Epithelial Fibronectin meshwork controls skin regeneration

Adult stem cell 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, which role is well characterized during wound healing. Here, using the hair follicle as a mini organ which regenerates, we discovered a previously unreported role for FN in epidermal regeneration. Hair follicle stem cells (HFSCs) undergo long-term self-renewal and multi-lineage differentiation. We show that FN displays a highly specific enrichment in stem cells at the onset of hair follicle regeneration. We reveal FN tracks along the regenerating hair follicles forming a meshwork. FN conditional deletion in HFSC compartments (Lrig1, K19) leads to impaired stem cell location and fate. Loss of this meshwork is accompanied by hair regeneration blocade. 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, via YAP/Taz. Thus, in epithelial cells, fibronectin-integrin-mechanotransduction finely tunes adult stem cell fate and tissue regenerative power.