ERRγ enhances cardiac maturation with T-tubule formation in human iPSC-derived cardiomyocytes.
ERRγ enhances cardiac maturation with T-tubule formation in human iPSC-derived cardiomyocytes.
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DOI：
10.1038/s41467-021-23816-3
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发表时间：
2021-06-21
影响因子：
16.6
通讯作者：
Yoshida Y
中科院分区：
文献类型：
--
作者：
Miki K;Deguchi K;Nakanishi-Koakutsu M;Lucena-Cacace A;Kondo S;Fujiwara Y;Hatani T;Sasaki M;Naka Y;Okubo C;Narita M;Takei I;Napier SC;Sugo T;Imaichi S;Monjo T;Ando T;Tamura N;Imahashi K;Nishimoto T;Yoshida Y
心肌细胞（CM）中最早的成熟步骤之一是肌节蛋白同种型在TNNI 1和TNNI 3（胎儿和新生儿/成人肌钙蛋白I）之间的转换。在这里，我们产生了携带TNNI 1 EmGFP和TNNI 3 mCherry双报告基因的人诱导多能干细胞（hiPSC），以监测和分离心脏分化过程中的成熟亚群。广泛的药物筛选确定了两种化合物，雌激素相关受体γ（ERRγ）激动剂和S期激酶相关蛋白2抑制剂，可增强心脏成熟和TNNI 3表达的显著变化。表达、形态学、功能和分子分析表明，经ERRγ激动剂处理的hiPSC-CM显示出更大的细胞尺寸、更长的肌节长度、横小管的存在以及增强的代谢功能和收缩和电特性。在这里，我们表明ERRγ处理的hiPSC-CM具有与新生儿CM一致的成熟细胞特性，并且可用于疾病建模和再生医学。源自人类诱导多能干细胞（hiPSC）的心肌细胞（CM）成熟有限。在本文中，作者将ERRγ激动剂确定为增强hiPSC衍生CM的心脏形态、代谢、收缩和电成熟以及T-小管形成的因子。
One of the earliest maturation steps in cardiomyocytes (CMs) is the sarcomere protein isoform switch between TNNI1 and TNNI3 (fetal and neonatal/adult troponin I). Here, we generate human induced pluripotent stem cells (hiPSCs) carrying a TNNI1EmGFP and TNNI3mCherry double reporter to monitor and isolate mature sub-populations during cardiac differentiation. Extensive drug screening identifies two compounds, an estrogen-related receptor gamma (ERRγ) agonist and an S-phase kinase-associated protein 2 inhibitor, that enhances cardiac maturation and a significant change to TNNI3 expression. Expression, morphological, functional, and molecular analyses indicate that hiPSC-CMs treated with the ERRγ agonist show a larger cell size, longer sarcomere length, the presence of transverse tubules, and enhanced metabolic function and contractile and electrical properties. Here, we show that ERRγ-treated hiPSC-CMs have a mature cellular property consistent with neonatal CMs and are useful for disease modeling and regenerative medicine. Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) suffer from limited maturation. Here the authors identify ERRγ agonist as a factor that enhances cardiac morphological, metabolic, contractile and electrical maturation of hiPSC-derived CMs with T-tubule formation.
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