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Regulation of axonal regeneration after mammalian spinal cord injury

Nature Reviews Molecular Cell Biology volume 24, pages 396–413 (2023)Cite this article

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Abstract

One hundred years ago, Ramón y Cajal, considered by many as the founder of modern neuroscience, stated that neurons of the adult central nervous system (CNS) are incapable of regenerating. Yet, recent years have seen a tremendous expansion of knowledge in the molecular control of axon regeneration after CNS injury. We now understand that regeneration in the adult CNS is limited by (1) a failure to form cellular or molecular substrates for axon attachment and elongation through the lesion site; (2) environmental factors, including inhibitors of axon growth associated with myelin and the extracellular matrix; (3) astrocyte responses, which can both limit and support axon growth; and (4) intraneuronal mechanisms controlling the establishment of an active cellular growth programme. We discuss these topics together with newly emerging hypotheses, including the surprising finding from transcriptomic analyses of the corticospinal system in mice that neurons revert to an embryonic state after spinal cord injury, which can be sustained to promote regeneration with neural stem cell transplantation. These gains in knowledge are steadily advancing efforts to develop effective treatment strategies for spinal cord injury in humans.

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Fig. 1: Forms of axonal repair and its regulation.
Fig. 2: Neuron-intrinsic control of axonal repair.
Fig. 3: Newly emerging hypotheses for regeneration of the CNS.
Fig. 4: Five strategies to promote functional recovery after spinal cord injury.

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References

  1. Ramón y Cajal, S. Degeneration and Regeneration of the Nervous System (Hafner, 1928).

  2. Geoffroy, C. G. & Zheng, B. Myelin-associated inhibitors in axonal growth after CNS injury. Curr. Opin. Neurobiol. 27C, 31–38 (2014).

    Article  Google Scholar 

  3. Schwab, M. E. & Strittmatter, S. M. Nogo limits neural plasticity and recovery from injury. Curr. Opin. Neurobiol. 27C, 53–60 (2014).

    Article  Google Scholar 

  4. Costigan, M., Scholz, J. & Woolf, C. J. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 32, 1–32 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rasmussen, J. P. & Sagasti, A. Learning to swim, again: axon regeneration in fish. Exp. Neurol. 287, 318–330 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. David, S. & Aguayo, A. J. Axonal elongation into peripheral nervous system ‘bridges’ after central nervous system injury in adult rats. Science 214, 931–933 (1981).

    Article  CAS  PubMed  Google Scholar 

  7. Schnell, L. & Schwab, M. E. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343, 269–272 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Bregman, B. S. et al. Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 378, 498–501 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Simonen, M. et al. Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron 38, 201–211 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Kim, J. E., Li, S., GrandPre, T., Qiu, D. & Strittmatter, S. M. Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 38, 187–199 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Zheng, B. et al. Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron 38, 213–224 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Steward, O., Zheng, B., Banos, K. & Yee, K. M. Response to: Kim et al., ‘Axon regeneration in young adult mice lacking Nogo-A/B.’ Neuron 38, 187–199. Neuron 54, 191–195 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Filbin, M. T. Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat. Rev. Neurosci. 4, 703–713 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. McKerracher, L. & Rosen, K. M. MAG, myelin and overcoming growth inhibition in the CNS. Front. Mol. Neurosci. 8, 51 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Geoffroy, C. G. et al. Effects of PTEN and Nogo codeletion on corticospinal axon sprouting and regeneration in mice. J. Neurosci. 35, 6413–6428 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Z’Graggen, W. J., Metz, G. A., Kartje, G. L., Thallmair, M. & Schwab, M. E. Functional recovery and enhanced corticofugal plasticity after unilateral pyramidal tract lesion and blockade of myelin-associated neurite growth inhibitors in adult rats. J. Neurosci. 18, 4744–4757 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Thallmair, M. et al. Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions. Nat. Neurosci. 1, 124–131 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Raineteau, O., Fouad, K., Noth, P., Thallmair, M. & Schwab, M. E. Functional switch between motor tracts in the presence of the mAb IN-1 in the adult rat. Proc. Natl Acad. Sci. USA 98, 6929–6934 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cafferty, W. B. & Strittmatter, S. M. The Nogo-Nogo receptor pathway limits a spectrum of adult CNS axonal growth. J. Neurosci. 26, 12242–12250 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee, J. K. et al. Assessing spinal axon regeneration and sprouting in Nogo-, MAG-, and OMgp-deficient mice. Neuron 66, 663–670 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Meves, J. M., Geoffroy, C. G., Kim, N. D., Kim, J. J. & Zheng, B. Oligodendrocytic but not neuronal Nogo restricts corticospinal axon sprouting after CNS injury. Exp. Neurol. 309, 32–43 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Maier, I. C. et al. Differential effects of anti-Nogo-A antibody treatment and treadmill training in rats with incomplete spinal cord injury. Brain 132, 1426–1440 (2009).

