Hypoxia-induced adipose derived stem cells-derived exosomes promote diabetic wound healing through circ-0001747/miR-199a-5p/HIF-1α axis

Diabetic foot ulcers (DFU) are a serious complication of diabetes that lead to significant morbidity and mortality. The studies reported that promoting angiogenesis is a key step in wound healing. Hypoxia-induced adipose-derived mesenchymal stem cell-derived exosomes (ADSC-Exo) were observed to promote skin wound healing and alleviate DFU development. Howere, the detailed molecular mechanism of hypoxia-induced ADSC-Exo in wound healing of DFU remain undetermined. In this study, we identified aberrantly expressed circRNAs in normoxic-induced ADSC-Exo (Exo) versus hypoxia-induced ADSC-Exo (HExo) by high-throughput sequencing. The expression of circ-0001747 in Exo and HExo were detected by qRT-PCR. Subsequently, the overexpression of circ_0001747-HExo was constructed to observe the wound healing and therapeutic effect of DFU mice. Bioinformatics analysis, luciferase reporter gene assays, qRT-PCR, flow cytometry and angiogenesis assay, were used to study the regulatory mechanism of circ-0001747. The results showed that circ-0001747 was higher in HExo. Compared with the Exo group, overexpression of circ-0001747-HExo significantly restored wound healing, promoted vascular differentiation, and inhibited cell apoptosis and ROS production. Additionally, miR-199a-5p and HIF1α were identified as downstream targets of circ-0001747 and further verified by luciferase reporter gene analysis. Notably, overexpression of miR-199a-5p or inhibition of HIF1α reversed the protective effects of the circ-0001747-mediated microenvironment on endothelial cells. These results showed that overexpression of circ-0001747-HExo inhibited endothelial cell damage and promotes wound healing by targeting the miR-199a-5p/HIF1α axis.