Gli2-serpinh1 drives fibroblast state transition during skin wound healing.

Abstract

Dermal fibroblasts exhibit spatiotemporal heterogeneity, transitioning from coordinating immune signaling and depositing a provisional extracellular matrix during the early inflammatory phase to driving directional migration and mature matrix synthesis in the proliferative phase of wound healing. However, the molecular mechanisms underlying these fibroblast state transitions remain unclear. Here, by integrating single-cell RNA-sequencing, spatial transcriptomics, and in vivo and in vitro analyses in both mouse and skin organoid models for functional validation, we identify a previously underappreciated Gli2-Serpinh1 regulatory axis that plays a key role in fibroblast state transitions during skin wound healing. Serpinh1⁺ fibroblast subsets drive wound closure through re-epithelialization, vascular regeneration, and actin-mediated filopodia formation. Gli2, as a key upstream regulator of Serpinh1, modulates fibroblast function in a level-dependent manner across different healing states. Leveraging organoid technology as a drug discovery platform, we further identify three traditional Chinese medicine candidates that enhance wound healing by activating the Gli2-Serpinh1 axis. Our study reveals the Gli2-Serpinih1 axis as a pivotal regulator of fibroblast state transitions, providing mechanistic insight into fibroblast heterogeneity during wound healing and opening new avenues for precision regenerative therapies.