Exosomes from circ-Astn1-modified adipose-derived mesenchymal stem cells enhance wound healing through miR-138-5p/SIRT1/FOXO1 axis regulation.

Background: Wound healing impairment is a dysfunction induced by hyperglycemia and its effect on endothelial precursor cells (EPCs) in type 2 diabetes mellitus. There is increasing evidence showing that exosomes (Exos) derived from adipose-derived mesenchymal stem cells (ADSCs) exhibit the potential to improve endothelial cell function along with wound healing. However, the potential therapeutic mechanism by which ADSC Exos contribute to wound healing in diabetic mice remains unclear.

Aim: To reveal the potential therapeutic mechanism of ADSC Exos in wound healing in diabetic mice.

Methods: Exos from ADSCs and fibroblasts were used for high-throughput RNA sequencing (RNA-Seq). ADSC-Exo-mediated healing of full-thickness skin wounds in a diabetic mouse model was investigated. We employed EPCs to investigate the therapeutic function of Exos in cell damage and dysfunction caused by high glucose (HG). We utilized a luciferase reporter (LR) assay to analyze interactions among circular RNA astrotactin 1 (circ-Astn1), sirtuin (SIRT) and miR-138-5p. A diabetic mouse model was used to verify the therapeutic effect of circ-Astn1 on Exo-mediated wound healing.

Results: High-throughput RNA-Seq analysis showed that circ-Astn1 expression was increased in ADSC Exos compared with Exos from fibroblasts. Exos containing high concentrations of circ-Astn1 had enhanced therapeutic effects in restoring EPC function under HG conditions by promoting SIRT1 expression. Circ-Astn1 expression enhanced SIRT1 expression through miR-138-5p adsorption, which was validated by the LR assay along with bioinformatics analyses. Exos containing high concentrations of circ-Astn1 had better therapeutic effects on wound healing in vivo compared to wild-type ADSC Exos. Immunofluorescence and immunohistochemical investigations suggested that circ-Astn1 enhanced angiopoiesis through Exo treatment of wounded skin as well as by suppressing apoptosis through promotion of SIRT1 and decreased forkhead box O1 expression.

Conclusion: Circ-Astn1 promotes the therapeutic effect of ADSC-Exos and thus improves wound healing in diabetes via miR-138-5p absorption and SIRT1 upregulation. Based on our data, we advocate targeting the circ-Astn1/miR-138-5p/SIRT1 axis as a potential therapeutic option for the treatment of diabetic ulcers.