Uncoupling desmosomal cadherin adhesion activates quiescent hair follicle stem cells and orchestrates self-organized regeneration through outside-in signaling

Stem cells (SC) are critical to maintain tissue homeostasis. However, it is currently not known whether signaling through cell adhesion proteins protects the epithelial stem cell (SC) reservoir from exhaustion during disease-inflicted injury. Using the autoimmune model disease Pemphigus vulgaris (PV), this study reveals an unexpected role for the cadherin desmoglein 3 (Dsg3) in governing SC quiescence and regeneration through adhesion signaling in the multipotent mouse hair follicle compartment known as the bulge. Autoantibody-mediated, mechanical uncoupling of Dsg3 transadhesion activates quiescent bulge SCs which lose their multipotency and stemness signature, start to actively cycle and finally delaminate from their epithelial niche. This feeds into a self-organized regenerative program which fully restores Dsg3 function and bulge morphology including SC quiescence and multipotency. These dramatic changes are triggered by the sole loss of Dsg3 transadhesion resulting in EGFR activation and Wnt modulation requiring longitudinal repression of Hedgehog signaling to drive successful SC regeneration. Taken together, this study unveils that a desmosomal cadherin acts as a gatekeeper of SC quiescence and niche integrity, and when functionally impaired, triggers a self-organized regenerative signaling program dependent on suppression of the Hedgehog pathway.