Abstract
After nerve injury, both Schwann cells and neurons switch to pro-regenerative states. For Schwann cells, this involves reprogramming of myelin and Remak cells to repair Schwann cells that provide the signals and mechanisms needed for the survival of injured neurons, myelin clearance, axonal regeneration and target reinnervation. Because functional repair cells are essential for regeneration, it is unfortunate that their phenotype is not robust. Repair cell activation falters as animals get older and the repair phenotype fades during chronic denervation. These malfunctions are important reasons for the poor outcomes after nerve damage in humans. This review will discuss injury-induced Schwann cell reprogramming and the concept of the repair Schwann cell, and consider the molecular control of these cells with emphasis on c-Jun. This transcription factor is required for the generation of functional repair cells, and failure of c-Jun expression is implicated in repair cell failures in older animals and during chronic denervation. Elevating c-Jun expression in repair cells promotes regeneration, showing in principle that targeting repair cells is an effective way of improving nerve repair. In this context, we will outline the emerging evidence that repair cells are sustained by autocrine signaling loops, attractive targets for interventions aimed at promoting regeneration.
Highlights
After nerve injury, both neurons and Schwann cells undergo radical change as they adopt phenotypes dedicated to support repair (Figure 1)
The presence of functional repair cells is indispensable for effective regeneration
It is unfortunate that the expression of their phenotype is not robust: repair cell activation falters as animals get older and the repair phenotype fades during chronic denervation
Summary
Both neurons and Schwann cells undergo radical change as they adopt phenotypes dedicated to support repair (Figure 1). This work has given rise to the idea that, in addition to the function of high Schwann cell c-Jun after injury, a more modest c-Jun elevation in uninjured nerves, even in Schwann cells that still retain myelin and Remak phenotypes, activates a neuron-supportive Schwann cell program that protects against neurological damage This is based on studies on the dose-dependence of c-Jun function using heterozygous (c-Jun OE/+) and homozygous (cJun OE/OE) c-Jun over-expressing mice, and on examining mouse models of Charcot-Marie-Tooth (CMT)1A and CMT1X disease (Hantke et al, 2014; Klein et al, 2014; Fazal et al, 2017). Time limited and reversible elevation of c-Jun, for instance by hijacking the autocrine signaling loops of repair cells, would likely be an effective therapy for promoting nerve regeneration
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