    Article  PubMed  Google Scholar 

  23. Dickson, B. J. Molecular mechanisms of axon guidance. Science 298, 1959–1964 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Benson, M. D. et al. Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth. Proc. Natl Acad. Sci. USA 102, 10694–10699 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Moreau-Fauvarque, C. et al. The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion. J. Neurosci. 23, 9229–9239 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Low, K., Culbertson, M., Bradke, F., Tessier-Lavigne, M. & Tuszynski, M. H. Netrin-1 is a novel myelin-associated inhibitor to axon growth. J. Neurosci. 28, 1099–1108 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. De Winter, F. et al. Injury-induced class 3 semaphorin expression in the rat spinal cord. Exp. Neurol. 175, 61–75 (2002).

    Article  PubMed  Google Scholar 

  28. Liu, Y. et al. Repulsive Wnt signaling inhibits axon regeneration after CNS injury. J. Neurosci. 28, 8376–8382 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hollis, E. R. II et al. Ryk controls remapping of motor cortex during functional recovery after spinal cord injury. Nat. Neurosci. 19, 697–705 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hollis, E. R. II & Zou, Y. Reinduced Wnt signaling limits regenerative potential of sensory axons in the spinal cord following conditioning lesion. Proc. Natl Acad. Sci. USA 109, 14663–14668 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Parikh, P. et al. Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons. Proc. Natl Acad. Sci. USA 108, E99–E107 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hata, K. et al. RGMa inhibition promotes axonal growth and recovery after spinal cord injury. J. Cell Biol. 173, 47–58 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kaneko, S. et al. A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord. Nat. Med. 12, 1380–1389 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Lee, J. K. et al. Combined genetic attenuation of myelin and Semaphorin-mediated growth inhibition is insufficient to promote serotonergic axon regeneration. J. Neurosci. 30, 10899–10904 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cruz-Orengo, L. et al. Reduction of EphA4 receptor expression after spinal cord injury does not induce axonal regeneration or return of tcMMEP response. Neurosci. Lett. 418, 49–54 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fabes, J., Anderson, P., Brennan, C. & Bolsover, S. Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord. Eur. J. Neurosci. 26, 2496–2505 (2007).

    Article  PubMed  Google Scholar 

  37. Goldshmit, Y., Galea, M. P., Wise, G., Bartlett, P. F. & Turnley, A. M. Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. J. Neurosci. 24, 10064–10073 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Herrmann, J. E., Shah, R. R., Chan, A. F. & Zheng, B. EphA4 deficient mice maintain astroglial-fibrotic scar formation after spinal cord injury. Exp. Neurol. 223, 582–598 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dixon, K. J., Munro, K. M., Boyd, A. W., Bartlett, P. F. & Turnley, A. M. Partial change in EphA4 knockout mouse phenotype: loss of diminished GFAP upregulation following spinal cord injury. Neurosci. Lett. 525, 66–71 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Zhou, X. et al. Microglia and macrophages promote corralling, wound compaction and recovery after spinal cord injury via Plexin-B2. Nat. Neurosci. 23, 337–350 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tang, X. Q., Heron, P., Mashburn, C. & Smith, G. M. Targeting sensory axon regeneration in adult spinal cord. J. Neurosci. 27, 6068–6078 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Silver, J. & Miller, J. H. Regeneration beyond the glial scar. Nat. Rev. Neurosci. 5, 146–156 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Bradbury, E. J. & Burnside, E. R. Moving beyond the glial scar for spinal cord repair. Nat. Commun. 10, 3879 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Moon, L. D., Asher, R. A., Rhodes, K. E. & Fawcett, J. W. Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nat. Neurosci. 4, 465–466 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Bradbury, E. J. et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636–640 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Houle, J. D. et al. Combining an autologous peripheral nervous system ‘bridge’ and matrix modification by chondroitinase allows robust, functional regeneration beyond a hemisection lesion of the adult rat spinal cord. J. Neurosci. 26, 7405–7415 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Alilain, W. J., Horn, K. P., Hu, H., Dick, T. E. & Silver, J. Functional regeneration of respiratory pathways after spinal cord injury. Nature 475, 196–200 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee, Y. S. et al. Nerve regeneration restores supraspinal control of bladder function after complete spinal cord injury. J. Neurosci. 33, 10591–10606 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shen, Y. et al. PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science 326, 592–596 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lang, B. T. et al. Modulation of the proteoglycan receptor PTPsigma promotes recovery after spinal cord injury. Nature 518, 404–408 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Carter, L. M. et al. The yellow fluorescent protein (YFP-H) mouse reveals neuroprotection as a novel mechanism underlying chondroitinase ABC-mediated repair after spinal cord injury. J. Neurosci. 28, 14107–14120 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Starkey, M. L., Bartus, K., Barritt, A. W. & Bradbury, E. J. Chondroitinase ABC promotes compensatory sprouting of the intact corticospinal tract and recovery of forelimb function following unilateral pyramidotomy in adult mice. Eur. J. Neurosci. 36, 3665–3678 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Rosenzweig, E. S. et al. Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury. Nat. Neurosci. 22, 1269–1275 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fawcett, J. W., Oohashi, T. & Pizzorusso, T. The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function. Nat. Rev. Neurosci. 20, 451–465 (2019).

