Dual inhibition of MAPK and PI3K/AKT pathways enhances maturation of human iPSC-derived cardiomyocytes.
Dual inhibition of MAPK and PI3K/AKT pathways enhances maturation of human iPSC-derived cardiomyocytes.
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DOI：
10.1016/j.stemcr.2022.07.003
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发表时间：
2022-09-13
影响因子：
5.9
通讯作者：
Perlingeiro, Rita R. C.
中科院分区：
文献类型：
--
作者：
Garay, Bayardo I.;Givens, Sophie;Abreu, Phablo;Liu, Man;Yucel, Dogacan;Baik, June;Stanis, Noah;Rothermel, Taylor M.;Magli, Alessandro;Abrahante, Juan E.;Goloviznina, Natalya A.;Soliman, Hossam A. N.;Dhoke, Neha R.;Kyba, Michael;Alford, Patrick W.;Dudley Jr, Samuel C.;van Berlo, Jop H.;Ogle, Brenda;Perlingeiro, Rita R. C.
人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）为人类心脏病理生理学的机械解剖提供了很大的机会;然而，hiPSC-CM相对于成人心脏仍然不成熟。为了确定在心脏发育过程中驱动成熟过程的新信号通路，我们分析了来自hiPSC-CM和产前和产后人类心脏的已发表的转录和表观遗传数据集。这些分析表明，MAPK和PI 3 K-AKT通路的几个组成部分在出生后的心脏下调。在这里，我们表明，这些途径的双重抑制仅5天就显著增强了第30天hiPSC-CM在许多领域的成熟：肥大、多核化、代谢、T-小管密度、钙处理和电生理学，许多相当于第60天hiPSC-CM。这些数据表明MAPK/PI 3 K/AKT通路参与心肌细胞成熟，并为操纵关键信号传导通路以实现最佳hiPSC-CM成熟提供了概念证明，这是心脏病理学的忠实体外建模和后续药物发现的关键方面。MAPK/PI 3 K/AKT信号通路在人心室心脏组织中随时间降低用MAPK/PI 3 K/AKT抑制剂处理hiPSC-CM 5天可促进成熟用抑制剂达到的CM成熟上级未处理的较老培养物。在这篇文章中，Garay及其同事表明，MAPK和PI 3 K/AKT信号通路在成人心室心脏组织中下调。在体外抑制这些信号通路仅5天，就可以增强人iPSC衍生的心肌细胞在多个领域的成熟状态。这个简短的协议打开了与其他已知的心脏成熟诱导剂协同使用的可能性，以潜在地达到成人水平的成熟。
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide great opportunities for mechanistic dissection of human cardiac pathophysiology; however, hiPSC-CMs remain immature relative to the adult heart. To identify novel signaling pathways driving the maturation process during heart development, we analyzed published transcriptional and epigenetic datasets from hiPSC-CMs and prenatal and postnatal human hearts. These analyses revealed that several components of the MAPK and PI3K-AKT pathways are downregulated in the postnatal heart. Here, we show that dual inhibition of these pathways for only 5 days significantly enhances the maturation of day 30 hiPSC-CMs in many domains: hypertrophy, multinucleation, metabolism, T-tubule density, calcium handling, and electrophysiology, many equivalent to day 60 hiPSC-CMs. These data indicate that the MAPK/PI3K/AKT pathways are involved in cardiomyocyte maturation and provide proof of concept for the manipulation of key signaling pathways for optimal hiPSC-CM maturation, a critical aspect of faithful in vitro modeling of cardiac pathologies and subsequent drug discovery. MAPK/PI3K/AKT signaling decreases across time in human ventricular heart tissue A 5 day treatment of hiPSC-CMs with MAPK/PI3K/AKT inhibitors advances maturation CM maturation reached with inhibitors is superior to untreated older cultures In this article, Garay and colleagues show that the MAPK and PI3K/AKT signaling pathways are downregulated in the adult ventricular heart tissue. Inhibition of these signaling pathways in vitro, for only 5 days, can enhance the maturation status of human iPSC-derived cardiomyocytes across multiple domains. This short protocol opens the possibility for synergistic use with other known inducers of cardiac maturation to potentially reach adult-level maturation.
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影响因子：
48
作者：
Burridge, Paul W.;Matsa, Elena;Shukla, Praveen;Lin, Ziliang C.;Churko, Jared M.;Ebert, Antje D.;Lan, Feng;Diecke, Sebastian;Huber, Bruno;Mordwinkin, Nicholas M.;Plews, Jordan R.;Abilez, Oscar J.;Cui, Bianxiao;Gold, Joseph D.;Wu, Joseph C.
通讯作者：
Wu, Joseph C.
影响因子：
5.9
作者：
Bedada, Fikru B.;Chan, Sunny S-K.;Metzger, Stefania K.;Zhang, Liying;Zhang, Jianyi;Garry, Daniel J.;Kamp, Timothy J.;Kyba, Michael;Metzger, Joseph M.
通讯作者：
Metzger, Joseph M.
DOI：
10.1073/pnas.1214608110
发表时间：
2013-01-22
影响因子：
11.1
作者：
Mollova, Mariya;Bersell, Kevin;Kuehn, Bernhard
通讯作者：
Kuehn, Bernhard
影响因子：
64.5
作者：
Bergmann, Olaf;Zdunek, Sofia;Frisen, Jonas
通讯作者：
Frisen, Jonas
影响因子：
10.5
作者：
Engel, FB;Schebesta, M;Keating, MT
通讯作者：
Keating, MT