Macrophage-to-Myofibroblast Transition Contributes to Cutaneous Scarring Formation Through the TGF-β/Smad3 Signaling Pathways.

Abstract

Cutaneous scarring typically arises after surgery, trauma, and infection, occurring when normal skin tissue is replaced by fibrous tissue during the healing process. Myofibroblasts have been identified as a significant contributor to this scarring. While the differentiation of fibroblasts into myofibroblasts is well-recognized as essential for wound healing and tissue repair, the mechanisms underlying the macrophage-myofibroblast transition (MMT) remain largely unexplored. This study aimed to investigate the role and potential mechanisms of MMT in cutaneous scarring. In specimens of hypertrophic scars, keloid and scleroderma, we confirmed the coexistence of MMT markers CD68 and α-smooth muscle actin (α-SMA) in areas of skin fibrosis. Additionally, most MMT cells in human cutaneous scar co-expressed the M2-type macrophage marker CD206. Fate-mapping in Lyz2-Cre/Rosa26-tdTomato mice further demonstrated that the majority of myofibroblasts in cutaneous scars were derived from bone marrow macrophages. Furthermore, higher levels of TGF-β were released from scar fibroblasts, which contributed to MMT through the Smad3 pathways. In vivo studies inhibiting Smad3 reduced MMT and scarring. Macrophage depletion with clodronate liposomes also reduced cutaneous scar formation. Our findings indicate that MMT plays a pivotal role in cutaneous scarring through the TGF-β/Smad3 pathways. Consequently, inhibiting MMT may be a novel strategy for the treatment of cutaneous scarring.