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.

Perspective on Schwann Cells Derived from Induced Pluripotent Stem Cells in Peripheral Nerve Tissue Engineering

“…Expression of the Sox2 transcription factor in repair SCs induces Robo1 receptor expression at the cell surface which binds to the Slit3 ligand released from macrophages surrounding the nerve bridge. This interaction is repellent and forces the repair SCs to remain on trajectory in the nerve bridge, supporting and directing the regenerating axons [ 12 , 13 ]. Axon pathfinding is defective in Slit3+/−, Slit3−/−, and Robo1+/− mice, as well as when Sox2 is knocked out in SCs [ 12 ].…”

Adipose tissue stem cells in peripheral nerve regeneration—In vitro and in vivo

“…Schwann cells (SCs) are crucial for peripheral nerve regeneration. They are specific glial cells and aligned along the axons; they are able to adjust their physiology to generate appropriate feedback responses to support and control neuronal function when releasing neurotrophic factors (Figure 3), such as the nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF), neurotrophin‐3 (Nt3), ciliary neurotrophic factor (CNTF), glial cell‐derived neurotrophic factor (GCNF), artemin, and vascular endothelial growth factor (VEGF)—especially during Wallerian degeneration (Bunge, 1993; Nocera & Jacob, 2020; Samara et al., 2013; Waller, 1851). NGF acts on the growth of sensory and sympathetic neurons in the peripheral nervous system (PNS) as it leads to an increased innervation density, neuron cell body size, axonal terminal sprouting, and dendritic outgrowth (Rocco et al., 2018).…”

Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

“…Schwann cell reprograming after nerve injury involves upregulation of trophic factors and cytokines, activation of EMT genes, and myelin autophagy for myelin clearance and downregulation of myelin genes ( Brushart et al, 2013 ; Arthur-Farraj et al, 2017 ; Clements et al, 2017 ; reviewed in Gröthe et al, 2006 ; Chen et al, 2007 ; Gambarotta et al, 2013 ; Glenn and Talbot, 2013 ; Jessen and Mirsky, 2016 ; Boerboom et al, 2017 ; Jessen and Arthur-Farraj, 2019 ; Nocera and Jacob, 2020 ). Myelin and Remak Schwann cells also increase in length by two-to-three fold and often branch as they convert to repair cells and form regeneration tracks, Bungner bands, that guide regenerating axons ( Gomez-Sanchez et al, 2017 ).…”