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

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 Junghof and Yoshinori Yoshida ()
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Yu Tian: Kyoto University
Antonio Lucena-Cacace: Kyoto University
Kanae Tani: Kyoto University
Amanda Putri Elvandari: Kyoto University
Megumi Narita: Kyoto University
Yasuko Matsumura: Kyoto University
Ian Costa Paixao: Kyoto University
Yutaro Miyoshi: Kyoto University
Azusa Inagaki: Kyoto University
Julia Junghof: Kyoto University
Yoshinori Yoshida: Kyoto University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60934-8

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