Tian Yu, Lucena-Cacace Antonio, Tani Kanae, Elvandari Amanda Putri, Allendes Osorio Rodolfo S, Narita Megumi, Matsumura Yasuko, Paixao Ian Costa, Miyoshi Yutaro, Inagaki Azusa, Junghof Julia, Yoshida Yoshinori
Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Nat Commun. 2025 Jul 1;16(1):5902. doi: 10.1038/s41467-025-60934-8.
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.
心脏损伤后重新激活人类心外膜有望实现心脏组织再生。尽管已有成功的分化方案可从诱导多能干细胞（iPSC）中产生纯净、自我更新的心外膜细胞，但这些细胞维持着胚胎期的增殖状态，阻碍了对成年心外膜重新激活的研究。我们引入了一种优化方法，该方法在胚胎心外膜中采用雷帕霉素靶蛋白（mTOR）信号抑制，诱导出一种静止状态，增强心外膜的多步骤成熟。这产生了功能成熟的心外膜，对模拟成年心外膜重新激活具有重要价值。此外，我们评估了含有心肌细胞和成熟心外膜的心脏类器官，探究心脏成熟过程中的心外膜静止调控分子机制。我们的结果突出了iPSC来源的成熟心外膜在研究成年心外膜重新激活方面的潜力，这对有效的心脏再生至关重要。此外，心脏类器官模型为深入了解心脏发育和再生过程中复杂的心肌细胞 - 心外膜相互作用提供了见解。