    Article  CAS  PubMed  Google Scholar 

  55. Blesch, A., Fischer, I. & Tuszynski, M. H. Gene therapy, neurotrophic factors and spinal cord regeneration. Handb. Clin. Neurol. 109, 563–574 (2012).

    Article  PubMed  Google Scholar 

  56. Huang, E. J. & Reichardt, L. F. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kromer, L. F. Nerve growth factor treatment after brain injury prevents neuronal death. Science 235, 214–216 (1987).

    Article  CAS  PubMed  Google Scholar 

  58. Schnell, L., Schneider, R., Kolbeck, R., Barde, Y. A. & Schwab, M. E. Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367, 170–173 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Tuszynski, M. H. et al. Fibroblasts genetically modified to produce nerve growth factor induce robust neuritic ingrowth after grafting to the spinal cord. Exp. Neurol. 126, 1–14 (1994).

    Article  CAS  PubMed  Google Scholar 

  60. Kobayashi, N. R. et al. BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and Tα1-tubulin mRNA expression, and promote axonal regeneration. J. Neurosci. 17, 9583–9595 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ramer, M. S., Priestley, J. V. & McMahon, S. B. Functional regeneration of sensory axons into the adult spinal cord. Nature 403, 312–316 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Grill, R., Murai, K., Blesch, A., Gage, F. H. & Tuszynski, M. H. Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J. Neurosci. 17, 5560–5572 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hollis, E. R. 2nd, Jamshidi, P., Low, K., Blesch, A. & Tuszynski, M. H. Induction of corticospinal regeneration by lentiviral trkB-induced Erk activation. Proc. Natl Acad. Sci. USA 106, 7215–7220 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Duan, X. et al. Subtype-specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mTOR signaling. Neuron 85, 1244–1256 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Liu, Y. et al. A sensitized IGF1 treatment restores corticospinal axon-dependent functions. Neuron 95, 817–833.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Alto, L. T. et al. Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury. Nat. Neurosci. 12, 1106–1113 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kadoya, K. et al. Combined intrinsic and extrinsic neuronal mechanisms facilitate bridging axonal regeneration one year after spinal cord injury. Neuron 64, 165–172 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Anderson, M. A. et al. Required growth facilitators propel axon regeneration across complete spinal cord injury. Nature 561, 396–400 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lu, P. et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150, 1264–1273 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lu, P. et al. Motor axonal regeneration after partial and complete spinal cord transection. J. Neurosci. 32, 8208–8218 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Koffler, J. et al. Biomimetic 3D-printed scaffolds for spinal cord injury repair. Nat. Med. 25, 263–269 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Park, K. K. et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322, 963–966 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lu, Y., Belin, S. & He, Z. Signaling regulations of neuronal regenerative ability. Curr. Opin. Neurobiol. 27C, 135–142 (2014).

    Article  Google Scholar 

  74. Hanz, S. et al. Axoplasmic importins enable retrograde injury signaling in lesioned nerve. Neuron 40, 1095–1104 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Sahoo, P. K. et al. A Ca2+-dependent switch activates axonal casein kinase 2alpha translation and drives G3BP1 granule disassembly for axon regeneration. Curr. Biol. 30, 4882–4895.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Liu, K. et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 13, 1075–1081 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Du, K. et al. Pten deletion promotes regrowth of corticospinal tract axons 1 year after spinal cord injury. J. Neurosci. 35, 9754–9763 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zukor, K. et al. Short hairpin RNA against PTEN enhances regenerative growth of corticospinal tract axons after spinal cord injury. J. Neurosci. 33, 15350–15361 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 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. 34, 9951–9962 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Geoffroy, C. G., Hilton, B. J., Tetzlaff, W. & Zheng, B. Evidence for an age-dependent decline in axon regeneration in the adult mammalian central nervous system. Cell Rep. 15, 238–246 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yang, L. et al. The mTORC1 effectors S6K1 and 4E-BP play different roles in CNS axon regeneration. Nat. Commun. 5, 5416 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Smith, P. D. et al. SOCS3 deletion promotes optic nerve regeneration in vivo. Neuron 64, 617–623 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bareyre, F. M. et al. In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration. Proc. Natl Acad. Sci. USA 108, 6282–6287 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sun, F. et al. Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature 480, 372–375 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Jin, D. et al. Restoration of skilled locomotion by sprouting corticospinal axons induced by co-deletion of PTEN and SOCS3. Nat. Commun. 6, 8074 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. Belin, S. et al. Injury-induced decline of intrinsic regenerative ability revealed by quantitative proteomics. Neuron 86, 1000–1014 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Moore, D. L. et al. KLF family members regulate intrinsic axon regeneration ability. Science 326, 298–301 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Blackmore, M. G. et al. Kruppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract. Proc. Natl Acad. Sci. USA 109, 7517–7522 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wang, Z. et al. KLF6 and STAT3 co-occupy regulatory DNA and functionally synergize to promote axon growth in CNS neurons. Sci. Rep. 8, 12565 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Qin, S., Zou, Y. & Zhang, C. L. Cross-talk between KLF4 and STAT3 regulates axon regeneration. Nat. Commun. 4, 2633 (2013).

