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Mechanisms of Disease: what factors limit the success of peripheral nerve regeneration in humans?

Abstract

Functional recovery after repair of peripheral nerve injury in humans is often suboptimal. Over the past quarter of a century, there have been significant advances in human nerve repair, but most of the developments have been in the optimization of surgical techniques. Despite extensive research, there are no current therapies directed at the molecular mechanisms of nerve regeneration. Multiple interventions have been shown to improve nerve regeneration in small animal models, but have not yet translated into clinical therapies for human nerve injuries. In many rodent models, regeneration occurs over relatively short distances, so the duration of denervation is short. By contrast, in humans, nerves often have to regrow over long distances, and the distal portion of the nerve progressively loses its ability to support regeneration during this process. This can be largely attributed to atrophy of Schwann cells and loss of a Schwann cell basal lamina tube, which results in an extracellular environment that is inhibitory to nerve regeneration. To develop successful molecular therapies for nerve regeneration, we need to generate animal models that can be used to address the following issues: improving the intrinsic ability of neurons to regenerate to increase the speed of axonal outgrowth; preventing loss of basal lamina and chronic denervation changes in the denervated Schwann cells; and overcoming inhibitory cues in the extracellular matrix.

Key Points

  • Functional recovery after peripheral nerve repairs in humans is suboptimal

  • Impaired nerve regeneration in humans is primarily attributable to chronic denervation changes in the distal nerve because of the limitations of speed of nerve regeneration and the distances involved

  • Better therapies for nerve regeneration will need to address the following issues: improving the intrinsic ability of neurons to regenerate to increase the speed of axonal outgrowth; preventing loss of basal lamina and chronic denervation changes in the denervated Schwann cells; and overcoming inhibitory cues in the extracellular matrix

  • Animal models that take these issues into consideration, such as secondary repair after chronic denervation in rats, are required to test new therapies that are relevant to human nerve regeneration

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Figure 1: Challenges to nerve regeneration in acute denervation versus chronic denervation in the peripheral nervous system.

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Höke, A. Mechanisms of Disease: what factors limit the success of peripheral nerve regeneration in humans?. Nat Rev Neurol 2, 448–454 (2006). https://doi.org/10.1038/ncpneuro0262

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  • DOI: https://doi.org/10.1038/ncpneuro0262

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