miR-138 from Adipose-Derived Stem-Cell Exosomes Accelerates Wound Healing in Diabetic Rats Through Targeting SIRT1/PTEN Signaling to Promote Angiogenesis and Fibrosis

Abstract

\n Background: Exosome (Exo) secretion by adipose-derived mesenchymal stem cells (ADSCs) promotes cutaneous wound healing by transfer of bioactive molecules. miR-138 is a micro (mi)RNA that stimulates endothelial progenitor cells and promotes proliferation and locomotion of human scar fibroblasts (HSFs). However, the underlying molecular mechanism is unclear. Methods: miR-138 activity in Exo-mediated healing was investigated by subcutaneous injection of exosomes isolated with ultracentrifugation from control ADSCs or ADSCs expressing miR-138 into full-thickness skin wounds in a rat diabetes model. Wound healing was evaluated by wound closure rate, histological evaluation, and immunofluorescence staining. Cultures of HSFs and human mammary epithelial cells (HMECs) were treated with Exos from wild-type and miR-138-modified ADSCs under high glucose conditions (HG). Cell proliferation and apoptosis were measured with cell counting kit (CCK)-8 assay and flow cytometry. Cell migration was assayed in Transwell chambers, and the effect of miR-138 on Exo-mediated angiogenesis and protein expression were evaluated. The miR-138 target was identified with a luciferase reporter assay. Results: ADSC-Exos were incorporated by endothelial cells and HSFs, and miR-138 enhanced cell proliferation and migration and suppressed apoptosis under HG conditions. Exos promoted endothelial tubule formation by HSFs, and western blotting showed that miR-138 mediated the therapeutic effects by reversing SIRT1/PTEN-mediated PI3K/Akt and ERK1/2 signaling inhibition. The luciferase reporter assay confirmed that miR-138 interacted with the 3 -UTR of SIRT1 to suppress SIRT1 mRNA expression. Injection of miR-138-enriched Exos into skin wounds accelerated re-epithelialization, reduced scar width, and enhanced angiogenesis. Conclusions: In conclusion, miR-138-enriched Exos promoted wound healing in a rat diabetes model by targeting SIRT1, and their effects in promoting soft tissue wound healing warrant further study.