Published online May 26, 2023. doi: 10.4252/wjsc.v15.i5.476
Peer-review started: June 13, 2022
First decision: June 23, 2022
Revised: July 5, 2022
Accepted: September 9, 2022
Article in press: September 9, 2022
Published online: May 26, 2023
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 the wound healing process.
The potential therapeutic mechanism of ADSC Exos in wound healing in diabetic mice remains unclear.
To verify the effect of treatment with Exos from circular RNA astrotactin 1 (circ-Astn1)-overexpressing ADSCs on high glucose (HG)-induced EPC dysfunction.
In this study, 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 utilized EPCs to investigate the therapeutic function of Exos in cell damage and dysfunction caused by HG. We utilized a luciferase reporter (LR) assay to detect interactions among circ-Astn1, SIRT1 and miR-138-5p. We employed diabetic mice to verify the therapeutic effect of circ-Astn1 on Exo-mediated wound healing.
High-throughput RNA-Seq detection 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 effect 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 LR assay along with bioinformatics analyses. Exos containing high concentrations of circ-Astn1 had better therapeutic effect 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 suppressing apoptosis through promotion of SIRT1 and decreased FOXO1 expression.
In summary, we concluded that circ-Astn1 promoted the therapeutic effect of ADSC-Exos and thus improved 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 alternative for treatment of diabetic ulcers.
More in-depth studies are required to determine the actual role of miR-138-5p/SIRT1/FOXO1 in wound healing.