1478 TEM1/endosialin/CD248 promotes pathologic scarring by augmenting TGF-β activity through its receptor stability in dermal fibroblasts

Keloids represent a common form of exaggerated cutaneous scarring that is difficult to prevent or treat effectively. TGF-β has been implicated in driving abnormal wound healing responses and in generating excessive extracellular matrix (ECM) deposition but the pathobiology of keloids remains poorly understood. Here, we show that mRNA and protein levels of tumor endothelial marker 1 (TEM1/endosialin/CD248), a glycosylated type I transmembrane protein member of the C-type lectin-like domain superfamily, are highly upregulated in keloid fibroblasts and tissues. A re-analysis of single-cell RNA-sequencing datasets reveals that a major profibrotic subpopulation of keloid fibroblasts greatly expresses TEM1, with expression increasing during fibroblast activation. TEM1 promotes activation, proliferation, and ECM production in human dermal fibroblasts by enhancing TGF-β1 signaling through binding with and stabilizing TGF-β receptors. Global deletion of Tem1 markedly reduces the amount of ECM synthesis and inflammation in a scar in a mouse model of stretch-induced hypertrophic scarring. Our data show that the synergistic effect of TEM1 on the TGF-β signaling pathway significantly contributes to dermal fibroblast activation and the biology of pathologic scarring. Targeting TEM1 may represent a novel therapeutic approach in reducing the morbidity of keloids and potentially other forms of pathologic scarring.