Mechanotransduction inhibition prevents scarring and yields regeneration in a large animal model

Inhibiting mechanotransduction (via Yes-associated protein [YAP] inhibition) in mouse wounds yields wound regeneration without scarring. However, rodents are loose-skinned and fail to recapitulate key aspects of human wound repair. We thus sought to elucidate the effects of YAP inhibition in red Duroc pig wounds, the most human-like model of scarring. We show that a single treatment with the YAP inhibitor verteporfin, immediately following wounding, is sufficient to prevent scarring and drive wound regeneration in pigs. By performing scRNA-seq for the first time on porcine wounds in conjunction with spatial protein analysis, we reveal perturbations in fibroblast subpopulation profiles with verteporfin treatment and the presence of putative pro-regenerative and pro-fibrotic fibroblast subsets enriched in regenerating and scarring pig wounds, respectively. Finally, we validate our findings in a human foreskin xenograft wound model, including scRNA-seq of human wound cells. Collectively, our findings provide critical support for the future translation of local mechanotransduction inhibitors to prevent human skin scarring.