miR-106a–363 cluster in extracellular vesicles promotes endogenous myocardial repair via Notch3 pathway in ischemic heart injury

An Editorial to this article was published on 19 March 2021


Endogenous capability of the post-mitotic human heart holds great promise to restore the injured myocardium. Recent evidence indicates that the extracellular vesicles (EVs) regulate cardiac homeostasis and regeneration. Here, we investigated the molecular mechanism of EVs for self-repair. We isolated EVs from human iPSC-derived cardiomyocytes (iCMs), which were exposed to hypoxic (hEVs) and normoxic conditions (nEVs), and examined their roles in in vitro and in vivo models of cardiac injury. hEV treatment significantly improved the viability of hypoxic iCMs in vitro and cardiac function of severely injured murine myocardium in vivo. Microarray analysis of the EVs revealed significantly enriched expression of the miR-106a–363 cluster (miR cluster) in hEVs vs. nEVs. This miR cluster preserved survival and contractility of hypoxia-injured iCMs and maintained murine left-ventricular (LV) chamber size, improved LV ejection fraction, and reduced myocardial fibrosis of the injured myocardium. RNA-Seq analysis identified Jag1-Notch3-Hes1 as a target intracellular pathway of the miR cluster. Moreover, the study found that the cell cycle activator and cytokinesis genes were significantly up-regulated in the iCMs treated with miR cluster and Notch3 siRNA. Together, these results suggested that the miR cluster in the EVs stimulated cardiomyocyte cell cycle re-entry by repressing Notch3 to induce cell proliferation and augment myocardial self-repair. The miR cluster may represent an effective therapeutic approach for ischemic cardiomyopathy.

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Induced pluripotent stem cell


IPSC‐derived iCM


Extracellular vesicles


EVs from normoxic iCM


EVs from hypoxic iCM

miR cluster:

MiR-106a–363 cluster


MiR-20b, miR-92a, miR-363


Myocardial infarction


Peri‐infarct region




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We thank Dr. Kyuho Han (Department of Genetics, Stanford University), and Dr. Hokyung Kay Chung (Department of Biology, Stanford University) for critical discussion in this project and sharing experimental protocols and reagents.


This work was supported by National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH) [K24 HL130553; UM1 HL113456] and the American Heart Association (AHA) [18POST34080005; 19CSLOI34700047-l].

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JHJ design conception, perform and data analysis, manuscript writing, and final approval; GI mice surgery and perform experiments; YT scan and analysis of mice MRI; DVB mice surgery and handling; CW, SL, YJJ, MS, AY, and CO: data collection and analysis; KR, EAA, MM, and JW: provide technical resources, advice, and supervision; and PCY: design conception, data analysis, financial support, manuscript writing, supervision, and final approval.

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Correspondence to Phillip C. Yang.

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Jung, JH., Ikeda, G., Tada, Y. et al. miR-106a–363 cluster in extracellular vesicles promotes endogenous myocardial repair via Notch3 pathway in ischemic heart injury. Basic Res Cardiol 116, 19 (2021). https://doi.org/10.1007/s00395-021-00858-8

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  • Myocardial Infarction
  • IPSCs
  • EVs
  • MiRNAs
  • Endogenous cardiac repair mechanism
  • Cell cycle re-entry