Decellularized ECM from Blastema Krt42⁺ Cells Promotes Skin Regeneration via Immunometabolic Modulation of Macrophages

Abstract Extracellular matrix (ECM)‐based materials hold significant therapeutic promise in tissue regeneration. Inspired by the remarkable regenerative capacity of the mouse digit tip regenerative blastema (RB), it is demonstrated that its intrinsic regenerative potential can be harnessed through decellularization for skin regeneration. Proteomic analysis of decellularized blastema (dRB) reveals that dRB‐specific proteins are associated with a distinct epithelial cell population (Krt42⁺). By immortalizing Krt42⁺ cells, large‐scale ECM is successfully produced in vitro, with regenerative capabilities comparable to dRB. Mechanistic studies reveal that this novel ECM material reduces inflammation and promotes oxidative metabolism in macrophages, resulting in a pro‐regenerative phenotype and enhanced secretion of growth factors. This study presents a novel ECM‐based material with substantial potential to advance wound healing and tissue regeneration.