Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The translational landscape in spinal cord injury: focus on neuroplasticity and regeneration

Abstract

Over the past decade, we have witnessed a flourishing of novel strategies to enhance neuroplasticity and promote axon regeneration following spinal cord injury, and results from preclinical studies suggest that some of these strategies have the potential for clinical translation. Spinal cord injury leads to the disruption of neural circuitry and connectivity, resulting in permanent neurological disability. Recovery of function relies on augmenting neuroplasticity to potentiate sprouting and regeneration of spared and injured axons, to increase the strength of residual connections and to promote the formation of new connections and circuits. Neuroplasticity can be fostered by exploiting four main biological properties: neuronal intrinsic signalling, the neuronal extrinsic environment, the capacity to reconnect the severed spinal cord via neural stem cell grafts, and modulation of neuronal activity. In this Review, we discuss experimental evidence from rodents, nonhuman primates and patients regarding interventions that target each of these four properties. We then highlight the strengths and challenges of individual and combinatorial approaches with respect to clinical translation. We conclude by considering future developments and providing views on how to bridge the gap between preclinical studies and clinical translation.

Key points

  • Spinal cord injury (SCI) is a complex pathological condition and although several therapeutic approaches have shown potential in preclinical studies, few have progressed to clinical trials.

  • Understanding the spatial and temporal changes in transcription and chromatin accessibility in selected neuronal subpopulations after SCI could help identify key proteins that orchestrate specific changes in neuroplasticity.

  • The use of chondroitinase ABC and anti-NogoA treatment to reduce inhibitory signalling in the neuronal extrinsic environment after SCI has shown promise in terms of promoting axon sprouting and recovery.

  • Unprecedented long-distance axon regeneration, cell replacement and relay formation have been achieved using spinal cord-derived neural stem cell grafts combined with growth factors.

  • Neuromodulation strategies including electrical epidural stimulation and brain–machine interfaces have demonstrated impressive improvements in voluntary motor function, and wireless systems will further improve the clinical utility of these strategies.

  • Combining mechanism-based biological strategies with targeted technological interventions to augment neuroplasticity, followed by rehabilitation to direct circuit reorganization, could facilitate clinically meaningful recovery after SCI.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Neuroplasticity and regeneration after spinal cord injury.
Fig. 2: Targeting of transcriptional and epigenetic pathways after spinal cord injury.
Fig. 3: Formation of neuronal relays after spinal cord injury.
Fig. 4: Neuromodulatory approaches to restore function after spinal cord injury.

Similar content being viewed by others

References

  1. Orr, M. B. & Gensel, J. C. Spinal cord injury scarring and inflammation: therapies targeting glial and inflammatory responses. Neurotherapeutics 15, 541–553 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ahuja, C. S., Martin, A. R. & Fehlings, M. Recent advances in managing a spinal cord injury secondary to trauma. F1000Res. 5, 1017 (2016).

    Article  CAS  Google Scholar 

  3. Krucoff, M. O., Rahimpour, S., Slutzky, M. W., Edgerton, V. R. & Turner, D. A. Enhancing nervous system recovery through neurobiologics, neural interface training, and neurorehabilitation. Front. Neurosci. 10, 584 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Taccola, G., Sayenko, D., Gad, P., Gerasimenko, Y. & Edgerton, V. R. And yet it moves: recovery of volitional control after spinal cord injury. Prog. Neurobiol. 160, 64–81 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sofroniew, M. V. Dissecting spinal cord regeneration. Nature 557, 343–350 (2018).

    CAS  PubMed  Google Scholar 

  6. Onifer, S. M., Smith, G. M. & Fouad, K. Plasticity after spinal cord injury: relevance to recovery and approaches to facilitate it. Neurotherapeutics 8, 283–293 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Beattie, M. S. et al. Endogenous repair after spinal cord contusion injuries in the rat. Exp. Neurol. 148, 453–463 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Blesch, A. & Tuszynski, M. H. Spinal cord injury: plasticity, regeneration and the challenge of translational drug development. Trends Neurosci. 32, 41–47 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Asboth, L. et al. Cortico-reticulo-spinal circuit reorganization enables functional recovery after severe spinal cord contusion. Nat. Neurosci. 21, 576–588 (2018).

