Abstract
Although extracellular vesicles (EVs) from mesenchymal stem cells have shown potential in skin wound repair, the diversity of EV sources and the optimization of delivery systems still need further exploration. This study is the first to demonstrate that extracellular vesicles from chemically induced mammary epithelial cells (CiMECs-EVs) possess distinct skin wound repair activity. To enhance the therapeutic efficacy of CiMECs-EVs and optimize their delivery efficiency, we innovatively combined them with a chitosan hydrogel to construct a composite repair system (CiMECs-EVs-chitosan hydrogel, CMECG). This system was then applied to a rat skin wound model. The results showed that CMECG significantly promoted the proliferation and migration of fibroblasts and mammary epithelial cells (MECs). In animal experiments, the relative wound closure efficiency of the control group was approximately 70% on day 14, while that of the CMECG group (loaded with 200 μg CiMECs-Exo) was enhanced to 90%, markedly accelerating the wound healing process. Histological analysis indicated that this system could effectively restore the structural continuity of various skin layers and significantly promote the synthesis and remodeling of collagen at the wound site. Mechanistically, the wound healing effect of CiMECs-EVs is closely associated with the endogenous miRNAs they encapsulate. These miRNAs can coordinately regulate cell proliferation, migration, and angiogenesis, modulate the inflammatory microenvironment, and inhibit excessive scar formation-thus regulating the entire repair process. This process involves multiple wound healing-related signaling pathways, including MAPK, PI3K-Akt, FoxO, TGF-β, and JAK-STAT. In summary, this study successfully constructed a novel EV-chitosan hydrogel repair system. This system is expected to provide an effective and innovative EV-based therapeutic strategy for the clinical treatment of skin wound repair.
Keywords:
extracellular vesicles; hydrogel; miRNA; skin; wound; wound repair.