroke and spinal cord injury. Glia, 2015, 63(8): 1469-1482. |
104. | Takeoka A, Jindrich DL, Muñoz-Quiles C, et al. Axon regeneration can facilitate or suppress hindlimb function after olfactory ensheathing glia transplantation. J Neurosci, 2011, 31(11): 4298-4310. |
- 1. Thuret S, Moon L, Gage FH. Therapeutic interventions after spinal cord injury. Nature Reviews Neuroscience, 2006, 7(8): 628-643.
- 2. Ahuja CS, Wilson JR, Nori S, et al. Traumatic spinal cord injury. Nat Rev Dis Primers, 2017, 3: 17018.
- 3. He Z, Koprivica V. The Nogo signaling pathway for regeneration block. Annu Rev Neurosci, 2004, 27: 341-368.
- 4. Filbin MT. Recapitulate development to promote axonal regeneration: good or bad approach? Philos Trans R Soc Lond B Biol Sci, 2006, 361(1473): 1565-1574.
- 5. Fitch MT, Silver J. CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Exp Neurol, 2008, 209(2): 294-301.
- 6. Kadoya K, Tsukada S, Lu P, et al. Combined intrinsic and extrinsic neuronal mechanisms facilitate bridging axonal regeneration one year after spinal cord injury. Neuron, 2009, 64(2): 165-172.
- 7. Giger RJ, Venkatesh K, Chivatakarn O, et al. Mechanisms of CNS myelin inhibition: evidence for distinct and neuronal cell type specific receptor systems. Restor Neurol Neurosci, 2008, 26(2-3): 97-115.
- 8. Sun F, He Z. Neuronal intrinsic barriers for axon regeneration in the adult CNS. Curr Opin Neurobiol, 2010, 20(4): 510-518.
- 9. Liu K, Tedeschi A, Park KK, et al. Neuronal intrinsic mechanisms of axon regeneration. Annu Rev Neurosci, 2011, 34: 131-152.
- 10. McCreedy DA, Sakiyama-Elbert SE. Combination therapies in the CNS: engineering the environment. Neurosci Lett, 2012, 519(2): 115-121.
- 11. Tedeschi A, Bradke F. Spatial and temporal arrangement of neuronal intrinsic and extrinsic mechanisms controlling axon regeneration. Curr Opin Neurobiol, 2017, 42: 118-127.
- 12. Selvarajah S, Hammond ER, Haider AH, et al. The burden of acute traumatic spinal cord injury among adults in the united states: an update. J Neurotrauma, 2014, 31(3): 228-238.
- 13. Wilson JR, Forgione N, Fehlings MG. Emerging therapies for acute traumatic spinal cord injury. Canadian Medical Association Journal, 2013, 185(6): 485-492.
- 14. Dvorak MF, Noonan VK, Fallah N, et al. The influence of time from injury to surgery on motor recovery and length of hospital stay in acute traumatic spinal cord injury: an observational Canadian cohort study. J Neurotrauma, 2015, 32(9): 645-654.
- 15. Giger RJ, Hollis ER 2nd, Tuszynski MH. Guidance molecules in axon regeneration. Cold Spring Harb Perspect Biol, 2010, 2(7): a001867.
- 16. Kwon BK, Oxland TR, Tetzlaff W. Animal models used in spinal cord regeneration research. Spine (Phila Pa 1976), 2002, 27(14): 1504-1510.
- 17. Akhtar AZ, Pippin JJ, Sandusky CB. Animal models in spinal cord injury: a review. Rev Neurosci, 2008, 19(1): 47-60.
- 18. Han Q, Jin W, Xiao Z, et al. The promotion of neural regeneration in an extreme rat spinal cord injury model using a collagen scaffold containing a collagen binding neuroprotective protein and an EGFR neutralizing antibody. Biomaterials, 2010, 31(35): 9212-9220.
- 19. Jeffery ND, Lakatos A, Franklin RJ. Autologous olfactory glial cell transplantation is reliable and safe in naturally occurring canine spinal cord injury. J Neurotrauma, 2005, 22(11): 1282-1293.
- 20. Han S, Li X, Xiao Z, et al. Complete canine spinal cord transection model: a large animal model for the translational research of spinal cord regeneration. Sci China Life Sci, 2018, 61(1): 115-117.
- 21. Raineteau O, Schwab ME. Plasticity of motor systems after incomplete spinal cord injury. Nat Rev Neurosci, 2001, 2(4): 263-273.
- 22. Courtine G, Song B, Roy RR, et al. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat Med, 2008, 14(1): 69-74.
- 23. Rosenzweig ES, Courtine G, Jindrich DL, et al. Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nat Neurosci, 2010, 13(12): 1505-1510.
- 24. Li X, Han J, Zhao Y, et al. Functionalized collagen scaffold neutralizing the myelin-inhibitory molecules promoted neurites outgrowth in vitro and facilitated spinal cord regeneration in vivo. ACS Appl Mater Interfaces, 2015, 7(25): 13960-13971.
- 25. Li X, Han J, Zhao Y, et al. Functionalized collagen scaffold implantation and cAMP administration collectively facilitate spinal cord regeneration. Acta Biomater, 2016, 30: 233-245.
- 26. Fan C, Li X, Xiao Z, et al. A modified collagen scaffold facilitates endogenous neurogenesis for acute spinal cord injury repair. Acta Biomater, 2017, 51: 304-316.
- 27. Xu B, Zhao Y, Xiao Z, et al. A Dual Functional Scaffold Tethered with EGFR Antibody Promotes Neural Stem Cell Retention and Neuronal Differentiation for Spinal Cord Injury Repair. Adv Healthc Mater, 2017, 6(9): 12.
- 28. Wang N, Xiao Z, Zhao Y, et al. Collagen scaffold combined with human umbilical cord-derived mesenchymal stem cells promote functional recovery after scar resection in rats with chronic spinal cord injury. J Tissue Eng Regen Med, 2018, 12(2): e1154-e1163.
- 29. Li, X, Liu SM, Zhao YN, et al. Training neural stem cells on functional collagen scaffolds for severe spinal cord injury repair. Advanced Functional Materials, 2016, 26(32): 5835-5847.
- 30. Zhao Y, Xiao Z, Chen B, et al. The neuronal differentiation microenvironment is essential for spinal cord injury repair. Organogenesis, 2017, 13(3): 63-70.
- 31. Han S, Wang B, Jin W, et al. The collagen scaffold with collagen binding BDNF enhances functional recovery by facilitating peripheral nerve infiltrating and ingrowth in canine complete spinal cord transection. Spinal Cord, 2014, 52(12): 867-873.
- 32. Han S, Wang B, Jin W, et al. The linear-ordered collagen scaffold-BDNF complex significantly promotes functional recovery after completely transected spinal cord injury in canine. Biomaterials, 2015, 41: 89-96.
- 33. Han S, Xiao Z, Li X, et al. Human placenta-derived mesenchymal stem cells loaded on linear ordered collagen scaffold improves functional recovery after completely transected spinal cord injury in canine. Sci China Life Sci, 2018, 61(1): 2-13.
- 34. Yin W, Li X, Zhao Y, et al. Taxol-modified collagen scaffold implantation promotes functional recovery after long-distance spinal cord complete transection in canines. Biomater Sci, 2018, 6(5): 1099-1108.
- 35. Li X, Tan J, Xiao Z, et al. Transplantation of hUCMSCs seeded collagen scaffolds reduces scar formation and promotes functional recovery in canines with chronic spinal cord injury. Sci Rep, 2017, 7: 43559.
- 36. Li X, Zhao Y, Cheng S, et al. Cetuximab modified collagen scaffold directs neurogenesis of injury-activated endogenous neural stem cells for acute spinal cord injury repair. Biomaterials, 2017, 137: 73-86.
- 37. Lu P, Wang Y, Graham L, et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell, 2012, 150(6): 1264-1273.
- 38. Jenkins AD, Kratochvil P, Stepto RFT, et al. Glossary of basic terms in polymer science. Pure and Applied Chemistry, 1996, 68(12): 2287-2311.