    Article  PubMed  Google Scholar 

  92. Norsworthy, M. W. et al. Sox11 expression promotes regeneration of some retinal ganglion cell types but kills others. Neuron 94, 1112–1120.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wang, Z., Reynolds, A., Kirry, A., Nienhaus, C. & Blackmore, M. G. Overexpression of Sox11 promotes corticospinal tract regeneration after spinal injury while interfering with functional recovery. J. Neurosci. 35, 3139–3145 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Yanik, M. F. et al. Neurosurgery: functional regeneration after laser axotomy. Nature 432, 822 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Hammarlund, M., Nix, P., Hauth, L., Jorgensen, E. M. & Bastiani, M. Axon regeneration requires a conserved MAP kinase pathway. Science 323, 802–806 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yan, D., Wu, Z., Chisholm, A. D. & Jin, Y. The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell 138, 1005–1018 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Chang, L. & Karin, M. Mammalian MAP kinase signalling cascades. Nature 410, 37–40 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Xiong, X. et al. Protein turnover of the Wallenda/DLK kinase regulates a retrograde response to axonal injury. J. Cell Biol. 191, 211–223 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Shin, J. E. et al. Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration. Neuron 74, 1015–1022 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Watkins, T. A. et al. DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury. Proc. Natl Acad. Sci. USA 110, 4039–4044 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Welsbie, D. S. et al. Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death. Proc. Natl Acad. Sci. USA 110, 4045–4050 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Welsbie, D. S. et al. Enhanced functional genomic screening identifies novel mediators of dual leucine zipper kinase-dependent injury signaling in neurons. Neuron 94, 1142–1154.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ghosh, A. S. et al. DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity. J. Cell Biol. 194, 751–764 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Itoh, A. et al. ZPK/DLK, a mitogen-activated protein kinase kinase kinase, is a critical mediator of programmed cell death of motoneurons. J. Neurosci. 31, 7223–7228 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Miller, B. R. et al. A dual leucine kinase-dependent axon self-destruction program promotes Wallerian degeneration. Nat. Neurosci. 12, 387–389 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Chen, M. et al. Leucine zipper-bearing kinase promotes axon growth in mammalian central nervous system neurons. Sci. Rep. 6, 31482 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chen, M. et al. Leucine zipper-bearing kinase is a critical regulator of astrocyte reactivity in the adult mammalian CNS. Cell Rep. 22, 3587–3597 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Le Pichon, C. E. et al. Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease. Sci. Transl Med. 9, eaag0394 (2017).

    Article  PubMed  Google Scholar 

  109. Wlaschin, J. J. et al. Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury. eLife 7, e33910 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Saikia, J. M. et al. A critical role for DLK and LZK in axonal repair in the mammalian spinal cord. J. Neurosci. 42, 3716–3732 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Okada, S. et al. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat. Med. 12, 829–834 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Herrmann, J. E. et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J. Neurosci. 28, 7231–7243 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Chen, C. H. et al. The role of the PI3K/Akt/mTOR pathway in glial scar formation following spinal cord injury. Exp. Neurol. 278, 27–41 (2016).

    Article  CAS  PubMed  Google Scholar 

  114. Finelli, M. J., Wong, J. K. & Zou, H. Epigenetic regulation of sensory axon regeneration after spinal cord injury. J. Neurosci. 33, 19664–19676 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Puttagunta, R. et al. PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system. Nat. Commun. 5, 3527 (2014).

    Article  PubMed  Google Scholar 

  116. Hutson, T. H. et al. Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models. Sci. Transl Med. 11, eaaw2064 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hervera, A. et al. PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure. EMBO J. 38, e101032 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Palmisano, I. et al. Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons. Nat. Neurosci. 22, 1913–1924 (2019).

    Article  CAS  PubMed  Google Scholar 

  119. Weng, Y. L. et al. An intrinsic epigenetic barrier for functional axon regeneration. Neuron 94, 337–346.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Loh, Y. E. et al. Comprehensive mapping of 5-hydroxymethylcytosine epigenetic dynamics in axon regeneration. Epigenetics 12, 77–92 (2017).

    Article  PubMed  Google Scholar 

  121. Lu, Y. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Xu, J. H. et al. Deletion of Kruppel-like factor-4 promotes axonal regeneration in mammals. Neural Regen. Res. 16, 166–171 (2021).

    Article  CAS  PubMed  Google Scholar 

  123. Oh, Y. M. et al. Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration. Proc. Natl Acad. Sci. USA 115, E12417–E12426 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kan, R. L., Chen, J. & Sallam, T. Crosstalk between epitranscriptomic and epigenetic mechanisms in gene regulation. Trends Genet. 38, 182–193 (2022).

