Fibronectin meshwork controls epithelial stem cell fate

Adult stem cell fate is tightly balanced by the local microenvironment called niche and sustain tissue regeneration^1–4. How niche signals are integrated and regulate regeneration remains largely unexplored. The extracellular matrix and integrin ligand fibronectin is a crucial and well-characterized wound healing actor that has never been involved in skin regeneration. Here, we show that fibronectin displays a highly specific enrichment in hair follicle stem cells (HFSC) at the onset of regeneration. Conditional deletion of fibronectin in HFSC compartment (Lrig1, K19) leads to hair regeneration blockade, impaired stem cell location and fate. Dermal injection of exogenous fibronectin rescues these phenotypes. To elucidate molecular mechanism underlying fibronectin function, we used conditional deletion models of SLC3A2, the main integrin coreceptor. We show that, via its role in integrin-dependent assembly of fibronectin matrix, SLC3A2 acts as molecular relay of niche signals. Thus, fibronectin-integrin-SLC3A2 cascade finely tunes HFSC fate and tissue regenerative power.