CD74⁺ fibroblasts proliferate upon mechanical stretching to promote angiogenesis in keloids

The healing of human skin wounds is susceptible to perturbation caused by excessive mechanical stretching, resulting in enlarged scars, hypertrophic scars, or even keloids in predisposed individuals. Keloids are fibro-proliferative scar tissues that extend beyond the initial wound boundary, consisting of the actively progressing periphery and the quiescent center. The stretch-associated outgrowth and enhanced angiogenesis are two features of the periphery of keloids. However, which cell population is responsible for transducing the mechanical stimulation to the progression of keloids remains unclear. Herein, through integrative analysis of single-cell RNA sequencing of keloids, we identified CD74⁺ fibroblasts, a previously unappreciated subset of fibroblasts with pro-angiogenic and stretch-induced proliferative capacities, as a key player in stretch-induced progression of keloids. Immunostaining of keloid cryosections depicted a predominant distribution of CD74⁺ fibroblasts in the periphery, interacting with the vasculature. In vitro tube formation assays on purified CD74⁺ fibroblasts ascertained their pro-angiogenic function. BrdU assays revealed that these cells proliferate upon stretching, through PIEZO1-mediated calcium influx and the downstream ERK and AKT signaling. Collectively, our findings propose a model wherein CD74⁺ fibroblasts serve as pivotal drivers of stretch-induced keloid progression, fueled by their proliferative and pro-angiogenic activities. Targeting the attributes of CD74⁺ fibroblasts holds promise as a therapeutic strategy for the management of keloids.