- 39. Williams DF. On the mechanisms of biocompatibility. Biomaterials, 2008, 29(20): 2941-2953.
- 40. Xiao ZF, Chen B, Dai JW. Building the regenerative microenvironment with functional Biomaterials for spinal cord injury repair. Journal of Spine, 2016, S7: 005.
- 41. 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.
- 42. 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.
- 43. Fan J, Xiao Z, Zhang H, et al. Linear ordered collagen scaffolds loaded with collagen-binding neurotrophin-3 promote axonal regeneration and partial functional recovery after complete spinal cord transection. J Neurotrauma, 2010, 27(9): 1671-1683.
- 44. Ibarra A, Hernández E, Lomeli J, et al. Cyclosporin-A enhances non-functional axonal growing after complete spinal cord transection. Brain Res, 2007, 1149: 200-209.
- 45. Guest JD, Herrera L, Margitich I, et al. Xenografts of expanded primate olfactory ensheathing glia support transient behavioral recovery that is independent of serotonergic or corticospinal axonal regeneration in nude rats following spinal cord transection. Exp Neurol, 2008, 212(2): 261-274.
- 46. Yang CC, Shih YH, Ko MH, et al. Transplantation of human umbilical mesenchymal stem cells from Wharton’s jelly after complete transection of the rat spinal cord. PLoS One, 2008, 3(10): e3336.
- 47. Abematsu M, Tsujimura K, Yamano M, et al. Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury. J Clin Invest, 2010, 120(9): 3255-3266.
- 48. Guo X, Zahir T, Mothe A, et al. The effect of growth factors and soluble Nogo-66 receptor protein on transplanted neural stem/progenitor survival and axonal regeneration after complete transection of rat spinal cord. Cell Transplant, 2012, 21(6): 1177-1197.
- 49. Lu P, Blesch A, Graham L, et al. Motor axonal regeneration after partial and complete spinal cord transection. J Neurosci, 2012, 32(24): 8208-8218.
- 50. Hou S, Tom VJ, Graham L, et al. Partial restoration of cardiovascular function by embryonic neural stem cell grafts after complete spinal cord transection. J Neurosci, 2013, 33(43): 17138-17149.
- 51. Lu P, Woodruff G, Wang Y, et al. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron, 2014, 83(4): 789-796.
- 52. Du BL, Xiong Y, Zeng CG, et al. Transplantation of artificial neural construct partly improved spinal tissue repair and functional recovery in rats with spinal cord transection. Brain Res, 2011, 1400: 87-98.
- 53. Gao M, Lu P, Bednark B, et al. Templated agarose scaffolds for the support of motor axon regeneration into sites of complete spinal cord transection. Biomaterials, 2013, 34(5): 1529-1536.
- 54. Yang Z, Zhang A, Duan H, et al. NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury. Proc Natl Acad Sci U S A, 2015, 112(43): 13354-13359.
- 55. Li X, Li M, Sun J, et al. Radially aligned electrospun fibers with continuous gradient of SDF1α for the guidance of neural stem cells. Small, 2016, 12(36): 5009-5018.
- 56. Ganz J, Shor E, Guo S, et al. Implantation of 3D constructs embedded with oral mucosa-derived cells induces functional recovery in rats with complete spinal cord transection. Front Neurosci, 2017, 11: 589.
- 57. Tuszynski MH, Steward O. Concepts and methods for the study of axonal regeneration in the CNS. Neuron, 2012, 74(5): 777-791.
- 58. Deng L, Ruan Y, Chen C, et al. Characterization of dendritic morphology and neurotransmitter phenotype of thoracic descending propriospinal neurons after complete spinal cord transection and GDNF treatment. Exp Neurol, 2016, 277: 103-114.
- 59. Kadoya K, Lu P, Nguyen K, et al. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med, 2016, 22(5): 479-487.
- 60. Khankan RR, Griffis KG, Haggerty-Skeans JR, et al. Olfactory ensheathing cell transplantation after a complete spinal cord transection mediates neuroprotective and immunomodulatory mechanisms to facilitate regeneration. J Neurosci, 2016, 36(23): 6269-6286.
