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

• DOI: 10.1126/sciadv.adq0638
• Publication Date: 2025-02-19T18:59:36Z
• Authors: Allen S. W. Oak; Amrit Bagchi; Matthew J. Brukman; Joshua Toth; Jamie Ford; Ying Zheng; Arben Nace; Ruifeng Yang; Jen-Chih Hsieh; James E. Hayden; Gordon Ruthel; Anisa Ray; Elaine Kim; Vivek B. Shenoy; George Cotsarelis
• Keywords: Mechanotransduction; Adherens junction; Hemidesmosome

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