Abstract

Fibroblast heterogeneity studies have shown that it vastly influences the outcome of wound repair (Griffin et al., 2020; Rinkevich et al., 2015). We aimed to characterize the origins of these heterogeneous populations in the publication I. Here we have shown that during dermal development there is an inherent inversion of fibroblast populations from abundant regenerative fibroblasts (ENFs) at early fetal stages of development, to abundant scar-producing fibroblasts (EPFs) during perinatal and adult life. Using novel imaging and analysis approaches, we have charted the dermal maturation dynamics of EPFs during the transition from scar-less (E12) to scarring stages (E16.5) of development. We then followed up on the role of scar-forming fibroblasts in postnatal and adult stages. In publication III, we identified the subcutaneous fascia as the main anatomical contributor of scars upon deep skin injury. Next, we followed the role of fascial scar producing cells, EPFs, and its contribution to scar formation in publication II. Here, we developed a relevant ex-vivo model called “scar-like tissue in a dish”- termed SCAD. We show that scars on SCADs emulate the bona fide in-vivo scar phenotype. Using this model, we visualize and chart live migration dynamics of EPFs at all stages of scar development. Further, using antibody screening and CRISPR-Cas9 based genetic approaches, we identified that N-Cadherin is the adhesion molecular that orchestrates EPF and fascial response to scarring. Finally, to check the clinical relevance, we validated our N-cadherin mechanistic findings in human skin biopsies from various anatomical locations. These findings provide a range of therapeutic avenues in modulating subcutaneous fascial response and prevention of pathological scars.