Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. May 26, 2023; 15(5): 476-489
Published online May 26, 2023. doi: 10.4252/wjsc.v15.i5.476
Exosomes from circ-Astn1-modified adipose-derived mesenchymal stem cells enhance wound healing through miR-138-5p/SIRT1/FOXO1 axis regulation
Zhi Wang, Cheng Feng, Hao Liu, Tian Meng, Wei-Qing Huang, Ke-Xin Song, You-Bin Wang
Zhi Wang, Cheng Feng, Hao Liu, Tian Meng, Wei-Qing Huang, Ke-Xin Song, You-Bin Wang, Department of Plastic and Cosmetic Surgery, Peking Union Medical College Hospital, Beijing 100730, China
Author contributions: Wang Z and Wang YB designed the project and drafted the paper based on feedback from the other authors; Feng C, Liu H, and Meng T performed all experiments and analyses; Huang WQ and Song KX took part in the analyses and draft revision.
Supported by The Beijing Municipal Natural Science Foundation, No. 7192160.
Institutional animal care and use committee statement: The Animal Care and Use Committee of Peking Union Medical College Hospital approved the investigation protocol (No: XHDW-2020-01). We carried out all postoperative animal care along with surgical interventions following the NIH Guide for Care and Use of Laboratory Animals. All surgery and euthanasia were performed under sodium pentobarbital anesthesia (30 mg/kg) by intraperitoneal injection, and all efforts were made to minimize suffering.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: The datasets used or/and analyzed during the current study are available from the corresponding author on reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Zhi Wang, MD, Doctor, Department of Plastic and Cosmetic Surgery, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China.
Received: June 13, 2022
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
Research 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 the wound healing process.

Research motivation

The potential therapeutic mechanism of ADSC Exos in wound healing in diabetic mice remains unclear.

Research objectives

To verify the effect of treatment with Exos from circular RNA astrotactin 1 (circ-Astn1)-overexpressing ADSCs on high glucose (HG)-induced EPC dysfunction.

Research methods

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.

Research results

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.

Research conclusions

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.

Research perspectives

More in-depth studies are required to determine the actual role of miR-138-5p/SIRT1/FOXO1 in wound healing.