    Article  CAS  PubMed  Google Scholar 

  10. Mosberger, A. C. et al. Axotomized corticospinal neurons increase supra-lesional innervation and remain crucial for skilled reaching after bilateral pyramidotomy. Cereb. Cortex 28, 625–643 (2018).

    PubMed  Google Scholar 

  11. Topka, H., Cohen, L. G., Cole, R. A. & Hallett, M. Reorganization of corticospinal pathways following spinal cord injury. Neurology 41, 1276–1283 (1991).

    Article  CAS  PubMed  Google Scholar 

  12. Raineteau, O. & Schwab, M. E. Plasticity of motor systems after incomplete spinal cord injury. Nat. Rev. Neurosci. 2, 263–273 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Hilton, B. J. et al. Re-establishment of cortical motor output maps and spontaneous functional recovery via spared dorsolaterally projecting corticospinal neurons after dorsal column spinal cord injury in adult mice. J. Neurosci. 36, 4080–4092 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hollis, E. R. 2nd 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 

  15. Martin, J. H. Harnessing neural activity to promote repair of the damaged corticospinal system after spinal cord injury. Neural Regen. Res. 11, 1389–1391 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Jiang, Y. Q., Zaaimi, B. & Martin, J. H. Competition with primary sensory afferents drives remodeling of corticospinal axons in mature spinal motor circuits. J. Neurosci. 36, 193–203 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bareyre, F. M. et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat. Neurosci. 7, 269–277 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Bareyre, F. M., Kerschensteiner, M., Misgeld, T. & Sanes, J. R. Transgenic labeling of the corticospinal tract for monitoring axonal responses to spinal cord injury. Nat. Med. 11, 1355–1360 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Weidner, N., Ner, A., Salimi, N. & Tuszynski, M. H. Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury. Proc. Natl. Acad. Sci. USA 98, 3513–3518 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Courtine, G. et al. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat. Med. 14, 69–74 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kathe, C., Hutson, T. H., McMahon, S. B. & Moon, L. D. F. Intramuscular Neurotrophin-3 normalizes low threshold spinal reflexes, reduces spasms and improves mobility after bilateral corticospinal tract injury in rats. eLife 5, e18146 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Angeli, C. A. et al. Recovery of over-ground walking after chronic motor complete spinal cord injury. N. Engl. J. Med. 379, 1244–1250 (2018).

    Article  PubMed  Google Scholar 

  23. 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 

  24. Terenzio, M., Schiavo, G. & Fainzilber, M. Compartmentalized signaling in neurons: from cell biology to neuroscience. Neuron 96, 667–679 (2017).

    Article  CAS  PubMed  Google Scholar 

  25. Curcio, M. & Bradke, F. Axon regeneration in the central nervous system: facing the challenges from the inside. Annu. Rev. Cell Dev. Biol. 34, 495–521 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sandner, B. et al. Systemic epothilone D improves hindlimb function after spinal cord contusion injury in rats. Exp. Neurol. 306, 250–259 (2018).

    Article  CAS  PubMed  Google Scholar 

  28. Zhao, W. et al. Mechanisms responsible for the inhibitory effects of epothilone B on scar formation after spinal cord injury. Neural Regen. Res. 12, 478–485 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. 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 

