Comparison of Non-Coding RNAs in Exosomes and Functional Efficacy of Human Embryonic Stem Cell- Versus Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Authors

  • Won Hee Lee,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
    2. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA, United States
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    • These authors contributed equally to this work.

  • Wenyi Chen,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
    2. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA, United States
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    • These authors contributed equally to this work.

  • Ning-Yi Shao,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
    2. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA, United States
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  • Dan Xiao,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
    2. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA, United States
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  • Xulei Qin,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
    2. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA, United States
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  • Natalie Baker,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
    2. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA, United States
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  • Hye Ryeong Michelle Bae,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
    2. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA, United States
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  • Praveen Shukla,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
    2. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA, United States
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  • Haodi Wu,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
    2. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA, United States
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  • Kazuki Kodo,

    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
    2. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA, United States
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  • Sang-Ging Ong,

    Corresponding author
    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
    2. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA, United States
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  • Joseph C. Wu

    Corresponding author
    1. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
    2. Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA, United States
    3. Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
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  • Author Contributions: Won Hee Lee: Conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, Wenyi Chen: Conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, Ning-Yi Shao: Sequencing data analysis and interpretation, Dan Xiao: Collection and/or assembly of data, Xulei Qin: Collection and/or assembly of data, data analysis and interpretation, Natalie Baker: Collection and/or assembly of data, Hye Ryeong Michelle Bae: Collection and/or assembly of data, Praveen Shukla: Collection and/or assembly of data, data analysis and interpretation, Haodi Wu: Collection and/or assembly of data, data analysis and interpretation, Kazuki Kodo: Collection and/or assembly of data, Sang-Ging Ong: Conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, Joseph C. Wu: Conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript

Abstract

Background: Both human embryonic stem cell-derived cardiomyocytes (ESC-CMs) and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can serve as unlimited cell sources for cardiac regenerative therapy. However, the functional equivalency between human ESC-CMs and iPSC-CMs for cardiac regenerative therapy has not been demonstrated. Here we performed a head-to-head comparison of ESC-CMs and iPSC-CMs in their ability to restore cardiac function in a rat myocardial infarction (MI) model as well as their exosomal secretome.

Methods and Results: Human ESCs and iPSCs were differentiated into cardiomyocytes using small molecule inhibitors. Fluorescence-activated cell sorting (FACS) analysis confirmed ∼85% and ∼83% of CMs differentiated from ESCs and iPSCs, respectively, were positive for cardiac troponin T. At a single-cell level, both cell types displayed similar calcium handling and electrophysiological properties, with gene expression comparable to the human fetal heart marked by striated sarcomeres. Sub-acute transplantation of ESC-CMs and iPSC-CMs into nude rats post-MI improved cardiac function, which was associated with increased expression of angiogenic genes in vitro following hypoxia. Profiling of exosomal microRNAs (miRs) and long non-coding RNAs (lncRNAs) revealed that both groups contain an identical repertoire of miRs and lncRNAs, including some that are known to be cardioprotective.

Conclusions: We demonstrate for the first time that both ESC-CMs and iPSC-CMs can facilitate comparable cardiac repair. This is advantageous because unlike allogeneic ESC-CMs used in therapy, autologous iPSC-CMs could potentially avoid immune rejection when used for cardiac cell transplantation in the future. This article is protected by copyright. All rights reserved.