    Article  CAS  PubMed  Google Scholar 

  125. Weng, Y. L. et al. Epitranscriptomic m(6)A regulation of axon regeneration in the adult mammalian nervous system. Neuron 97, 313–325.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Venkatesh, I., Mehra, V., Wang, Z., Califf, B. & Blackmore, M. G. Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons. Dev. Neurobiol. 78, 960–977 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wang, X. W. et al. Lin28 signaling supports mammalian PNS and CNS axon regeneration. Cell Rep. 24, 2540–2552.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Nathan, F. M. et al. Upregulating Lin28a promotes axon regeneration in adult mice with optic nerve and spinal cord injury. Mol. Ther. 28, 1902–1917 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hur, E. M. et al. Engineering neuronal growth cones to promote axon regeneration over inhibitory molecules. Proc. Natl Acad. Sci. USA 108, 5057–5062 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Wang, X. W. et al. Knocking out non-muscle myosin II in retinal ganglion cells promotes long-distance optic nerve regeneration. Cell Rep. 31, 107537 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Matamoros, A. J. et al. Knockdown of fidgetin improves regeneration of injured axons by a microtubule-based mechanism. J. Neurosci. 39, 2011–2024 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Pinto-Costa, R. et al. Profilin 1 delivery tunes cytoskeletal dynamics toward CNS axon regeneration. J. Clin. Invest. 130, 2024–2040 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Hellal, F. et al. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 331, 928–931 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ruschel, J. et al. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury. Science 348, 347–352 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Nawabi, H. et al. Doublecortin-like kinases promote neuronal survival and induce growth cone reformation via distinct mechanisms. Neuron 88, 704–719 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Fawcett, J. W. The struggle to make CNS axons regenerate: why has it been so difficult? Neurochem. Res. 45, 144–158 (2020).

    Article  CAS  PubMed  Google Scholar 

  137. Terenzio, M. et al. Locally translated mTOR controls axonal local translation in nerve injury. Science 359, 1416–1421 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Perry, R. B. et al. Subcellular knockout of importin beta1 perturbs axonal retrograde signaling. Neuron 75, 294–305 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Dalla Costa, I. et al. The functional organization of axonal mRNA transport and translation. Nat. Rev. Neurosci. 22, 77–91 (2021).

    Article  CAS  PubMed  Google Scholar 

  140. Petrova, V. et al. Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS. Nat. Commun. 11, 5614 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Zhou, B. et al. Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits. J. Cell Biol. 214, 103–119 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Han, Q. et al. Restoring cellular energetics promotes axonal regeneration and functional recovery after spinal cord injury. Cell Metab. 31, 623–641.e8 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Huang, N. et al. Reprogramming an energetic AKT-PAK5 axis boosts axon energy supply and facilitates neuron survival and regeneration after injury and ischemia. Curr. Biol. 31, 3098–3114.e7 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Cartoni, R. et al. The mammalian-specific protein Armcx1 regulates mitochondrial transport during axon regeneration. Neuron 92, 1294–1307 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Li, F. et al. Glial metabolic rewiring promotes axon regeneration and functional recovery in the central nervous system. Cell Metab. 32, 767–785.e7 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Kadoya, K. et al. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat. Med. 22, 479–487 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Dulin, J. N. et al. Injured adult motor and sensory axons regenerate into appropriate organotypic domains of neural progenitor grafts. Nat. Commun. 9, 84 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Kumamaru, H., Lu, P., Rosenzweig, E. S., Kadoya, K. & Tuszynski, M. H. Regenerating corticospinal axons innervate phenotypically appropriate neurons within neural stem cell grafts. Cell Rep. 26, 2329–2339.e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Poplawski, G. H. D. et al. Injured adult neurons regress to an embryonic transcriptional growth state. Nature 581, 77–82 (2020).

    Article  CAS  PubMed  Google Scholar 

  150. Lu, P. et al. Origins of neural progenitor cell-derived axons projecting caudally after spinal cord injury. Stem Cell Rep. 13, 105–114 (2019).

    Article  CAS  Google Scholar 

  151. Ceto, S., Sekiguchi, K. J., Takashima, Y., Nimmerjahn, A. & Tuszynski, M. H. Neural stem cell grafts form extensive synaptic networks that integrate with host circuits after spinal cord injury. Cell Stem Cell 27, 430–440.e5 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Meves, J. M. & Zheng, B. Synaptic suppression of axon regeneration. Neuron 92, 267–269 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. Zheng, B., Lorenzana, A. O. & Ma, L. Understanding the axonal response to injury by in vivo imaging in the mouse spinal cord: a tale of two branches. Exp. Neurol. 318, 277–285 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Di Maio, A. et al. In vivo imaging of dorsal root regeneration: rapid immobilization and presynaptic differentiation at the CNS/PNS border. J. Neurosci. 31, 4569–4582 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Filous, A. R. 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. 34, 16369–16384 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Lorenzana, A. O., Lee, J. K., Mui, M., Chang, A. & Zheng, B. A surviving intact branch stabilizes remaining axon architecture after injury as revealed by in vivo imaging in the mouse spinal cord. Neuron 86, 947–954 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Tedeschi, A. et al. The calcium channel subunit Alpha2delta2 suppresses axon regeneration in the adult CNS. Neuron 92, 419–434 (2016).

