Zeng ZF, Rao J, Xia XB, Chen XY, He HX, Liu B, Chen Q, Liu YD, Wang GJ, Cheng PC, Wang JN, Wang P, Yu Y, Wang ZN. Hypoxic preconditioned mesenchymal stem cell-derived exosomes alleviate oxidative stress-induced cardiomyocyte apoptosis through miR-486-5p. World J Stem Cells 2025; 17(12): 112207 [DOI: 10.4252/wjsc.v17.i12.112207]
Corresponding Author of This Article
Zhi-Nong Wang, PhD, Professor, Department of Cardiothoracic Surgery, Changzheng Hospital, Naval Medical University, No. 415 Fengyang Road, Huangpu District, Shanghai 200003, China. wangzn007@smmu.edu.cn
Research Domain of This Article
Cell & Tissue Engineering
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/
Dec 26, 2025 (publication date) through Dec 31, 2025
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Journal Information of This Article
Publication Name
World Journal of Stem Cells
ISSN
1948-0210
Publisher of This Article
Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
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Zeng ZF, Rao J, Xia XB, Chen XY, He HX, Liu B, Chen Q, Liu YD, Wang GJ, Cheng PC, Wang JN, Wang P, Yu Y, Wang ZN. Hypoxic preconditioned mesenchymal stem cell-derived exosomes alleviate oxidative stress-induced cardiomyocyte apoptosis through miR-486-5p. World J Stem Cells 2025; 17(12): 112207 [DOI: 10.4252/wjsc.v17.i12.112207]
Zi-Feng Zeng, Jin Rao, Xi-Bei Xia, Xiang-Yu Chen, Hong-Xiang He, Bin Liu, Qiong Chen, Yu-Di Liu, Guo-Ji Wang, Peng-Chao Cheng, Jun-Nan Wang, Pei Wang, Yue Yu, Zhi-Nong Wang
Zi-Feng Zeng, Jin Rao, Xi-Bei Xia, Xiang-Yu Chen, Yu-Di Liu, Guo-Ji Wang, Peng-Chao Cheng, Jun-Nan Wang, Pei Wang, Yue Yu, Zhi-Nong Wang, Department of Cardiothoracic Surgery, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
Hong-Xiang He, School of Gongli Hospital Medical Technology, University of Shanghai for Science and Technology, Shanghai 200135, China
Bin Liu, Naval Medical Center, Naval Medical University, Shanghai 200433, China
Qiong Chen, Precision Medical Center of Nanfang Hospital, Southern Medical University, Guangzhou 510405, Guangdong Province, China
Co-first authors: Zi-Feng Zeng and Jin Rao.
Co-corresponding authors: Yue Yu and Zhi-Nong Wang.
Author contributions: Zeng ZF, Rao J, Xia XB, and Chen XY performed the experiments and wrote the paper; He HX, Liu B, Chen Q, Liu YD, and Wang GJ acquired and analyzed the data; Cheng PC, Wang JN, and Wang P contributed to the conceptualization and supervision; Yu Y and Wang ZN were engaged in the design of the study and the revision of the manuscript; Yu Y and Wang ZN participated equally and shared the corresponding authorship; All authors read and approved the version of the article to be published. Zeng ZF and Rao J made equal contributions to this article as co-first authors.
Institutional review board statement: Human umbilical cord-derived mesenchymal stem cells were provided by the Precision Medical Center of Nanfang Hospital, with the informed consent of all participants and approved by the Medical Ethics Committee of the hospital (Approval No. NFEC-202110-K17-01).
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
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: Zhi-Nong Wang, PhD, Professor, Department of Cardiothoracic Surgery, Changzheng Hospital, Naval Medical University, No. 415 Fengyang Road, Huangpu District, Shanghai 200003, China. wangzn007@smmu.edu.cn
Received: July 22, 2025 Revised: August 25, 2025 Accepted: November 14, 2025 Published online: December 26, 2025 Processing time: 157 Days and 2 Hours
Abstract
BACKGROUND
Emerging evidence indicates that hypoxic preconditioning boosts the antioxidant and anti-apoptotic capacities of mesenchymal stem cell-derived exosomes; however, the specific mechanisms remain incompletely elucidated. This study explored the impact of hypoxia-preconditioned mesenchymal stem cell-derived exosomes (hypo-Exos) vs normoxic counterparts on the apoptotic response in cardiomyocytes triggered by oxidative stress.
AIM
To determine whether and how hypoxic preconditioning augments the cardioprotective efficacy of hypo-Exos against oxidative stress-induced cardiomyocyte apoptosis.
METHODS
H9C2 cardiomyocytes were treated with hydrogen peroxide (H2O2) to induce oxidative injury. Assessments of cell viability, oxidative biomarkers, and apoptotic activity were conducted to evaluate the therapeutic efficacy of hypo-Exos and normoxic counterparts. High-throughput sequencing was performed to identify potential target microRNAs (miRNAs). Luciferase reporter assays were conducted to confirm selected miRNAs binding to target genes. Hypo-Exos loaded with selected miRNAs antagomirs or negative controls were administered to H2O2-treated H9C2 cells to validate the downstream signaling pathways involved.
RESULTS
Hypo-Exos significantly enhanced cell viability, reduced oxidative stress, and inhibited apoptosis of cardiomyocytes. Hypoxic preconditioning significantly increased the expression of exosomal miR-486-5p, which directly targeted the phosphatase and tensin homolog. Additionally, hypo-Exos markedly activated the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. Moreover, deletion of miR-486-5p in hypo-Exos counteracted the anti-apoptotic effects and suppressed PI3K/Akt pathway activation.
CONCLUSION
Hypoxic preconditioning augments anti-apoptotic properties of exosomes, primarily via miR-486-5p upregulation, which mediates its function by modulating the phosphatase and tensin homolog/PI3K/Akt axis.
Core Tip: Hypoxic preconditioning enhances the therapeutic properties of mesenchymal stem cell-derived exosomes with elevated miR-486-5p, which directly inhibits phosphatase and tensin homolog to activate the phosphoinositide 3-kinase/protein kinase B signaling, thereby halting oxidative stress-driven cardiomyocyte apoptosis. This work reveals a microRNA-mediated mechanism that allows exosomes to have powerful cardioprotective effects, suggesting a cell-free therapeutic strategy for treating oxidative-related cardiac injury.