- 61. Knudsen EB, Moxon KA. Restoration of hindlimb movements after complete spinal cord injury using brain-controlled functional electrical stimulation. Front Neurosci, 2017, 11: 715.
- 62. Lee YS, Wu S, Arinzeh TL, et al. Enhanced noradrenergic axon regeneration into schwann cell-filled PVDF-TrFE conduits after complete spinal cord transection. Biotechnol Bioeng, 2017, 114(2): 444-456.
- 63. Ren S, Liu ZH, Wu Q, et al. Polyethylene glycol-induced motor recovery after total spinal transection in rats. CNS Neurosci Ther, 2017, 23(8): 680-685.
- 64. Tian T, Yu Z, Zhang N, et al. Modified acellular nerve-delivering PMSCs improve functional recovery in rats after complete spinal cord transection. Biomater Sci, 2017, 5(12): 2480-2492.
- 65. Yang C, Li X, Sun L, et al. Potential of human dental stem cells in repairing the complete transection of rat spinal cord. J Neural Eng, 2017, 14(2): 026005.
- 66. Coumans JV, Lin TT, Dai HN, et al. Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins. J Neurosci, 2001, 21(23): 9334-9344.
- 67. Kim JE, Li S, GrandPré T, et al. Axon regeneration in young adult mice lacking Nogo-A/B. Neuron, 2003, 38(2): 187-199.
- 68. Simonen M, Pedersen V, Weinmann O, et al. Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron, 2003, 38(2): 201-211.
- 69. Zheng B, Ho C, Li S, et al. Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron, 2003, 38(2): 213-224.
- 70. Lee JK, Chan AF, Luu SM, et al. Reassessment of corticospinal tract regeneration in Nogo-deficient mice. J Neurosci, 2009, 29(27): 8649-8654.
- 71. Zukor K, Belin S, Wang C, et al. Short hairpin RNA against PTEN enhances regenerative growth of corticospinal tract axons after spinal cord injury. J Neurosci, 2013, 33(39): 15350-15361.
- 72. Lewandowski G, Steward O. AAVshRNA-mediated suppression of PTEN in adult rats in combination with salmon fibrin administration enables regenerative growth of corticospinal axons and enhances recovery of voluntary motor function after cervical spinal cord injury. J Neurosci, 2014, 34(30): 9951-9962.
- 73. Danilov CA, Steward O. Conditional genetic deletion of PTEN after a spinal cord injury enhances regenerative growth of CST axons and motor function recovery in mice. Experimental Neurology, 2015, 266: 147-160.
- 74. Du K, Zheng S, Zhang Q, et al. Pten deletion promotes regrowth of corticospinal tract axons 1 year after spinal cord injury. J Neurosci, 2015, 35(26): 9754-9763.
- 75. Jin D, Liu Y, Sun F, et al. Restoration of skilled locomotion by sprouting corticospinal axons induced by co-deletion of PTEN and SOCS3. Nat Commun, 2015, 6: 8074.
- 76. Geoffroy CG, Lorenzana AO, Kwan JP, et al. Effects of PTEN and Nogo codeletion on corticospinal axon sprouting and regeneration in mice. J Neurosci, 2015, 35(16): 6413-6428.
- 77. Fabes J, Anderson P, Brennan C, et al. Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord. Eur J Neurosci, 2007, 26(9): 2496-2505.
- 78. Omoto S, Ueno M, Mochio S, et al. Corticospinal tract fibers cross the ephrin-B3-negative part of the midline of the spinal cord after brain injury. Neurosci Res, 2011, 69(3): 187-195.
- 79. Blackmore MG, Wang Z, Lerch JK, et al. Krüppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract. Proc Natl Acad Sci U S A, 2012, 109(19): 7517-7522.
- 80. Lang C, Bradley PM, Jacobi A, et al. STAT3 promotes corticospinal remodelling and functional recovery after spinal cord injury. EMBO Rep, 2013, 14(10): 931-937.
- 81. Wang X, Hu J, She Y, et al. Cortical PKC inhibition promotes axonal regeneration of the corticospinal tract and forelimb functional recovery after cervical dorsal spinal hemisection in adult rats. Cereb Cortex, 2014, 24(11): 3069-3079.
