Swarms of specialized fibroblasts drive scarring through N-cadherin

ABSTRACT: Injury in mammals induces a connective tissue response to either regenerate as before, or to scar. The fibroblastic actions and mechanisms that underlie these connective tissue responses remain obscure, as direct observation in animals is too difficult and current assays do not faithfully reproduce physiology. Here, we developed a skin explant technique termed scar-in-a-dish (SCAD) that faithfully recapitulates uniform scars with contraction and reveals how scarring occurs in unprecedented detail. By growing mouse SCADs, with a traceable scar-progenitor fibroblast lineage, we observed previously unseen intercellular connections form between scar-progenitors that then collectively swarm into the nascent wound in highly regular periodic movements that progressively contract the skin and form scars. Swarming is exclusive to scar progenitors and absent from oral cavity fibroblasts that regenerate scarless. By testing a panel of adhesion molecules that might instigate intercellular connections, we found swarming was induced by the upregulation of N-cadherin in scar progenitors. Impeding N-cadherin binding inhibited swarming and contraction, and led to reduced scarring in SCAD and in mice. Blocking N-cadherin and scar-progenitor swarming thus provides a novel therapeutic space to curtail pathological fibrotic responses across a range of medical settings.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skin

SUBMITTER: Christoph Mayr  

LAB HEAD: Yuval Rinkevich

PROVIDER: PXD016068 | Pride | 2020-10-26

REPOSITORIES: Pride