Abstract

Wound healing outcomes vary across tissues, with skin forming fibrotic scars whereas oral mucosa regenerates without fibrosis. The mechanisms underlying this differential response remain poorly understood. Here we performed single-cell transcriptomic analysis of murine oral mucosa and facial skin across a time course of wound repair, complemented by human wound healing validation. We show that scarless healing is defined, by transient, self-resolving activation of mechanosensitive gene programsincluding core mechanotransducers, ion channels and cytoskeletal proteins, that peak at day 2 post-wound and return to baseline by day 7. In contrast, fibrotic skin wounds exhibit sustained elevation of core mechanosensors without coordinated ion channel or cytoskeletal dynamics. YAP1 positive myofibroblasts in oral mucosa engage innate immune pathways, whereas skin myofibroblasts activate pro-fibrotic transcriptional and contractile programs. Human wounds confirm that YAP1 and PIEZO1 expression resolves to baseline during scarless repair. Our findings establish that regenerative healing requires precise temporal calibration of mechanosignaling rather than its absence, with direct implications for anti-fibrotic therapeutic strategies.