- 82. Wang Z, Reynolds A, Kirry A, et al. Overexpression of Sox11 promotes corticospinal tract regeneration after spinal injury while interfering with functional recovery. J Neurosci, 2015, 35(7): 3139-3145.
- 83. Al-Ali H, Ding Y, Slepak T, et al. The mTOR substrate S6 kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential grug target for central nervous system injury. J Neurosci, 2017, 37(30): 7079-7095.
- 84. Lu P, Kadoya K, Tuszynski MH. Axonal growth and connectivity from neural stem cell grafts in models of spinal cord injury. Curr Opin Neurobiol, 2014, 27: 103-109.
- 85. Bonner JF, Connors TM, Silverman WF, et al. Grafted neural progenitors integrate and restore synaptic connectivity across the injured spinal cord. J Neurosci, 2011, 31(12): 4675-4686.
- 86. Cusimano M, Biziato D, Brambilla E, et al. Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. Brain, 2012, 135(Pt 2): 447-460.
- 87. Mothe AJ, Tator CH. Review of transplantation of neural stem/progenitor cells for spinal cord injury. Int J Dev Neurosci, 2013, 31(7): 701-713.
- 88. Meletis K, Barnabé-Heider F, Carlén M, et al. Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biol, 2008, 6(7): e182.
- 89. Hamilton LK, Truong MK, Bednarczyk MR, et al. Cellular organization of the central canal ependymal zone, a niche of latent neural stem cells in the adult mammalian spinal cord. Neuroscience, 2009, 164(3): 1044-1056.
- 90. McDonough A, Martínez-Cerdeño V. Endogenous proliferation after spinal cord injury in animal models. Stem Cells Int, 2012, 2012: 387513.
- 91. Lacroix S, Hamilton LK, Vaugeois A, et al. Central canal ependymal cells proliferate extensively in response to traumatic spinal cord injury but not demyelinating lesions. PLoS One, 2014, 9(1): e85916.
- 92. 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(1): 177-187.
- 93. Sabelström H, Stenudd M, Frisén J. Neural stem cells in the adult spinal cord. Exp Neurol, 2014, 260: 44-49.
- 94. Barnabé-Heider F, Göritz C, Sabelström H, et al. Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell, 2010, 7(4): 470-482.
- 95. Karimi-Abdolrezaee S, Billakanti R. Reactive astrogliosis after spinal cord injury-beneficial and detrimental effects. Mol Neurobiol, 2012, 46(2): 251-264.
- 96. 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.
- 97. Li X, Dai J . Bridging the gap with functional collagen scaffolds: tuning endogenous neural stem cells for severe spinal cord injury repair. Biomater Sci, 2018, 6(2): 265-271.
- 98. Chen B, Xiao ZF, Zhao YN, et al. Functional biomaterial-based regenerative microenvironment for spinal cord injury repair. National Science Review, 2017, 4(4): 530-532.
- 99. Mar FM, Bonni A, Sousa MM. Cell intrinsic control of axon regeneration. EMBO Rep, 2014, 15(3): 254-263.
- 100. Kaplan A, Ong Tone S, Fournier AE. Extrinsic and intrinsic regulation of axon regeneration at a crossroads. Front Mol Neurosci, 2015, 8: 27.
- 101. Weng YL, Joseph J, An R, et al. Epigenetic regulation of axonal regenerative capacity. Epigenomics, 2016, 8(10): 1429-1442.
- 102. Hilton BJ, Bradke F. Can injured adult CNS axons regenerate by recapitulating development? Development, 2017, 144(19): 3417-3429.
- 103. Grégoire CA, Goldenstein BL, Floriddia EM, et al. Endogenous neural stem cell responses to stroke and spinal cord injury. Glia, 2015, 63(8): 1469-1482.
- 104. Takeoka A, Jindrich DL, Muñoz-Quiles C, et al. Axon regeneration can facilitate or suppress hindlimb function after olfactory ensheathing glia transplantation. J Neurosci, 2011, 31(11): 4298-4310.