Wnt signaling modulates mechanotransduction in the epidermis to drive hair follicle regeneration

Most wounds form scars without hair follicles. However, in the wound-induced hair neogenesis (WIHN) model of skin regeneration, wounds regenerate hair follicles if tissue rigidity is optimal. Although WIHN depends on Wnt signaling, whether Wnt performs a mechanoregulatory role that contributes to regeneration remains uncharacterized. Here, we demonstrate that Wnt signaling affects mechanosensitivity at both cellular and tissue levels to drive WIHN. Atomic force microscopy revealed an attenuated substrate rigidity response in epidermal but not dermal cells of healing wounds. Super-resolution microscopy and nanoneedle probing of intracellular compartments in live human keratinocytes revealed that Wnt-induced chromatin remodeling triggers a 10-fold drop in nuclear rigidity without jeopardizing the nucleocytoskeletal mechanical coupling. Mechanistically, Wnt signaling orchestrated a massive reorganization of actin architecture and recruited adherens junctions to generate a mechanical syncytium—a cohesive contractile unit with superior capacity for force coordination and collective durotaxis. Collectively, our findings unveil Wnt signaling’s mechanoregulatory role that manipulates the machinery of mechanotransduction to drive regeneration.