    Article  CAS  PubMed  Google Scholar 

  158. Hilton, B. J. et al. An active vesicle priming machinery suppresses axon regeneration upon adult CNS injury. Neuron 110, 51–69.e7 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Fehlings, M. G. et al. Efficacy and safety of methylprednisolone sodium succinate in acute spinal cord injury: a systematic review. Glob. Spine J. 7, 116S–137S (2017).

    Article  Google Scholar 

  160. Ransom, S. C. et al. Hypothermia therapy for traumatic spinal cord injury: an updated review. J. Clin. Med. 11, 1585 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Ahmed, Z., Alhajlah, S., Thompson, A. M. & Fairclough, R. J. Clinic-ready inhibitor of MMP-9/-12 restores sensory and functional decline in rodent models of spinal cord injury. Clin. Transl Med. 12, e884 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Garcia-Alias, G., Barkhuysen, S., Buckle, M. & Fawcett, J. W. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat. Neurosci. 12, 1145–1151 (2009).

    Article  CAS  PubMed  Google Scholar 

  163. Courtine, G. & Sofroniew, M. V. Spinal cord repair: advances in biology and technology. Nat. Med. 25, 898–908 (2019).

    Article  CAS  PubMed  Google Scholar 

  164. Angeli, C. A., Edgerton, V. R., Gerasimenko, Y. P. & Harkema, S. J. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain 137, 1394–1409 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Wagner, F. B. et al. Targeted neurotechnology restores walking in humans with spinal cord injury. Nature 563, 65–71 (2018).

    Article  CAS  PubMed  Google Scholar 

  166. Gill, M. L. et al. Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia. Nat. Med. 24, 1677–1682 (2018).

    Article  CAS  PubMed  Google Scholar 

  167. Chen, B. et al. Reactivation of dormant relay pathways in injured spinal cord by KCC2 manipulations. Cell 174, 521–535.e13 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Bei, F. et al. Restoration of visual function by enhancing conduction in regenerated axons. Cell 164, 219–232 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Wang, J. et al. Robust myelination of regenerated axons induced by combined manipulations of GPR17 and microglia. Neuron 108, 876–886.e4 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Breasted, J. H. The Edwin Smith Surgical Papyrus (Univ. Chicago Press, 1930).

  171. Tello, F. La influencia del neurotropismo en la regeneracion de las centros nerviosos. Trab. Lab. Invest. Biol. Univ. Madr. 9, 123–159 (1911).

    Google Scholar 

  172. Richardson, P. M., McGuinness, U. M. & Aguayo, A. J. Axons from CNS neurons regenerate into PNS grafts. Nature 284, 264–265 (1980).

    Article  CAS  PubMed  Google Scholar 

  173. Keirstead, S. A. et al. Electrophysiologic responses in hamster superior colliculus evoked by regenerating retinal axons. Science 246, 255–257 (1989).

    Article  CAS  PubMed  Google Scholar 

  174. Likhanski, L. In Search of the Lost Cord: Solving the Mystery of Spinal Cord Regeneration (Joseph Henry Press, 2001).

  175. McQuarrie, I. G., Grafstein, B. & Gershon, M. D. Axonal regeneration in the rat sciatic nerve: effect of a conditioning lesion and of dbcAMP. Brain Res. 132, 443–453 (1977).

    Article  CAS  PubMed  Google Scholar 

  176. Richardson, P. M. & Issa, V. M. Peripheral injury enhances central regeneration of primary sensory neurones. Nature 309, 791–793 (1984).

    Article  CAS  PubMed  Google Scholar 

  177. Neumann, S. & Woolf, C. J. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron 23, 83–91 (1999).

    Article  CAS  PubMed  Google Scholar 

  178. Neumann, S., Bradke, F., Tessier-Lavigne, M. & Basbaum, A. I. Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. Neuron 34, 885–893 (2002).

    Article  CAS  PubMed  Google Scholar 

  179. Qiu, J. et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 895–903 (2002).

    Article  CAS  PubMed  Google Scholar 

  180. Goldberg, J. L., Klassen, M. P., Hua, Y. & Barres, B. A. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science 296, 1860–1864 (2002).

    Article  CAS  PubMed  Google Scholar 

  181. Raivich, G. & Kreutzberg, G. W. Peripheral nerve regeneration: role of growth factors and their receptors. Int. J. Dev. Neurosci. 11, 311–324 (1993).

    Article  CAS  PubMed  Google Scholar 

  182. Terenghi, G. Peripheral nerve regeneration and neurotrophic factors. J. Anat. 194, 1–14 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Tuszynski, M. H. & Gage, F. H. Bridging grafts and transient nerve growth factor infusions promote long-term central nervous system neuronal rescue and partial functional recovery. Proc. Natl Acad. Sci. USA 92, 4621–4625 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. O’Shea, T. M., Burda, J. E. & Sofroniew, M. V. Cell biology of spinal cord injury and repair. J. Clin. Invest. 127, 3259–3270 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Anderson, M. A. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Sofroniew, M. V. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16, 249–263 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Bush, T. G. et al. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23, 297–308 (1999).

