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

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 Abstract

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

“…Removal of the TGF‐β receptor II in Schwann cells shows that TGF‐β has a role specifically at the site of nerve injury for promoting Schwann cell migration from the proximal stump, across a bridge region to reconnect with the distal stump. Disruption of this Schwann cell migration leads to mis‐targetting of axons at the injury site, although long‐term axonal regeneration and functional recovery were normal in the absence of Schwann cell TGF‐β signaling (Cattin et al, ; Clements et al, ; Parrinello et al, ).…”

“…A recent contribution to this debate, namely the identification of partial epithelial–mesenchymal transition (EMT) in injured nerves (Arthur‐Farraj et al, ; Clements et al, ), highlights how our understanding of the Schwann cell injury response has progressed by degrees, with each step providing new insights into this complex process.…”

“…The most recent addition to the changing picture of the Schwann cell injury response, namely the finding that it includes upregulation of the genes associated with EMT and stemness, brings Schwann cells into line with several other systems in which injury also activates EMT/stemness genes (Arthur‐Farraj et al, ; Clements et al, ). This adds important components to our understanding of the repair program, and makes biological sense because EMT‐like changes typically provide cells with increased motility and morphological flexibility.…”

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

“…Several resources are available to identify SC-specific genes, including (1) expression profiles of peripheral nerve development and response to injury, [37][38][39][40][41][42][43][44] (2) profiling of sorted cell types in mouse embryonic skin, 30 and (3) RNA-seq profiling of >400 human tibial nerve samples, 45 along with many other tissues (Broad Institute; gtexportal.org). Several resources are available to identify SC-specific genes, including (1) expression profiles of peripheral nerve development and response to injury, [37][38][39][40][41][42][43][44] (2) profiling of sorted cell types in mouse embryonic skin, 30 and (3) RNA-seq profiling of >400 human tibial nerve samples, 45 along with many other tissues (Broad Institute; gtexportal.org).…”

A change of fate for nerve repair

“…It has long been thought that, following injury, myelinating Schwann cells rapidly dedifferentiate to an unmyelinating progenitor state that facilitates axonal regeneration and repair. But writing in Neuron, Clements et al 4 challenge this simple notion. When a nerve in the PNS is cut, the section still connected to the PNS remains intact, whereas the section below (distal to) the cut degenerates.…”