Cell-cell adhesion plays a critical role in the mechanochemical feedback control of tissue homeostasis and disease. However, in mammalian epithelial SC compartments the contribution of classical cadherins in controlling stem cell (SC) quiescence known from lower vertebrates has remained unmatched. We here demonstrate that mechanical uncoupling of desmosomal cadherin desmoglein 3 (Dsg3) by experimental pemphigus vulgaris antibodies activates quiescent SCs in the multipotent hair follicle compartment known as the bulge. Bulge SCs lose their stemness signature within the first 24 hours and start to actively cycle while delaminating from their epithelial niche. The identified self-organized longitudinal SC program, hitherto undescribed, implicates extensive plasticity and supports morphological repair to restore quiescence and multipotency. It thereby hijacks, as a proof of concept, signaling pathways enforcing bulge SC quiescence such as Wnt, BMP and Sonic Hedgehog. Our study demonstrates that the desmosomal cadherin Dsg3 acts as a gate-keeper of SC quiescence and niche integrity, which has direct relevance not only to pemphigus disease, but to the basic understanding of the biology of the epidermis with implications ranging from clinical SC therapies to cancer treatments.

ESDR320 - Desmoglein 3-mediated mechanical transadhesion controls epithelial stem cell quiescence

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING