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Generation of mature epicardium derived from human-induced pluripotent stem cells via inhibition of mTOR signaling

Author

Listed:
  • Yu Tian

    (Kyoto University
    Kyoto University)

  • Antonio Lucena-Cacace

    (Kyoto University
    The University of Osaka)

  • Kanae Tani

    (Kyoto University
    Kyoto University)

  • Amanda Putri Elvandari

    (Kyoto University)

  • Rodolfo S. Allendes Osorio
  • Megumi Narita

    (Kyoto University)

  • Yasuko Matsumura

    (Kyoto University)

  • Ian Costa Paixao

    (Kyoto University)

  • Yutaro Miyoshi

    (Kyoto University
    Kyoto University)

  • Azusa Inagaki

    (Kyoto University)

  • Julia Junghof

    (Kyoto University
    Kyoto University)

  • Yoshinori Yoshida

    (Kyoto University)

Abstract

Reactivating the human epicardium post-cardiac injury holds promise for cardiac tissue regeneration. Despite successful differentiation protocols yielding pure, self-renewing epicardial cells from induced pluripotent stem cells (iPSCs), these cells maintain an embryonic, proliferative state, impeding adult epicardial reactivation investigation. We introduce an optimized method that employs mammalian target of rapamycin (mTOR) signaling inhibition in embryonic epicardium, inducing a quiescent state that enhances multi-step epicardial maturation. This yields functionally mature epicardium, valuable for modeling adult epicardial reactivation. Furthermore, we assess cardiac organoids with cardiomyocytes and mature epicardium, probing molecular mechanisms governing epicardial quiescence during cardiac maturation. Our results highlight iPSC-derived mature epicardium’s potential in investigating adult epicardial reactivation, pivotal for effective cardiac regeneration. Additionally, the cardiac organoid model offers insight into intricate cardiomyocyte-epicardium interactions in cardiac development and regeneration.

Suggested Citation

  • Yu Tian & Antonio Lucena-Cacace & Kanae Tani & Amanda Putri Elvandari & Rodolfo S. Allendes Osorio & Megumi Narita & Yasuko Matsumura & Ian Costa Paixao & Yutaro Miyoshi & Azusa Inagaki & Julia Jungho, 2025. "Generation of mature epicardium derived from human-induced pluripotent stem cells via inhibition of mTOR signaling," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60934-8
    DOI: 10.1038/s41467-025-60934-8
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    References listed on IDEAS

    as
    1. Nicola Smart & Catherine A. Risebro & Athalie A. D. Melville & Kelvin Moses & Robert J. Schwartz & Kenneth R. Chien & Paul R. Riley, 2007. "Thymosin β4 induces adult epicardial progenitor mobilization and neovascularization," Nature, Nature, vol. 445(7124), pages 177-182, January.
    2. Yonatan R. Lewis-Israeli & Aaron H. Wasserman & Mitchell A. Gabalski & Brett D. Volmert & Yixuan Ming & Kristen A. Ball & Weiyang Yang & Jinyun Zou & Guangming Ni & Natalia Pajares & Xanthippi Chatzis, 2021. "Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Mariana A. Branco & Tiago P. Dias & Joaquim M. S. Cabral & Perpetua Pinto-do-Ó & Maria Margarida Diogo, 2022. "Human multilineage pro-epicardium/foregut organoids support the development of an epicardium/myocardium organoid," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    4. Kenji Miki & Kohei Deguchi & Misato Nakanishi-Koakutsu & Antonio Lucena-Cacace & Shigeru Kondo & Yuya Fujiwara & Takeshi Hatani & Masako Sasaki & Yuki Naka & Chikako Okubo & Megumi Narita & Ikue Takei, 2021. "ERRγ enhances cardiac maturation with T-tubule formation in human iPSC-derived cardiomyocytes," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
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