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Generation of mature compact ventricular cardiomyocytes from human pluripotent stem cells

Author

Listed:
  • Shunsuke Funakoshi

    (University Health Network)

  • Ian Fernandes

    (University Health Network
    University of Toronto)

  • Olya Mastikhina

    (University Health Network)

  • Dan Wilkinson

    (BlueRock Therapeutics)

  • Thinh Tran

    (University of Toronto)

  • Wahiba Dhahri

    (University Health Network)

  • Amine Mazine

    (University Health Network
    University of Toronto)

  • Donghe Yang

    (University Health Network
    University of Toronto)

  • Benjamin Burnett

    (BlueRock Therapeutics)

  • Jeehoon Lee

    (BlueRock Therapeutics)

  • Stephanie Protze

    (University Health Network
    University of Toronto)

  • Gary D. Bader

    (University of Toronto
    University of Toronto
    University of Toronto)

  • Sara S. Nunes

    (University Health Network
    University of Toronto
    University of Toronto
    University of Toronto)

  • Michael Laflamme

    (University Health Network
    University of Toronto
    University Health Network)

  • Gordon Keller

    (University Health Network
    University of Toronto)

Abstract

Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. Here, we established a differentiation strategy that promotes the specification, proliferation and maturation of compact ventricular cardiomyocytes from human pluripotent stem cells (hPSCs). The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force. These ventricular cells undergo metabolic changes indicative of those associated with heart failure when challenged in vitro with pathological stimuli and were found to generate grafts consisting of more mature cells than those derived from immature cardiomyocytes following transplantation into infarcted rat hearts. hPSC-derived atrial cardiomyocytes also responded to the maturation cues identified in this study, indicating that the approach is broadly applicable to different subtypes of the heart. Collectively, these findings highlight the power of recapitulating key aspects of embryonic and postnatal development for generating therapeutically relevant cell types from hPSCs.

Suggested Citation

  • Shunsuke Funakoshi & Ian Fernandes & Olya Mastikhina & Dan Wilkinson & Thinh Tran & Wahiba Dhahri & Amine Mazine & Donghe Yang & Benjamin Burnett & Jeehoon Lee & Stephanie Protze & Gary D. Bader & Sar, 2021. "Generation of mature compact ventricular cardiomyocytes from human pluripotent stem cells," Nature Communications, Nature, vol. 12(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23329-z
    DOI: 10.1038/s41467-021-23329-z
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    Cited by:

    1. Ian Fernandes & Shunsuke Funakoshi & Homaira Hamidzada & Slava Epelman & Gordon Keller, 2023. "Modeling cardiac fibroblast heterogeneity from human pluripotent stem cell-derived epicardial cells," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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