Injury triggers fascia fibroblast collective cell migration to drive scar formation through N-cadherin

Dongsheng Jiang,Vijayanand Rajendran,Valerio Lupperger,Qing Yu,Ursula Mirastschijski,Li Wan,Herbert B Schiller,Simon Christ,Yuval Rinkevich,Carsten Marr,Donovan Correa-Gallegos,Martin Mück-Häusl,Christoph H Mayr,Pushkar Ramesh,Juliane Wannemacher,Shruthi Kalgudde Gopal,Juan Liu,Thomas Volz,Haifeng Ye

doi:10.1038/s41467-020-19425-1

Abstract

Scars are more severe when the subcutaneous fascia beneath the dermis is injured upon surgical or traumatic wounding. Here, we present a detailed analysis of fascia cell mobilisation by using deep tissue intravital live imaging of acute surgical wounds, fibroblast lineage-specific transgenic mice, and skin-fascia explants (scar-like tissue in a dish – SCAD). We observe that injury triggers a swarming-like collective cell migration of fascia fibroblasts that progressively contracts the skin and form scars. Swarming is exclusive to fascia fibroblasts, and requires the upregulation of N-cadherin. Both swarming and N-cadherin expression are absent from fibroblasts in the upper skin layers and the oral mucosa, tissues that repair wounds with minimal scar. Impeding N-cadherin binding inhibits swarming and skin contraction, and leads to reduced scarring in SCADs and in animals. Fibroblast swarming and N-cadherin thus provide therapeutic avenues to curtail fascia mobilisation and pathological fibrotic responses across a range of medical settings.

Highlights

Scars are more severe when the subcutaneous fascia beneath the dermis is injured upon surgical or traumatic wounding
By using intravital probing into deep wounds of live mice and an ex vivo explant technique termed scar-like tissue in a dish (SCAD) coupled with genetically traceable scar-forming EPFs, we show that upon wounding fascia EPFs upregulate N-cadherin, which is required for the collective migration and subsequent swarming of fascia EPFs towards wound centre and drives scar formation
We previously discovered that scars developed from a specific type of fibroblast that temporarily expressed Engrailed-1 early in embryogenesis

Summary

Introduction

Scars are more severe when the subcutaneous fascia beneath the dermis is injured upon surgical or traumatic wounding. Fibroblast swarming and Ncadherin provide therapeutic avenues to curtail fascia mobilisation and pathological fibrotic responses across a range of medical settings Organisms such as planaria, hydra, zebrafish and certain amphibians, are able to fully regenerate tissues and organs upon injury with minimal scarring. Despite extensive study into scarring, the underlying mechanism of how scars emerge remains incompletely understood Understanding this universal wound-repair event would allow us to control, restore and preserve the functions of physically damaged adult tissues and pave the way towards clinically regenerating severe skin injuries. We have shown that injury induces fascia mobilisation across the skin, and that fascia mobilisation repairs breaches in the structural continuums of the skin, thereby preserving skin integrity and function It remains unclear why fascia EPFs are prone to form scars, whereas upper dermal or oral mucosa fibroblasts do not. Blocking N-cadherin by peptide inhibitor or genetic modification reduces scarring

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