Abstract
Pathological scar treatment remains a clinical challenge, and novel efficient and safe approaches are urgently needed. Regulation of cell fate transition has promising potential for disease treatment and tissue regeneration. Skin fibrosis is linked to a specific fibroblast subtype marked by dipeptidyl peptidase IV (DPP4(+)), by which various agents, including sitagliptin, an established antidiabetic medication, can inhibit. In this study, it is hypothesized that pharmacological inhibition of DPP4 with sitagliptin could redirect fibroblasts toward adipogenic lineages, consequently, preventing scar formation. Fibroblasts from human keloid tissues are first isolated and characterized, confirming their mesenchymal stem cell (MSCs) properties and termed them as keloid-derived MSCs (KMSCs). The analyses reveal that DPP4(-) KMSCs exhibit enhanced adipogenic potential, whereas DPP4(+) KMSCs display greater fibrotic potential. In KMSCs, sitagliptin promotes adipogenesis by inhibiting DPP4-mediated IGF1 truncation, thereby enhancing IGF1 signaling. Furthermore, sitagliptin-loaded microneedle patches are developed capable of sustained, controlled release of sitagliptin or IGF1 into cutaneous wounds, effectively reducing scar formation by promoting the conversion of fibroblasts into adipocytes in vivo. Overall, the findings propose a novel application for sitagliptin in preventing scar formation via cell fate modulation during wound healing, thereby advancing clinical treatment strategies for scars.