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Hypoxia-preconditioned mesenchymal stem cell-derived exosomes attenuate myocardial ischemia/reperfusion injury by miR-29b-3p via PINK1/Parkin-mediated mitophagy
Wen Wen, Chen-Xi Liu, Yong Wang, Xiao-Jiong Lu, Chao Yang, Shuang-Jing Chen, Zhi-Tao Jin, Ming-Yue Qu, Jing-Yu Deng, Zheng Zhang
Wen Wen, Chen-Xi Liu, Xiao-Jiong Lu, Department of Cardiology, The Postgraduate Training Base of Jinzhou Medical University and Department of Cardiology, The PLA Rocket Force Characteristic Medical Center, Beijing 100088, China
Yong Wang, Department of Nuclear Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
Chao Yang, Shuang-Jing Chen, Ming-Yue Qu, The PLA Rocket Force Characteristic Medical Center, Beijing 100088, China
Zhi-Tao Jin, Zheng Zhang, Department of Cardiology, The PLA Rocket Force Characteristic Medical Center, Beijing 100088, China
Jing-Yu Deng, Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
Co-corresponding authors: Jing-Yu Deng and Zheng Zhang.
Author contributions: Wen W, Deng JY, and Zhang Z designed the research study and reviewed and edited the manuscript; Wen W, Liu CX, Wang Y, Lu XJ, Yang C, Chen SJ, Jin ZT, Qu MY, Deng JY, and Zhang Z performed the research; Wen W analyzed the data and wrote the original draft; Deng JY and Zhang Z supervised the study and contributed equally to this manuscript as co-corresponding authors; All authors read and approved the final version of the manuscript.
Supported by Beijing Natural Science Foundation, No. 7222229.
Institutional animal care and use committee statement: All animal experiments were reviewed and approved by the Ethics Committee of the PLA Rocket Force Characteristic Medical Center (Approval No. KY202527) and were conducted in accordance with institutional guidelines for the care and use of laboratory animals.
Conflict-of-interest statement: All 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: Sequencing data available from the corresponding author at
faithword@163.com.
Corresponding author: Zheng Zhang, MD, Associate Chief Physician, Department of Cardiology, The PLA Rocket Force Characteristic Medical Center, No. 16 Xinjiekouwai Dajie, Xicheng District, Beijing 100088, China.
faithword@163.com
Received: November 18, 2025
Revised: January 12, 2026
Accepted: February 24, 2026
Published online: May 26, 2026
Processing time: 190 Days and 5.3 Hours
BACKGROUND
Accumulating studies suggest that mesenchymal stem cell (MSC)-derived extracellular vesicles mitigate myocardial injury by modulating intercellular communication pathways. Notably, exosomes from hypoxia-preconditioned MSCs (HPC-Exo) demonstrate superior therapeutic efficacy in ischemic heart disease compared with those from normoxic MSCs although the underlying molecular mechanisms remain largely unclear.
AIM
To investigate the cardioprotective effects of HPC-Exo on myocardial ischemia/reperfusion (I/R) injury and to elucidate the potential mechanisms involved.
METHODS
Exosomes from MSCs cultured under normoxic or hypoxic conditions were isolated and characterized by electron microscopy and surface marker analysis. Cardioprotective effects were evaluated in hypoxia/reperfusion-treated cardiomyocytes and a murine I/R model with cardiac function assessed by echocardiography. MicroRNA sequencing identified miR-29b-3p enrichment in HPC-Exo. Functional studies using miR-29b-3p modulation, mitochondrial assays, and PINK1 silencing assessed apoptosis, reactive oxygen species production, and mitophagy via transferase dUTP nick end labeling, MitoSOX flow cytometry, and western blot.
RESULTS
HPC-Exo significantly attenuated myocardial I/R injury and improved cardiac function. Next-generation sequencing identified miR-29b-3p as highly enriched in HPC-Exo. Overexpression of miR-29b-3p alleviated hypoxia/reperfusion-induced cellular injury, reduced mitochondrial damage, and promoted mitophagy. Mechanistically, the PINK1/Parkin pathway mediated these protective effects. Knockdown of PINK1 suppressed Parkin expression, impaired mitophagy, and exacerbated reperfusion injury, ultimately diminishing the protective effects of miR-29b-3p.
CONCLUSION
Our findings demonstrated that HPC-Exo protect against myocardial I/R injury primarily through miR-29b-3p-mediated activation of PINK1/Parkin-dependent mitophagy.
Core Tip: This study identified hypoxia-preconditioned mesenchymal stem cell-derived exosomes as a potent therapeutic strategy for myocardial ischemia/reperfusion injury. High-throughput sequencing revealed miR-29b-3p as a key protective cargo that restores mitochondrial homeostasis by activating PINK1/Parkin-dependent mitophagy. miR-29b-3p significantly reduced oxidative stress, preserved mitochondrial integrity, and improve cardiac function in vivo, highlighting a promising exosome-based and mitochondria-targeted approach for future cardioprotection.
