Hair follicle stem cell progeny heal blisters while pausing skin development

Abstract

Subepidermal blisters form through the detachment of the epidermis from the dermis.Despite such blisters being common in clinical practice, how they heal has not been fully elucidated. Here, we uncover the precise cellular contribution to subepidermal blister healing. The growth of hair follicles (HFs) was retarded during the healing processes of subepidermal blisters. The progeny of HF junctional zone stem cells (SCs), rather than those of epidermal SCs, were the main contributors to blister healing, and HF depletion from the wound bed through Col17a1 knockout verified the contribution of epidermal SC progeny. The wedge-shaped morphology of keratinocytes in the blistered skin helped cover the epidermal defects and was reduced by Col7a1 knockout or by extracellular calcium administration, resulting in delayed blister healing. These findings, corroborated by mathematical modeling and human blister samples, demonstrate that subepidermal blisters heal primarily via the replenishment of keratinocytes from HF pools at the expense of HF growth and through the proper morphological transformation of the regenerated cells. Our study paves the way for tailoring therapeutic interventions for subepidermal blistering diseases, including epidermolysis bullosa and pemphigoid diseases.