  30. Popovich, P. G., Tovar, C. A., Lemeshow, S., Yin, Q. & Jakeman, L. B. Independent evaluation of the anatomical and behavioral effects of Taxol in rat models of spinal cord injury. Exp. Neurol. 261, 97–108 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Mao, L. et al. Epothilone B impairs functional recovery after spinal cord injury by increasing secretion of macrophage colony-stimulating factor. Cell Death Dis. 8, e3162 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hsu, S. T. et al. Effects of taxol on regeneration in a rat sciatic nerve transection model. Sci. Rep. 7, 42280 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Alabed, Y. Z., Grados-Munro, E., Ferraro, G. B., Hsieh, S. H. & Fournier, A. E. Neuronal responses to myelin are mediated by rho kinase. J. Neurochem. 96, 1616–1625 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Matsui, T. et al. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J. 15, 2208–2216 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Amano, M. et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J. Biol. Chem. 271, 20246–20249 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Fournier, A. E., Takizawa, B. T. & Strittmatter, S. M. Rho kinase inhibition enhances axonal regeneration in the injured CNS. J. Neurosci. 23, 1416–1423 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ellezam, B. et al. Inactivation of intracellular Rho to stimulate axon growth and regeneration. Prog. Brain Res. 137, 371–380 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Dergham, P. et al. Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22, 6570–6577 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nishio, Y. et al. Delayed treatment with Rho-kinase inhibitor does not enhance axonal regeneration or functional recovery after spinal cord injury in rats. Exp. Neurol. 200, 392–397 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Sahoo, P. K., Smith, D. S., Perrone-Bizzozero, N. & Twiss, J. L. Axonal mRNA transport and translation at a glance. J. Cell Sci. 131, jcs196808 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Google Scholar 

  42. Song, M. S., Salmena, L. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor. Nat. Rev. Mol. Cell Biol. 13, 283–296 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. 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 

  44. 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 

  45. 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 

  46. 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 

  47. 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 

  48. Joshi, Y. et al. The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury. Brain 138, 1843–1862 (2015).

    Article  PubMed  Google Scholar 

  49. Kolevzon, A. et al. A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome. Mol. Autism 5, 54 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. 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 

  51. Warner, F. M. et al. Early administration of gabapentinoids improves motor recovery after human spinal cord injury. Cell Rep. 18, 1614–1618 (2017).

    Article  CAS  PubMed  Google Scholar 

  52. Kaila, K., Price, T. J., Payne, J. A., Puskarjov, M. & Voipio, J. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat. Rev. Neurosci. 15, 637–654 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen, B. et al. Reactivation of dormant relay pathways in injured spinal cord by KCC2 manipulations. Cell 174, 1599 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Smith, D. S. & Skene, J. H. A transcription-dependent switch controls competence of adult neurons for distinct modes of axon growth. J. Neurosci. 17, 646–658 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Moore, D. L. & Goldberg, J. L. Multiple transcription factor families regulate axon growth and regeneration. Dev. Neurobiol. 71, 1186–1211 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tedeschi, A. Tuning the orchestra: transcriptional pathways controlling axon regeneration. Front. Mol. Neurosci. 4, 60 (2011).

    PubMed  Google Scholar 

  57. 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 

  58. Li, W. Y. et al. AAV-KLF7 promotes descending propriospinal neuron axonal plasticity after spinal cord injury. Neural. Plast. 2017, 1621629 (2017).

    PubMed  PubMed Central  Google Scholar 

  59. 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 

  60. Floriddia, E. M. et al. p53 regulates the neuronal intrinsic and extrinsic responses affecting the recovery of motor function following spinal cord injury. J. Neurosci. 32, 13956–13970 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Vassilev, L. T. Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 3, 419–421 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Sakamoto, K., Karelina, K. & Obrietan, K. CREB: a multifaceted regulator of neuronal plasticity and protection. J. Neurochem. 116, 1–9 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Siddiq, M. M. & Hannila, S. S. Looking downstream: the role of cyclic AMP-regulated genes in axonal regeneration. Front. Mol. Neurosci. 8, 26 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Gao, Y. et al. Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo. Neuron 44, 609–621 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. Costa, L. M. et al. Rolipram promotes functional recovery after contusive thoracic spinal cord injury in rats. Behav. Brain Res. 243, 66–73 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Bielekova, B. et al. Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood–brain barrier disruption in multiple sclerosis. Mult. Scler. 15, 1206–1214 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yan, Y. et al. Stat3 signaling is present and active during development of the central nervous system and eye of vertebrates. Dev. Dyn. 231, 248–257 (2004).