    Article  CAS  PubMed  Google Scholar 

  188. Faulkner, J. R. et al. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J. Neurosci. 24, 2143–2155 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Silver, J. The glial scar is more than just astrocytes. Exp. Neurol. 286, 147–149 (2016).

    Article  PubMed  Google Scholar 

  190. Hawthorne, A. L. et al. The unusual response of serotonergic neurons after CNS injury: lack of axonal dieback and enhanced sprouting within the inhibitory environment of the glial scar. J. Neurosci. 31, 5605–5616 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Jones, L. L., Yamaguchi, Y., Stallcup, W. B. & Tuszynski, M. H. NG2 is a major chondroitin sulfate proteoglycan produced after spinal cord injury and is expressed by macrophages and oligodendrocyte progenitors. J. Neurosci. 22, 2792–2803 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Sofroniew, M. V. Astrogliosis. Cold Spring Harb. Perspect. Biol. 7, a020420 (2014).

    Article  PubMed  Google Scholar 

  193. Escartin, C. et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat. Neurosci. 24, 312–325 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Francos-Quijorna, I. et al. Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury. Nat. Commun. 13, 2933 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Goritz, C. et al. A pericyte origin of spinal cord scar tissue. Science 333, 238–242 (2011).

    Article  PubMed  Google Scholar 

  196. Soderblom, C. et al. Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury. J. Neurosci. 33, 13882–13887 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Dias, D. O. et al. Reducing pericyte-derived scarring promotes recovery after spinal cord injury. Cell 173, 153–165.e22 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Li, Y. et al. Microglia-organized scar-free spinal cord repair in neonatal mice. Nature 587, 613–618 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Nogueira-Rodrigues, J. et al. Rewired glycosylation activity promotes scarless regeneration and functional recovery in spiny mice after complete spinal cord transection. Dev. Cell 57, 440–450.e7 (2022).

    Article  CAS  PubMed  Google Scholar 

  200. Narang, A. & Zheng, B. To scar or not to scar. Trends Mol. Med. 24, 522–524 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Bjorklund, A., Katzman, R., Stenevi, U. & West, K. A. Development and growth of axonal sprouts from noradrenaline and 5-hydroxytryptamine neurones in the rat spinal cord. Brain Res. 31, 21–33 (1971).

    Article  CAS  PubMed  Google Scholar 

  202. Gage, F. H. Mammalian neural stem cells. Science 287, 1433–1438 (2000).

    Article  CAS  PubMed  Google Scholar 

  203. Lepore, A. C. & Fischer, I. Lineage-restricted neural precursors survive, migrate, and differentiate following transplantation into the injured adult spinal cord. Exp. Neurol. 194, 230–242 (2005).

    Article  CAS  PubMed  Google Scholar 

  204. Mitsui, T., Shumsky, J. S., Lepore, A. C., 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. 25, 9624–9636 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Bonner, J. F. et al. Grafted neural progenitors integrate and restore synaptic connectivity across the injured spinal cord. J. Neurosci. 31, 4675–4686 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Gaillard, A. et al. Reestablishment of damaged adult motor pathways by grafted embryonic cortical neurons. Nat. Neurosci. 10, 1294–1299 (2007).

    Article  CAS  PubMed  Google Scholar 

  207. Rosenzweig, E. S. et al. Restorative effects of human neural stem cell grafts on the primate spinal cord. Nat. Med. 24, 484–490 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Poplawski, G. H. D. et al. Adult rat myelin enhances axonal outgrowth from neural stem cells. Sci. Transl Med. 10, eaal2563 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Kumamaru, H. et al. Generation and post-injury integration of human spinal cord neural stem cells. Nat. Methods 15, 723–731 (2018).

    Article  CAS  PubMed  Google Scholar 

  210. Cummings, B. J. et al. Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc. Natl Acad. Sci. USA 102, 14069–14074 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Keirstead, H. S. et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J. Neurosci. 25, 4694–4705 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Lindsay, S. L. & Barnett, S. C. Therapeutic potential of niche-specific mesenchymal stromal cells for spinal cord injury repair. Cells 10, 901 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Monje, P. V., Deng, L. & Xu, X. M. Human schwann cell transplantation for spinal cord injury: prospects and challenges in translational medicine. Front. Cell Neurosci. 15, 690894 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Anderson, K. D. et al. Safety of autologous human schwann cell transplantation in subacute thoracic spinal cord injury. J. Neurotrauma 34, 2950–2963 (2017).

    Article  PubMed  Google Scholar 

  215. Gant, K. L. et al. Phase 1 safety trial of autologous human schwann cell transplantation in chronic spinal cord injury. J. Neurotrauma 39, 285–299 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Li, Y., Field, P. M. & Raisman, G. Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 277, 2000–2002 (1997).

    Article  CAS  PubMed  Google Scholar 

  217. Ramon-Cueto, A., Cordero, M. I., Santos-Benito, F. F. & Avila, J. Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron 25, 425–435 (2000).

