Ye ZQ, Meng XH, Fang X, Liu HY, Mwindadi HH. MiR-126 regulates the effect of mesenchymal stem cell vascular repair on carotid atherosclerosis through MAPK/ERK signaling pathway. World J Stem Cells 2025; 17(6): 106520 [DOI: 10.4252/wjsc.v17.i6.106520]
Corresponding Author of This Article
Xiao-Hu Meng, Department of Vascular Surgery, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, No. 261 Huansha Road, Shangcheng District, Hangzhou 310006, Zhejiang Province, China. 1193970654@qq.com
Research Domain of This Article
Cell Biology
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/
Zi-Qiu Ye, The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
Xiao-Hu Meng, Xin Fang, Han-Yi Liu, Department of Vascular Surgery, Affiliated Hangzhou First People's Hospital,Westlake University School of Medicine, Hangzhou 310006, Zhejiang Province,China
Hassan Hamisi Mwindadi, The First Clinical Medical College, China Medical University, Shenyang 110001, Liaoning Province, China
Co-corresponding authors: Xiao-Hu Meng and Xin Fang.
Author contributions: Meng XH and Fang X are co-corresponding authors and contributed equally to this study. Fang X conceived the initial research idea, systematically designed the experimental protocols, and supervised the entire research process; Meng XH led all in vivo experimental procedures, ensuring the standardization of animal model construction and sample collection; Liu HY conducted all in vitro experiments, independently performed cell function assays and molecular mechanism investigations, and was responsible for data collection, organization, and statistical analysis; Ye ZQ drafted the initial manuscript and participated in multiple rounds of revision to optimize the logical presentation of the research results; Mwindadi HH provided professional language editing and polishing to ensure compliance with international academic standards. All authors have read and approved the final manuscript.
Supported by Hangzhou Bio-Medicine and Health Industry Development Support Science and Technology Project, No. 2022WJC005 and No. 2024WJC105.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Qingdao Harwars Biology Group Ltd. (IACUC protocol number: No. AUP-QY-C-S-2024-004).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
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: Xiao-Hu Meng, Department of Vascular Surgery, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, No. 261 Huansha Road, Shangcheng District, Hangzhou 310006, Zhejiang Province, China. 1193970654@qq.com
Received: February 28, 2025 Revised: April 2, 2025 Accepted: June 3, 2025 Published online: June 26, 2025 Processing time: 117 Days and 21 Hours
Abstract
BACKGROUND
Carotid atherosclerosis is a complex disease involving multiple cellular and molecular pathways. Mesenchymal stem cells (MSCs) show therapeutic potential, but their optimal targets and efficacy are still under study. MiR-126 enhances endothelial function and promotes angiogenesis by relieving vascular endothelial growth factor signaling suppression, suggesting its potential in vascular regeneration. However, its role in directing stem cell differentiation toward endothelial lineages remains unclear. We hypothesize that miR-126 may influence MSCs’ immunomodulatory and vascular reparative functions via the mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathway, thereby improving carotid atherosclerosis. This study explores this mechanism to provide novel insights and support the development of miR-126-based therapeutic strategies.
AIM
To verify if miR-126 inhibits carotid atherosclerosis via the MAPK/ERK pathway.
METHODS
Rat bone marrow MSCs (product No. CP-R131, Wuhan, China) were verified by flow cytometry. The effects of miR-126 on MSCs’ proliferation, migration, apoptosis, and cytokine expression were explored using microRNA mimics and inhibitors. Fluorescence staining quantified CD31+ cells to evaluate endothelial differentiation. In vivo differentiation was assessed, and MSCs were transplanted into a rat carotid artery balloon dilatation model. Rats were randomly divided into five groups: Control, negative control mimics, miR-126 mimics, negative control inhibitor, and miR-126 inhibitor.
RESULTS
In vitro, MSCs treated with miR-126 mimics demonstrated enhanced proliferation, increased migration, and reduced apoptosis. These miR-126 mimics also significantly increased the secretion of vascular endothelial growth factor and basic fibroblast growth factor. Fluorescence and tissue staining indicated a higher proportion of CD31+ cells in the miR-126 mimics group. Additionally, the expression of endothelial-related genes (von Willebrand factor, endothelial nitric oxide synthase, and vascular endothelial-cadherin) was upregulated in this group. In vivo, miR-126-transfected MSCs effectively reduced neointimal thickness and promoted endothelial coverage in rats. MiR-126 stimulated MSC proliferation in a dose-dependent manner and reduced p38 and ERK1/2 phosphorylation. Conversely, miR-126 inhibition or blank controls resulted in opposing effects.
CONCLUSION
MiR-126 exerts significant modulatory effects on the immunoregulatory and vascular reparative functions of MSCs through the MAPK/ERK signaling pathway, promoting their differentiation into endothelial cells and thereby mitigating atherosclerosis.
Core Tip: Carotid atherosclerosis is closely linked to endothelial dysfunction, a relationship validated in rat models. As traditional drugs fall short in curing the disease and surgery carries risks, researchers are exploring gene-based therapies. MiR-126 emerges as a potential therapeutic factor. Experiments show it promotes mesenchymal stem cell differentiation into endothelial cells. Molecularly, miR-126 synergizes with the mitogen-activated protein kinases/extracellular signal-regulated kinase pathway. By modulating this pathway, miR-126 suppresses atherosclerotic lesion progression and shows promise in enhancing vascular health. These findings underscore the potential of miR-126 mimics in treating carotid atherosclerosis, laying a foundation for clinical translation.
