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

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An Editorial to this article was published on 19 March 2021

Abstract

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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Abbreviations

iPSC:

Induced pluripotent stem cell

iCM:

IPSC‐derived iCM

EVs:

Extracellular vesicles

nEV:

EVs from normoxic iCM

hEV:

EVs from hypoxic iCM

miR cluster:

MiR-106a–363 cluster

Core-miR:

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

MI:

Myocardial infarction

PIR:

Peri‐infarct region

EdU:

5-Ethynyl-2′-deoxyuridine

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Acknowledgements

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.

Funding

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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Authors and Affiliations

  1. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Ji-Hye Jung, Gentaro Ikeda, Yuko Tada, Michelle R. Santoso, Connor G. O’brien & Phillip C. Yang

  2. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Ji-Hye Jung, Gentaro Ikeda, Yuko Tada, Christine Wahlquist, Mark Mercola & Phillip C. Yang

  3. Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Daniel von Bornstädt & Joseph Woo

  4. Department of Biology, Stanford University, Stanford, CA, 94305, USA

    Siyeon Rhee & Kristy Red-Horse

  5. Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea

    Young-Jun Jeon

  6. Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA

    Anthony C. Yu & Eric A. Appel

  7. Stanford University School of Medicine, 240 Pasteur Dr, BMI 3053, Palo Alto, CA, 94304, USA

    Phillip C. Yang

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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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A comment to this article is available at https://doi.org/10.1007/s00395-021-00857-9.

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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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