Resveratrol Enhances Wound Healing in Type 1 Diabetes Mellitus by Promoting the Expression of Extracellular Vesicle-Carried MicroRNA-129 Derived from Mesenchymal Stem Cells

Recent studies have shown the promotive effect of resveratrol on wound healing. This study aims to explore the underlying molecular mechanism of resveratrol in type 1 diabetes mellitus (T1DM) through microRNA (miR)-129-containing extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) based on in silico analysis. The rat model of T1DM was established by intraperitoneal injection of sodium citrate containing streptozotocin, and the wound was made around the deep fascia. Rat MSCs were isolated and treated with resveratrol (SRT501), and the corresponding EVs (SRT501-EVs) were isolated, where the expression of miR-129 was determined. By performing function experiments, the effect of SRT501-EVs and miR-129 on the biological functions of human umbilical vein endothelial cells (HUVECs) was determined. Finally, the binding relationship between miR-129 and tumor necrosis factor receptor-associated factor 6 (TRAF6) was also determined by the dual-luciferase reporter gene assay. miR-129 was shown as a candidate related to both resveratrol and wound healing in T1DM. SRT501-EVs promoted the skin wound healing of T1DM rats and also further improved the proliferative, migratory, and tube formation potentials of HUVECs. Resveratrol inhibited the expression of TRAF6 in HUVECs stimulated by MSC-conditioned medium and promoted the transfer of miR-129 via EVs, while TRAF6 was confirmed as a target gene of miR-129. Furthermore, inhibition of miR-129 attenuated the proangiogenic effect of resveratrol on HUVECs. Resveratrol exerts promotive role in wound healing in T1DM through downregulation of TRAF6 via MSC-EV-carried miR-129, suggesting a regulatory network involved in the wound healing process in T1DM.