Human Mesenchymal Stem Cell Derived Exosomes Endowed with miR-13474 as a Therapeutic Delivery Vehicle for Diabetic Wound Healing by Targeting the CPEB2/TWIST1 Axis

A delayed healing process in diabetic wounds is intractable. In this study, a high-glucose condition was found to be responsible for skin structure destruction, inflammatory infiltration, and vital cell dysfunction. Extracellular vesicles, particularly exosomes secreted by hucMSCs, contribute to improved diabetic wound healing, largely by promoting tissue repair and re-establishing normal function in affected cells. Small RNA-sequencing revealed that hucMSC-derived exosomes (hucMSC-Ex) were highly enriched in NC_000019.10_13474 (miR-13474), which was predicted to be an miRNA with an undiscovered function. miR-13474 showed a reduced expression level in high-glucose-treated skin cells as well as diabetic foot ulcer (DFU) rats. Moreover, there is also a significant expression difference between the wound area and the wound edge in DFU patients, indicating the potential clinical value of miR-13474. Blocking miR-13474 in hucMSC-Ex obviously diminished the therapeutic effects. Furthermore, exosomal miR-13474 was found to target the CPEB2/TWIST1 axis to improve the impaired function of skin cells. On this basis, hucMSC-Ex were used as a vehicle for the delivery of therapeutic miR-13474 to optimize the repairing effect. The study has revealed the role of hucMSC-derived exosomes and the underlying molecular mechanism in diabetic wound healing and proposes a cell-free-based modification strategy for refractory wound management.