    Article  PubMed  CAS  Google Scholar 

  69. 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 

  70. Lang, C., Bradley, P. M., Jacobi, A., Kerschensteiner, M. & Bareyre, F. M. STAT3 promotes corticospinal remodelling and functional recovery after spinal cord injury. EMBO Rep. 14, 931–937 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Saha, R. N. & Pahan, K. HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ. 13, 539–550 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Mueller, W. C. & von Deimling, A. Gene regulation by methylation. Recent Results Cancer Res. 171, 217–239 (2009).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  74. 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 

  75. Cho, Y. & Cavalli, V. HDAC5 is a novel injury-regulated tubulin deacetylase controlling axon regeneration. EMBO J. 31, 3063–3078 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  77. 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 

  78. Venkatesh, I. & Blackmore, M. G. Selecting optimal combinations of transcription factors to promote axon regeneration: why mechanisms matter. Neurosci. Lett. 652, 64–73 (2017).

    Article  CAS  PubMed  Google Scholar 

  79. Silver, J., Schwab, M. E. & Popovich, P. G. Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb. Perspect. Biol. 7, a020602 (2014).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  81. 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 

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

    Article  CAS  PubMed  Google Scholar 

  83. 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 

  84. Burnside, E. R. et al. Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury. Brain 141, 2362–2381 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Miao, Q. L., Ye, Q. & Zhang, X. H. Perineuronal net, CSPG receptor and their regulation of neural plasticity. Sheng Li Xue Bao 66, 387–397 (2014).

    CAS  PubMed  Google Scholar 

  86. 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 

  87. 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 

  88. Fry, E. J., Chagnon, M. J., Lopez-Vales, R., Tremblay, M. L. & David, S. Corticospinal tract regeneration after spinal cord injury in receptor protein tyrosine phosphatase sigma deficient mice. Glia 58, 423–433 (2010).

    PubMed  Google Scholar 

  89. 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 

  90. 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 

  91. Liddelow, S. A. & Barres, B. A. Reactive astrocytes: production, function, and therapeutic potential. Immunity 46, 957–967 (2017).

    Article  CAS  PubMed  Google Scholar 

  92. McKerracher, L. et al. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13, 805–811 (1994).

    Article  CAS  PubMed  Google Scholar 

  93. Wang, K. C. et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941–944 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Chen, M. S. et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403, 434–439 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. GrandPre, T., Nakamura, F., Vartanian, T. & Strittmatter, S. M. Identification of the Nogo inhibitor of axon regeneration as a reticulon protein. Nature 403, 439–444 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Domeniconi, M. & Filbin, M. T. Overcoming inhibitors in myelin to promote axonal regeneration. J. Neurol. Sci. 233, 43–47 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Zorner, B. & Schwab, M. E. Anti-Nogo on the go: from animal models to a clinical trial. Ann. New Y. Acad. Sci. 1198, E22–E34 (2010).

    Article  Google Scholar 

  98. Gonzenbach, R. R. et al. Delayed anti-Nogo-A antibody application after spinal cord injury shows progressive loss of responsiveness. J. Neurotrauma 29, 567–578 (2012).