    Article  CAS  PubMed  Google Scholar 

  218. Curt, A. et al. The damaged spinal cord is a suitable target for stem cell transplantation. Neurorehabil. Neural Repair 34, 758–768 (2020).

    Article  PubMed  Google Scholar 

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Acknowledgements

Research in the B.Z. laboratory has been funded by NIH/NINDS (NS093055, NS054734), VA (RX002483), CIRM, Wings for Life and Craig H. Neilsen Foundations, aided by UCSD School of Medicine/Neuroscience Microscopy Core (NS047101). Research in the M.H.T. laboratory has been funded by NIH/NINDS (NS104442, NS114043, NS105478, NS042291), VA (RX001706, the Veterans Administration Gordon Mansfield Consortium IP50RX001045 and RR&D B7332R), CIRM, the Bernard and Anne Spitzer Charitable Trust, Wings for Life, the Craig H. Neilsen Foundation, the Gerbic Family Foundation, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. The contents do not represent the views of the US Department of Veterans Affairs or the United States Government.

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  1. Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA, USA

    Binhai Zheng & Mark H. Tuszynski

  2. VA San Diego Research Service, San Diego, CA, USA

    Binhai Zheng & Mark H. Tuszynski

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Glossary

Astrogliosis

Also known as reactive astrogliosis, astrocytosis or astrocyte reactivity, refers to the astrocyte response to injury, disease or other insults and challenges in the central nervous system (CNS). Astrocytes proliferate, undergo hypertrophy and express increased levels of markers of reactivity, including glial fibrillary acidic protein (GFAP) and vimentin. At the injury border, highly reactive astrocytes form the astrocyte border that contains the fibrotic scar and lesion core.

Central nervous system

(CNS). Part of the nervous system that consists primarily of the brain and spinal cord. The optic nerve is unusual among the cranial nerves in that it is part of the CNS and is often used as a model to study CNS axon regeneration.

Corticospinal tract

(CST). Controls voluntary movement in humans. In rodents, the CST is often used as a model to study axon regeneration after spinal cord injury. The neurons that give rise to the CST are called corticospinal neurons, sometimes referred to as corticospinal motor neurons.

Chondroitin sulfate proteoglycans

(CSPGs). A group of molecules that have a protein core and a chondroitin sulfate side chain. Examples include neurocan, aggrecan, brevican, phosphacan and versican. CSPGs are considered inhibitory to axonal repair after central nervous system (CNS) injury.

Dorsal root ganglion

(DRG). Dorsal root ganglia are located outside the spinal cord and contain the cell bodies of sensory neurons that are pseudo-unipolar in morphology, meaning that they extend one axon from the cell body, but this axon soon bifurcates into two major axonal branches with one branch travelling in the peripheral nervous system (PNS) and the other extending into the central nervous system (CNS). This unique anatomical feature makes DRG neurons an appealing model to study the differential regenerative capabilities between the CNS and the PNS.

Growth cones

Hand-like structures at the tip of developing or regenerating axons. The outer region is mainly supported by the actin cytoskeleton and the inner region is mainly supported by the microtubule cytoskeleton. Growth cones are responsible for sensing, interpreting and responding to environmental cues. They are critical for axon growth and regeneration.

Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway

This pathway responds to extracellular signalling molecules, such as cytokines and growth factors, to trigger cellular responses through the regulation of transcription. Ligand-receptor interaction activates JAKs, which then activate STATs, which in turn regulate transcription.

Neural stem cell

(NSC). Can give rise to a variety of cells of neural lineages, including neurons and glia. NSC transplantation has the potential to improve functional recovery by promoting regeneration and neuronal relay. In transplantation studies, NSCs may be referred to as neural progenitor cells due to the uncertain or mixed developmental stage of the transplanted cells.

Oligodendrocyte progenitor cells

These glial cells are marked by their expression of neural/glial antigen 2 (NG2) and can proliferate and differentiate into mature myelinating oligodendrocytes in injury or disease. Oligodendrocyte progenitor cells are also known to contribute to scar formation after spinal cord injury.

Peripheral nerve bridges

A piece of peripheral nerve is taken from the peripheral nervous system (PNS) and transplanted into the central nervous system (CNS), where it serves as a conduit or bridge for axons to regenerate through. This is based on the observation that the PNS provides an environment conducive to axonal regeneration.

Peripheral nervous system

(PNS). Part of the nervous system outside the brain and the spinal cord that comprises the nerves and the ganglia. The PNS has a much higher capacity for axon regeneration than the central nervous system (CNS).

Retinal ganglion cells

(RGCs). Neurons in the mammalian retina that convey information from the retina to the rest of the brain. Their accessibility and long axonal projections make RGCs an excellent model system to study axon regeneration after optic nerve injury.

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Zheng, B., Tuszynski, M.H. Regulation of axonal regeneration after mammalian spinal cord injury. Nat Rev Mol Cell Biol 24, 396–413 (2023). https://doi.org/10.1038/s41580-022-00562-y

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