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Research Paper|Volume 13, Issue 4|pp 6156—6170

Extracellular vesicles from anoxia preconditioned mesenchymal stem cells alleviate myocardial ischemia/reperfusion injury

Chengyu Mao1, Dongjiu Li1, En Zhou1, Erhe Gao2, Tiantian Zhang1, Shufang Sun1, Lin Gao1, Yuqi Fan1, Changqian Wang1
  • 1Shanghai Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • 2Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19122, USA
* Equal contribution
Received: October 16, 2020Accepted: December 23, 2020Published: February 12, 2021
https://doi.org/10.18632/aging.202611

Copyright: © 2021 Mao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Extracellular vesicles (EVs) produced by anoxia-preconditioned mesenchymal stem cells (MSCs) may afford greater cardioprotection against myocardial ischemia-reperfusion injury (MIRI) than EVs derived from normoxic MSCs. Here, we isolated EVs from mouse adipose-derived MSCs (ADSCs) subjected to anoxia preconditioning or normoxia and evaluated their ability to promote survival of mouse cardiomyocytes following MIRI in vivo and anoxia/reoxygenation (AR) in vitro. Injection of anoxia-preconditioned ADSC EVs (Int-EVs) reduced both infarct size and cardiomyocyte apoptosis to a greater extent than normoxic ADSC EVs (NC-EVs) in mice subjected to MIRI. Sequencing EV-associated miRNAs revealed differential upregulation of ten miRNAs predicted to bind thioredoxin-interacting protein (TXNIP), an inflammasome- and pyroptosis-related protein. We confirmed direct binding of miRNA224-5p, the most upregulated miRNA in Int-EVs, to TXNIP and asserted through western blotting and apoptosis assays a critical protective role for this miRNA against AR-induced cardiomyocyte death. Our results suggest that ischemia-reperfusion triggers TXNIP-induced inflammasome activation in cardiomyocytes, which leads to apoptosis rather than pyroptosis due to low basal levels of the pyroptosis executioner protein gasdermin D in these cells. The antiapoptotic effect of EV-associated miRNA224-5p would in turn result from TXNIP downregulation, which prevents caspase-1-mediated degradation of GATA4 and sustains the expression of Bcl-2.