    Article  PubMed  Google Scholar 

  99. Schwab, M. E. Nogo and axon regeneration. Curr. Opin. Neurobiol. 14, 118–124 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Cafferty, W. B., McGee, A. W. & Strittmatter, S. M. Axonal growth therapeutics: regeneration or sprouting or plasticity? Trends Neurosci. 31, 215–220 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Pernet, V. & Schwab, M. E. The role of Nogo-A in axonal plasticity, regrowth and repair. Cell Tissue Res. 349, 97–104 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Liebscher, T. et al. Nogo-A antibody improves regeneration and locomotion of spinal cord-injured rats. Ann. Neurol. 58, 706–719 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Freund, P. et al. Nogo-A-specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates. Nat. Med. 12, 790–792 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Freund, P. et al. Anti-Nogo-A antibody treatment promotes recovery of manual dexterity after unilateral cervical lesion in adult primates — re-examination and extension of behavioral data. Eur. J. Neurosci. 29, 983–996 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Wang, X. et al. Human NgR-Fc decoy protein via lumbar intrathecal bolus administration enhances recovery from rat spinal cord contusion. J. Neurotrauma 31, 1955–1966 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Kucher, K. et al. First-in-man intrathecal application of neurite growth-promoting anti-Nogo-A antibodies in acute spinal cord injury. Neurorehabil. Neural. Repair 32, 578–589 (2018).

    Article  PubMed  Google Scholar 

  107. Chen, K. et al. Sequential therapy of anti-Nogo-A antibody treatment and treadmill training leads to cumulative improvements after spinal cord injury in rats. Exp. Neurol. 292, 135–144 (2017).

    Article  CAS  PubMed  Google Scholar 

  108. 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 

  109. Assinck, P., Duncan, G. J., Hilton, B. J., Plemel, J. R. & Tetzlaff, W. Cell transplantation therapy for spinal cord injury. Nat. Neurosci. 20, 637–647 (2017).

    Article  CAS  PubMed  Google Scholar 

  110. Abbaszadeh, H. A. et al. Stem cell transplantation and functional recovery after spinal cord injury: a systematic review and meta-analysis. Anat. Cell Biol. 51, 180–188 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Priest, C. A., Manley, N. C., Denham, J., Wirth, E. D. 3rd & Lebkowski, J. S. Preclinical safety of human embryonic stem cell-derived oligodendrocyte progenitors supporting clinical trials in spinal cord injury. Regen. Med. 10, 939–958 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Curtis, E. et al. A first-in-human, phase I study of neural stem cell transplantation for chronic spinal cord injury. Cell Stem Cell 22, 941–950.e6 (2018).

    Article  CAS  PubMed  Google Scholar 

  113. Cyranoski, D. Japan’s approval of stem-cell treatment for spinal-cord injury concerns scientists. Nature 565, 544–545 (2019).

    Article  CAS  PubMed  Google Scholar 

  114. 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 

  115. Bonner, J. F., Blesch, A., Neuhuber, B. & Fischer, I. Promoting directional axon growth from neural progenitors grafted into the injured spinal cord. J. Neurosci. Res. 88, 1182–1192 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 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 

  117. Lu, P. et al. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron 83, 789–796 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 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 

  119. Brock, J. H., Graham, L., Staufenberg, E., Im, S. & Tuszynski, M. H. Rodent neural progenitor cells support functional recovery after cervical spinal cord contusion. J. Neurotrauma 35, 1069–1078 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  120. 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 

  121. 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  CAS  Google Scholar 

  122. 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 

  123. Steward, O., Sharp, K. G., Yee, K. M., Hatch, M. N. & Bonner, J. F. Characterization of ectopic colonies that form in widespread areas of the nervous system with neural stem cell transplants into the site of a severe spinal cord injury. J. Neurosci. 34, 14013–14021 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Romero, M. I. et al. Extensive sprouting of sensory afferents and hyperalgesia induced by conditional expression of nerve growth factor in the adult spinal cord. J. Neurosci. 20, 4435–4445 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hofstetter, C. P. et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat. Neurosci. 8, 346–353 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. 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 

  127. Gerasimenko, Y. P. et al. Noninvasive reactivation of motor descending control after paralysis. J. Neurotrauma 32, 1968–1980 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Grahn, P. J. et al. Enabling task-specific volitional motor functions via spinal cord neuromodulation in a human with paraplegia. Mayo Clin. Proc. 92, 544–554 (2017).

