Epithelial Fibronectin Meshwork Controls Skin Regeneration

Abstract

Adult stem cell (SC) fate is tightly balanced by the local microenvironment, called niche, and sustains tissue regeneration. How niche signals are integrated and regulate regeneration remains largely unexplored. Fibronectin (FN) is a major extracellular matrix component and integrin ligand, whose role is well-characterized during wound healing. In this study, using the hair follicle as a mini organ that regenerates, we discovered a previously unreported role for FN in epidermal regeneration. Hair follicle SCs undergo long-term self-renewal and multilineage differentiation. We show that FN displays a highly specific enrichment in SCs at the onset of hair follicle regeneration. We reveal that FN tracks along the regenerating hair follicles, forming a meshwork. FN-conditional deletion in hair follicle SC compartments (LRIG1, keratin 19) leads to impaired SC location and fate. Loss of this meshwork is accompanied by hair regeneration blockade. Dermal injection of exogenous FN rescues these phenotypes. Analyzing the molecular mechanisms underlying FN function led us to identify integrin-dependent mechanotransduction as the main player in hair follicle regeneration, through YAP/Taz. Thus, in epithelial cells, FN-integrin-mechanotransduction finely tunes adult SC fate and tissue regenerative power.

Keywords: Fibronectin; Hair follicle stem cells; Mechanosignaling; Meshwork: Tissue regeneration.