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.

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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.

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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

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