Pathways regulating modality-specific axonal regeneration in peripheral nerve

Abstract

Following peripheral nerve injury, the distal nerve is primed for regenerating axons by generating a permissive environment replete with glial cells, cytokines, and neurotrophic factors to encourage axonal growth. However, increasing evidence demonstrates that regenerating axons within peripheral nerves still encounter axonal-growth inhibitors, such as chondroitin sulfate proteoglycans. Given the generally poor clinical outcomes following peripheral nerve injury and reconstruction, the use of pharmacological therapies to augment axonal regeneration and overcome inhibitory signals has gained considerable interest. Joshi et al. (2014) have provided evidence for preferential or modality-specific (motor versus sensory) axonal growth and regeneration due to inhibitory signaling from Rho-associated kinase (ROCK) pathway regulation. By providing inhibition to the ROCK signaling pathway through Y-27632, they demonstrate that motor neurons regenerating their axons are impacted to a greater extent compared to sensory neurons. In light of this evidence, we briefly review the literature regarding modality-specific axonal regeneration to provide context to their findings. We also describe potential and novel barriers, such as senescent Schwann cells, which provide additional axonal-growth inhibitory factors for future consideration following peripheral nerve injury.

Keywords: Axon modality; Chondroitin sulfate proteoglycan; Motor neuron; Nerve regeneration; Peripheral nerve; ROCK; RhoA; Schwann cell; Sensory neuron; Y-27632.

Figure 1. Pathways influencing modality-specific axonal regeneration

Within the regenerative pathway, axons (Ax) encounter glial cells (Schwann cells (Sc)), tropic factors derived from end-organs (exosomes (Ex)), and endoneurial architecture (En). These components modulate the growth response of sensory and motor neurons and their axons as they respond to this environment.