The Wound Microenvironment Reprograms Schwann Cells to Invasive Mesenchymal-like Cells to Drive Peripheral Nerve Regeneration

Melanie P Clements,Elizabeth Byrne,Luis F Camarillo Guerrero,Anne-Laure Cattin,Leila Zakka,Azhaar Ashraf,Jemima J Burden,Sanjay Khadayate,Alison C Lloyd,Samuel Marguerat,Simona Parrinello

doi:10.1016/j.neuron.2017.09.008

Melanie P Clements, Elizabeth Byrne + Show 9 more

Open Access

https://doi.org/10.1016/j.neuron.2017.09.008

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Abstract

SummarySchwann cell dedifferentiation from a myelinating to a progenitor-like cell underlies the remarkable ability of peripheral nerves to regenerate following injury. However, the molecular identity of the differentiated and dedifferentiated states in vivo has been elusive. Here, we profiled Schwann cells acutely purified from intact nerves and from the wound and distal regions of severed nerves. Our analysis reveals novel facets of the dedifferentiation response, including acquisition of mesenchymal traits and a Myc module. Furthermore, wound and distal dedifferentiated Schwann cells constitute different populations, with wound cells displaying increased mesenchymal character induced by localized TGFβ signaling. TGFβ promotes invasion and crosstalks with Eph signaling via N-cadherin to drive collective migration of the Schwann cells across the wound. Consistently, Tgfbr2 deletion in Schwann cells resulted in misdirected and delayed reinnervation. Thus, the wound microenvironment is a key determinant of Schwann cell identity, and it promotes nerve repair through integration of multiple concerted signals.Video

Highlights

The adult peripheral nervous system (PNS) retains significant regenerative potential, enabling the repair of even severe injuries such as full transection of the nerve trunk (Chen et al, 2007)
TdTomato is a suitable marker for purification of differentiated and dedifferentiated SCs from their in vivo microenvironment using fluorescence-activated cell sorting (FACS)
Nerve tissue was dissociated to single cells, and SCs were sorted from other tdTomatoÀ nerve cells based on tdTomato expression (Figure 1B)

Summary

Introduction

The adult peripheral nervous system (PNS) retains significant regenerative potential, enabling the repair of even severe injuries such as full transection of the nerve trunk (Chen et al, 2007). Unlike central nervous system axons, damaged peripheral axons are able to regrow and reinnervate their targets (Chen et al, 2007) This process is underpinned by the remarkable plasticity of the PNS glia, the Schwann cells (SCs) (Jessen et al, 2015; Kim et al, 2013a). Dedifferentiated SCs switch off the myelination program and acquire an array of new phenotypes, which coordinately support nerve repair These phenotypes include 1) secretion of neurotrophic factors to promote axonal survival, 2) clearance of myelin debris and expression of axonal guidance and adhesive cues to generate a favorable environment for axonal regrowth, 3) initiation of an inflammatory response to promote wound healing, and 4) proliferation to replace lost cells (Jessen et al, 2015)

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