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Neuron. 2017 Sep 27;96(1):98-114.e7. doi: 10.1016/j.neuron.2017.09.008.

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

Author information

1
Cell Interactions and Cancer Group, MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom.
2
Cell Interactions and Cancer Group, MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom; Quantitative Gene Expression Group, MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, United Kingdom.
3
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
4
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, United Kingdom.
5
Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom; Quantitative Gene Expression Group, MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, United Kingdom.
6
Cell Interactions and Cancer Group, MRC London Institute of Medical Sciences, Du Cane Road, London W12 0NN, United Kingdom; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom. Electronic address: simona.parrinello@imperial.ac.uk.

Abstract

Schwann 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.

KEYWORDS:

Eph signaling; PNS regeneration; Schwann cell; TGFb signaling; dedifferentiation; plasticity

PMID:
28957681
PMCID:
PMC5626803
DOI:
10.1016/j.neuron.2017.09.008
[Indexed for MEDLINE]
Free PMC Article

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