Yuan MJ, Huang HC, Shi HS, Hu XM, Zhao Z, Chen YQ, Fan WJ, Sun J, Liu GB. MicroRNA-122-5p is upregulated in diabetic foot ulcers and decelerates the transition from the inflammatory to the proliferative stage. World J Diabetes 2025; 16(4): 100113 [DOI: 10.4239/wjd.v16.i4.100113]
Corresponding Author of This Article
Guo-Bin Liu, MD, Chief Doctor, Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No. 528 Zhangheng Road, Pudong New Area, Shanghai 201203, China. 15800885533@163.com
Research Domain of This Article
Medicine, Research & Experimental
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
Mei-Jie Yuan, He-Chen Huang, Hong-Shuo Shi, Xiao-Ming Hu, Zhuo Zhao, Wei-Jing Fan, Guo-Bin Liu, Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Yu-Qi Chen, Department of Pathology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Jian Sun, Department of Medical Oncology and Cancer Institute of Integrative Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Co-corresponding authors: Jian Sun and Guo-Bin Liu.
Author contributions: Yuan MJ and Sun J conceptualized the study; Yuan MJ prepared the initial draft of the manuscript, and Fan WJ contributed to its revision; Yuan MJ, Huang HC, Shi HS, Hu XM, Zhao Z, and Chen YQ were involved in the design, execution, and analysis of the experiments; Liu GB supervised the study and secured funding; All authors reviewed and approved the final manuscript for publication.
Supported by the National Natural Science Foundation of China, No. 82274528.
Institutional review board statement: This study was approved by the Ethics committee of SHUTCM (Approval No. 2024-1443-026-01), and all participants gave their informed consent. The use of human tissue samples and data were performed in accordance with relevant guidelines and regulations.
Institutional animal care and use committee statement: All animal experiments were approved by the Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine (Approval No. PZSHUTCM2303090001). All methods were performed in accordance with the relevant guidelines and regulation.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Guo-Bin Liu, MD, Chief Doctor, Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No. 528 Zhangheng Road, Pudong New Area, Shanghai 201203, China. 15800885533@163.com
Received: August 7, 2024 Revised: December 17, 2024 Accepted: January 16, 2025 Published online: April 15, 2025 Processing time: 205 Days and 1.4 Hours
Abstract
BACKGROUND
Shifting from the inflammatory to the proliferative phase represents a pivotal step during managing diabetic foot ulcers (DFUs); however, existing medical interventions remain insufficient. MicroRNAs (miRs) highlight notable capacity for accelerating the repair process of DFUs. Previous research has demonstrated which miR-122-5p regulates matrix metalloproteinases under diabetic conditions, thereby influencing extracellular matrix dynamics.
AIM
To investigate the impact of miR-122-5p on the transition from the inflammatory to the proliferative stage in DFU.
METHODS
Analysis for miR-122-5p expression in skin tissues from diabetic ulcer patients and mice was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). A diabetic wound healing model induced by streptozotocin was used, with mice receiving intradermal injections of adeno-associated virus -DJ encoding empty vector or miR-122. Skin tissues were retrieved at 3, 7, and 14 days after injury for gene expression analysis, histology, immunohistochemistry, and network studies. The study explored miR-122-5p’s role in macrophage-fibroblast interactions and its effect on transitioning from inflammation to proliferation in DFU healing.
RESULTS
High-throughput sequencing revealed miR-122-5p as crucial for DFU healing. qRT-PCR showed significant upregulation of miR-122-5p within diabetic skin among DFU individuals and mice. Western blot, along with immunohistochemical and enzyme-linked immunosorbent assay, demonstrating the upregulation of inflammatory mediators (hypoxia inducible factor-1α, matrix metalloproteinase 9, tumor necrosis factor-α) and reduced fibrosis markers (fibronectin 1, α-smooth muscle actin) by targeting vascular endothelial growth factor. Fluorescence in situ hybridization indicated its expression localized to epidermal keratinocytes and fibroblasts in diabetic mice. Immunofluorescence revealed enhanced increased presence of M1 macrophages and reduced M2 polarization, highlighting its role in inflammation. MiR-122-5p elevated inflammatory cytokine levels while suppressing fibrotic activity from fibroblasts exposed to macrophage-derived media, highlighting its pivotal role in regulating DFU healing.
CONCLUSION
MiR-122-5p impedes cutaneous healing of diabetic mice via enhancing inflammation and inhibiting fibrosis, offering insights into miR roles in human skin wound repair.
Core Tip: The shift from the inflammatory to the proliferative stage is essential for effective treatment of diabetic foot ulcers (DFUs). Through bioinformatics analysis and experimental studies, we evaluated the role of microRNA (miR)-122-5p in DFU. MiR-122-5p was found to delay wound repair in DFU by disrupting re-epithelialization and intensifying inflammation throughout the healing process.
