Mechanisms of Schwann cell plasticity involved in peripheral nerve repair after injury

Abstract

The great plasticity of Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), is a critical feature in the context of peripheral nerve regeneration following traumatic injuries and peripheral neuropathies. After a nerve damage, SCs are rapidly activated by injury-induced signals and respond by entering the repair program. During the repair program, SCs undergo dynamic cell reprogramming and morphogenic changes aimed at promoting nerve regeneration and functional recovery. SCs convert into a repair phenotype, activate negative regulators of myelination and demyelinate the damaged nerve. Moreover, they express many genes typical of their immature state as well as numerous de-novo genes. These genes modulate and drive the regeneration process by promoting neuronal survival, damaged axon disintegration, myelin clearance, axonal regrowth and guidance to their former target, and by finally remyelinating the regenerated axon. Many signaling pathways, transcriptional regulators and epigenetic mechanisms regulate these events. In this review, we discuss the main steps of the repair program with a particular focus on the molecular mechanisms that regulate SC plasticity following peripheral nerve injury.

Keywords: Axonal regeneration; Chromatin remodeling enzymes; Nerve injury and repair; Plasticity; Remyelination; Reprogramming; Schwann cell; Signaling pathways; Transcription factors.

Fig. 1

Repair program in the PNS. Illustration of the main steps of the repair program orchestrated by SCs after peripheral nerve injury. Each step shows a schematic representation of a single neuron (blue) interacting with SCs (light yellow) within an adult peripheral nerve undergoing a traumatic lesion. In step 4, macrophages (green cells) help SCs to clear axon and myelin debris

Fig. 2

Summary of the main factors regulated after peripheral nerve injury. Overview of factors downregulated during demyelination (blue area), factors expressed during the repair program (green area), and factors involved in re-myelination post-injury (red area). Uphill areas indicate a high expression, whereas downhill areas indicate a low expression. Regulation of factors is illustrated throughout the different steps of the regeneration process