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 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.

The repair Schwann cell and its function in regenerating nerves

“…This repair programme includes a number of components. First, the up-regulation of neurotrophic factors and surface proteins that promote axonal elongation and the survival of injured neurons, including glial cell line-derived neurotrophic factor (GDNF), artemin, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), nerve growth J Physiol 594.13 factor (NGF), vascular endothelial growth factor (VEGF), erythropoietin, pleiotrophin, p75NTR and N-cadherin (Fontana et al 2012;Brushart et al 2013;reviewed in Boyd & Gordon, 2003;Chen et al 2007;Scheib & Höke, 2013;Wood & Mackinnon, 2015). Second, it involves the activation of an innate immune response, including the upregulation of cytokines including tumour necrosis factor α (TNFα), interleukin-1α (Il-1α), Il-1β, leukaemia inhibitory factor (LIF) and monocyte chemotactic protein 1 (MCP-1) by the Schwann cells in the distal stump (reviewed in Martini et al 2008;Rotshenker, 2011 and, in particular, recruit macrophages to the nerve.…”

“…; reviewed in Boyd & Gordon, ; Chen et al . ; Scheib & Höke, ; Wood & Mackinnon, ). Second, it involves the activation of an innate immune response, including the upregulation of cytokines including tumour necrosis factor α (TNFα), interleukin‐1α (Il‐1α), Il‐1β, leukaemia inhibitory factor (LIF) and monocyte chemotactic protein 1 (MCP‐1) by the Schwann cells in the distal stump (reviewed in Martini et al .…”

Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves

“…The other component of the injury response is the sequential activation of a diverse features all of which support repair: (a) Upregulation of proteins that support neuronal survival and promote axonal regeneration, such as GDNF, artemin, BDNF, NT3, NGF, VEGF, erythropoietin, pleiotrophin, p75NTR, and N‐cadherin (Brushart et al, ; Chen et al, ; Fontana et al, ; reviewed in Boyd & Gordon, ; Scheib & Hőke, ; Wood & Mackinnon, ). (b) Activation of an innate immune response, comprising the upregulation of cytokines including TNFα, LIF Il‐1α, Il‐1β, LIF, and MCP‐1 (reviewed in Martini et al, ; Rotshenker, ).…”

Neural Progenitor-Like Cells Induced from Human Gingiva-Derived Mesenchymal Stem Cells Regulate Myelination of Schwann Cells in Rat Sciatic Nerve Regeneration

“…Injuries to the peripheral nervous system (PNS) are debilitating and usually lead to considerable long‐term disability as a result of loss of nerve and end‐organ target functions . Even though the endogenous repair process is initiated after nerve injury, intrinsic regenerative capability is rather limited, especially when there is a large gap between the damaged nerve stumps , . In the last decade, even though significant effort has been made to develop various types of bioengineered nerve grafts to facilitate peripheral nerve regeneration , the overall clinical outcomes still remain suboptimal .…”