    Article  PubMed  Google Scholar 

  129. Chen, K. H. et al. The effect of chronic intracortical microstimulation on the electrode-tissue interface. J. Neural. Eng. 11, 026004 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Minev, I. R. et al. Biomaterials. Electronic dura mater for long-term multimodal neural interfaces. Science 347, 159–163 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. Yu, K. J. et al. Bioresorbable silicon electronics for transient spatiotemporal mapping of electrical activity from the cerebral cortex. Nat. Mater. 15, 782–791 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Guo, Y. et al. Biocompatibility and magnetic resonance imaging characteristics of carbon nanotube yarn neural electrodes in a rat model. Biomed. Eng. Online 14, 118 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  133. James, N. D., McMahon, S. B., Field-Fote, E. C. & Bradbury, E. J. Neuromodulation in the restoration of function after spinal cord injury. Lancet Neurol. 17, 905–917 (2018).

    Article  PubMed  Google Scholar 

  134. Rejc, E., Angeli, C. A., Atkinson, D. & Harkema, S. J. Motor recovery after activity-based training with spinal cord epidural stimulation in a chronic motor complete paraplegic. Sci. Rep. 7, 13476 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Moraud, E. M. et al. Mechanisms underlying the neuromodulation of spinal circuits for correcting gait and balance deficits after spinal cord injury. Neuron 89, 814–828 (2016).

    Article  CAS  PubMed  Google Scholar 

  136. Capogrosso, M. et al. A brain-spine interface alleviating gait deficits after spinal cord injury in primates. Nature 539, 284–288 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Hofstoetter, U. S., Freundl, B., Binder, H. & Minassian, K. Common neural structures activated by epidural and transcutaneous lumbar spinal cord stimulation: elicitation of posterior root-muscle reflexes. PLoS One 13, e0192013 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Mills, P. B. & Dossa, F. Transcutaneous electrical nerve stimulation for management of limb spasticity: a systematic review. Am. J. Phys. Med. Rehabil. 95, 309–318 (2016).

    Article  PubMed  Google Scholar 

  139. Takeoka, A., Vollenweider, I., Courtine, G. & Arber, S. Muscle spindle feedback directs locomotor recovery and circuit reorganization after spinal cord injury. Cell 159, 1626–1639 (2014).

    Article  CAS  PubMed  Google Scholar 

  140. Wenger, N. et al. Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury. Nat. Med. 22, 138–145 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Inanici, F. et al. Transcutaneous electrical spinal stimulation promotes long-term recovery of upper extremity function in chronic tetraplegia. IEEE Trans. Neural Syst. Rehabil. Eng. 26, 1272–1278 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Gomes-Osman, J. & Field-Fote, E. C. Cortical vs. afferent stimulation as an adjunct to functional task practice training: a randomized, comparative pilot study in people with cervical spinal cord injury. Clin. Rehabil. 29, 771–782 (2015).

    Article  PubMed  Google Scholar 

  143. Gomes-Osman, J. & Field-Fote, E. C. Improvements in hand function in adults with chronic tetraplegia following a multiday 10-Hz repetitive transcranial magnetic stimulation intervention combined with repetitive task practice. J. Neurol. Phys. Ther. 39, 23–30 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Alexeeva, N. & Calancie, B. Efficacy of QuadroPulse rTMS for improving motor function after spinal cord injury: three case studies. J. Spinal Cord Med. 39, 50–57 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Bunday, K. L. & Perez, M. A. Motor recovery after spinal cord injury enhanced by strengthening corticospinal synaptic transmission. Curr. Biol. 22, 2355–2361 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Carmel, J. B., Berrol, L. J., Brus-Ramer, M. & Martin, J. H. Chronic electrical stimulation of the intact corticospinal system after unilateral injury restores skilled locomotor control and promotes spinal axon outgrowth. J. Neurosci. 30, 10918–10926 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Carmel, J. B., Kimura, H. & Martin, J. H. Electrical stimulation of motor cortex in the uninjured hemisphere after chronic unilateral injury promotes recovery of skilled locomotion through ipsilateral control. J. Neurosci. 34, 462–466 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Song, W., Amer, A., Ryan, D. & Martin, J. H. Combined motor cortex and spinal cord neuromodulation promotes corticospinal system functional and structural plasticity and motor function after injury. Exp. Neurol. 277, 46–57 (2016).

