Molecular Mechanisms Involved in Schwann Cell Plasticity

Abstract

Schwann cell incredible plasticity is a hallmark of the utmost importance following nerve damage or in demyelinating neuropathies. After injury, Schwann cells undergo dedifferentiation before redifferentiating to promote nerve regeneration and complete functional recovery. This review updates and discusses the molecular mechanisms involved in the negative regulation of myelination as well as in the reprogramming of Schwann cells taking place early following nerve lesion to support repair. Significant advance has been made on signaling pathways and molecular components that regulate SC regenerative properties. These include for instance transcriptional regulators such as c-Jun or Notch, the MAPK and the Nrg1/ErbB2/3 pathways. This comprehensive overview ends with some therapeutical applications targeting factors that control Schwann cell plasticity and highlights the need to carefully modulate and balance this capacity to drive nerve repair.

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

“…The Schwann cell injury response has been reviewed elsewhere (Boerboom et al, ; Chen et al, ; Jessen & Mirsky, , ; Monk, Feltri, & Taveggia, ). Briefly, it has two principal components.…”

“…ERK1/2 phosphorylation is rapidly induced in Schwann cells after injury, and implicated in the upregulation of the major macrophage recruitment signal MCP‐1 (Fischer, Weishaupt, Troppmair, & Martin, ; Sheu, Kulhanek, & Eckenstein, ). Pharmacological inhibition of ERK1/2 activation, or genetic inactivation of CEMIP, a protein that stimulates ERK1/2 activity, delays myelin clearance after injury (Harrisingh et al, ; Napoli et al, ; reviewed in Boerboom et al, ). Conversely, strong activation of ERK1/2, whether by constitutively active Raf or MEK1, promotes macrophage recruitment, myelin breakdown and suppression of myelin genes.…”

“…It has long been recognized that after injury to a peripheral nerve, Schwann cells undergo a radical change in identity by converting to denervated Schwann cells, which unlike the Schwann cells of uninjured nerves provide powerful support for regeneration (reviewed in Jessen & Mirsky, , , ; Chen, Yu, & Strickland, ; Zochodne, ; Glenn & Talbot, ; Scheib & Hőke, ; Brosius Lutz & Barres, ; Faroni, Mobasseri, Kingham, & Reid, ; Jessen, Mirsky, & Lloyd, ; Cattin & Lloyd, ; Boerboom, Dion, Chariot, & Franzen, ). Although this Schwann cell injury response is central to nerve repair, the nature of this process has been uncertain and disputed (Figure ).…”

KIAA1199: A novel regulator of MEK/ERK‐induced Schwann cell dedifferentiation

“…cJun, Notch or MEK1/ERK1/2 signalling belong to numerous components and signalling pathways that modulate SC dedifferentiation and peripheral nerve repair (Harrisingh et al, ; Woodhoo et al, ; Arthur‐Farraj et al, ; Napoli et al, ). However, even if major progress has been made in unravelling mechanisms that regulate SC plasticity, the implication of some pathways such as Nrg1/ErbB signalling remains unclear and little is known about their temporal and quantitative activation and the interactions between them (Boerboom, Dion, Chariot, & Franzen, ).…”

Advances in peripheral nerve regeneration as it relates to VCA

“…It has been demonstrated that chronically denervated Schwann cells, which lack axonal interaction for extended periods of time, become quiescent and cease to proliferate and secrete neurotrophic factors. 91 Another issue more specific to VCA is the possibility that allogeneic Schwann cells in the transplanted nerve may undergo rejection. 67 Therefore, strategies to create an environment of supportive Schwann cells in the distal aspect of the regenerating nerve are of paramount research interest.…”