circ-Erbb2ip from adipose-derived mesenchymal stem cell-derived exosomes promotes wound healing in diabetic mice by inducing the miR-670-5p/Nrf1 axis

Background: To investigate the mechanism of exosomes (Exo) secretion by hypoxic pretreated adipose-derived mesenchymal stem cells (ADSCs) promoting skin wound healing in diabetic (DM) mice. Methods: High-throughput sequencing was used to investigate abnormal expression of circRNA in hypoxic pretreatment ADSCs exosome (HExo) and ADSCs exosome (Exo). Bioinformatics analysis and luciferase reporting analysis were used to clarify the interacted relationship among circRNA, miRNA and mRNA. EPCs cells were employ to analysis the ROS, inflammatory cytokines expression, angiogenic differentiation function under hypoxic condition by using immunofluorescence, ELISA detection and tube forming experiment. DM ulceration mice model were constructed and the therapeutic effect of Exo were detected using immunohistochemistry, immunofluorescence. Results: The result show that HExo have more treatment effect than Exo in promotes cutaneous wound healing of DM mice. High-throughput sequencing found that circ-Erbb2ip play a role in HExo mediated tissues repair. Downregulation circ-Erbb2ip decreased the therapeutic effect of HExo to wound healing in diabetic mice. Bioinformatics analysis and luciferase reporting analysis confirmed that both miR-670-5p and Nrf1 were downstream targets of circ-Erbb2ip. Downregulation of Nrf1 or overexpression of miR-670-5p reversed the protective effect of circ-Erbb2ip to EPCs after exposure to high glucose microenvironment. Upregulation circ-Erbb2ip increased the therapeutic effect of Exo to wound healing in diabetic mice by increased angiogenesis and decreased ROS, inflammatory cytokines expression. Conclusion: In conclusion, ADSC-Exos containing circ-Erbb2ip promotes wound healing by targeting miR-670-5p/ Nrf1 pathway, and their effects in promoting soft tissue wound healing warrant further study.