    Article  PubMed  Google Scholar 

  149. Zareen, N. et al. Motor cortex and spinal cord neuromodulation promote corticospinal tract axonal outgrowth and motor recovery after cervical contusion spinal cord injury. Exp. Neurol. 297, 179–189 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Hochberg, L. R. et al. Reach and grasp by people with tetraplegia using a neurally controlled robotic arm. Nature 485, 372–375 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Lebedev, M. A. & Nicolelis, M. A. Brain-machine interfaces: from basic science to neuroprostheses and neurorehabilitation. Physiol. Rev. 97, 767–837 (2017).

    Article  PubMed  Google Scholar 

  152. Bouton, C. E. et al. Restoring cortical control of functional movement in a human with quadriplegia. Nature 533, 247–250 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. Alam, M., Rodrigues, W., Pham, B. N. & Thakor, N. V. Brain-machine interface facilitated neurorehabilitation via spinal stimulation after spinal cord injury: recent progress and future perspectives. Brain Res. 1646, 25–33 (2016).

    Article  CAS  PubMed  Google Scholar 

  154. Nishimura, Y., Perlmutter, S. I. & Fetz, E. E. Restoration of upper limb movement via artificial corticospinal and musculospinal connections in a monkey with spinal cord injury. Front. Neural. Circuits 7, 57 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Zimmermann, J. B. & Jackson, A. Closed-loop control of spinal cord stimulation to restore hand function after paralysis. Front. Neurosci. 8, 87 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Bonizzato, M. et al. Brain-controlled modulation of spinal circuits improves recovery from spinal cord injury. Nat. Commun. 9, 3015 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. 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 

  158. Zhao, R. R. et al. Combination treatment with anti-Nogo-A and chondroitinase ABC is more effective than single treatments at enhancing functional recovery after spinal cord injury. Eur. J. Neurosci. 38, 2946–2961 (2013).

    PubMed  Google Scholar 

  159. Wahl, A. S. et al. Neuronal repair. Asynchronous therapy restores motor control by rewiring of the rat corticospinal tract after stroke. Science 344, 1250–1255 (2014).

    Article  CAS  PubMed  Google Scholar 

  160. Takeoka, A. et al. Axon regeneration can facilitate or suppress hindlimb function after olfactory ensheathing glia transplantation. J. Neurosci. 31, 4298–4310 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. van den Brand, R. et al. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science 336, 1182–1185 (2012).

    Article  PubMed  CAS  Google Scholar 

  162. Lemon, R. N. Descending pathways in motor control. Annu. Rev Neurosci 31, 195–218 (2008).

    Article  CAS  PubMed  Google Scholar 

  163. Lawrence, D. G. & Kuypers, H. G. Pyramidal and non-pyramidal pathways in monkeys: anatomical and functional correlation. Science 148, 973–975 (1965).

    Article  CAS  PubMed  Google Scholar 

  164. Raposo, C. & Schwartz, M. Glial scar and immune cell involvement in tissue remodeling and repair following acute CNS injuries. Glia 62, 1895–1904 (2014).

    Article  PubMed  Google Scholar 

  165. Callahan, A. et al. Developing a data sharing community for spinal cord injury research. Exp. Neurol. 295, 135–143 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

Both authors contributed to all aspects of the article.

Corresponding author

Correspondence to Simone Di Giovanni.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neurology thanks M. Tuszynski and other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hutson, T.H., Di Giovanni, S. The translational landscape in spinal cord injury: focus on neuroplasticity and regeneration. Nat Rev Neurol 15, 732–745 (2019). https://doi.org/10.1038/s41582-019-0280-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-019-0280-3

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing