Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Feb 26, 2022; 14(2): 183-199
Published online Feb 26, 2022. doi: 10.4252/wjsc.v14.i2.183
Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells alleviates myocardial injury by targeting thioredoxin-interacting protein-mediated hypoxia-inducible factor-1α pathway
Cheng-Yu Mao, Tian-Tian Zhang, Dong-Jiu Li, En Zhou, Yu-Qi Fan, Qing He, Chang-Qian Wang, Jun-Feng Zhang
Cheng-Yu Mao, Tian-Tian Zhang, Dong-Jiu Li, En Zhou, Yu-Qi Fan, Qing He, Chang-Qian Wang, Jun-Feng Zhang, Department of Cardiology, Shanghai Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200010, China
Author contributions: Mao CY, Zhang TT, Li DJ, and Zhou E contributed equally to this work, performed the experiments, and reviewed and edited the manuscript; Fan YQ and He Q wrote the paper; Zhang JF, and Wang CQ conceived of and funded the study; all authors read and approved the final manuscript.
Supported by National Natural Science Foundation of China, No. 81870264 and No. 81470546; the Shanghai Committee of Science and Technology, No. 18411950500; the Major Disease Joint Project of Shanghai Health System, No. 2014ZYJB0501; and Talent Cultivation Project of The Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. JC202005.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Shanghai Ninth People’s Hospital.
Institutional animal care and use committee statement: All animal procedures were approved by the Shanghai Ninth People’s Hospital Institutional Ethics Committee and conducted in accordance with the guidelines of the Directive 2010/63/EU of the European Parliament.
Conflict-of-interest statement: The authors declare that they have no competing interests regarding this study.
Data sharing statement: The data that support the findings of this study are available from the corresponding author upon 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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jun-Feng Zhang, MD, PhD, Professor, Department of Cardiology, Shanghai Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine, No. 280 Mohe Road, Baoshan District, Shanghai 200010, China. junfengzhang9hos@163.com
Received: October 13, 2021
Peer-review started: October 13, 2021
First decision: November 8, 2021
Revised: November 29, 2021
Accepted: January 25, 2022
Article in press: January 25, 2022
Published online: February 26, 2022
Processing time: 134 Days and 20.8 Hours
ARTICLE HIGHLIGHTS
Research background

Previous studies have demonstrated that extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) reveal the cardioprotective effects against myocardial infarction (MI). Hypoxia-preconditioned EVs (HP-EVs) derived from MSCs are thought to have better cardioprotective effects, and the underlying mechanisms have garnered increasing attention from scholars.

Research motivation

Although some scholars have focused on the effect of hypoxia preconditioning on MSCs, the underlying mechanisms remain unclear. Thus, this study focused on the mechanism underlying the cardioprotective effect of HP-EVs from MSCs.

Research objectives

We explored the cardioprotective mechanism of HP-EVs from MSCs.

Research methods

HP-EVs from mouse adipose-derived MSCs (ADSCs) were extracted, and their cardioprotective effect on improving the survival of cardiomyocytes (CMs) and ameliorating cardiac function were evaluated by Evans Blue/2,3,5-triphenyltetrazolium chloride staining and echocardiography. Mechanistically, microRNA (miRNA) sequencing was adopted to investigate the functional RNA diversity between HP-EVs or normoxic EVs (NC-EVs) from mouse ADSCs. Subsequently, the molecular mechanism of EVs in mediating thioredoxin-interacting protein (TXNIP) and TXNIP-mediated hypoxia-inducible factor-1 alpha (HIF-1α) ubiquitination were verified by the dual-luciferase reporter assay, immunoprecipitation, western blotting, and immunofluorescence.

Research results

HP-EVs reduced both infarct size (necrosis area) and the degree of apoptosis to a greater extent than NC-EVs in CMs subjected to hypoxia in vitro and mice suffering from MI in vivo. We showed that EV miRNA224-5p directly bound to the 3’-untranslated region of TXNIP and had a critical protective role against hypoxia-associated CM injury. Our results suggested that MI triggered TXNIP-mediated HIF-1α ubiquitination and degradation via the chromosomal region maintenance 1-dependent nuclear transport pathway in CMs, which led to aggravated injury and hypoxia tolerance in CMs in the early stage of MI.

Research conclusions

The anti-apoptotic effect of HP-EVs, which improves tolerance toward MI or hypoxic conditions and alleviates the degree of CM apoptosis until reperfusion therapy, may partly result from EV miR-224-5p targeting TXNIP.

Research perspectives

This study partly reveals the mechanism underlying the cardioprotective effect of HP-EVs and provides insights into potential therapies against MI.