PDF(Pubmed)
Abstract：
As research on in vitro cardiotoxicity assessment and cardiac disease modeling becomes more important, the demand for human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is increasing. However, it has been reported that differentiated hPSC-CMs are in a physiologically immature state compared to in vivo adult CMs. Since immaturity of hPSC-CMs can lead to poor drug response and loss of acquired heart disease modeling, various approaches have been attempted to promote maturation of CMs. Here, we confirm that peroxisome proliferator-activated receptor alpha (PPARα), one of the representative mechanisms of CM metabolism and cardioprotective effect also affects maturation of CMs. To upregulate PPARα expression, we treated hPSC-CMs with fenofibrate (Feno), a PPARα agonist used in clinical hyperlipidemia treatment, and demonstrated that the structure, mitochondria-mediated metabolism, and electrophysiology-based functions of hPSC-CMs were all mature. Furthermore, as a result of multi electrode array (MEA)-based cardiotoxicity evaluation between control and Feno groups according to treatment with arrhythmia-inducing drugs, drug response was similar in a dose-dependent manner. However, main parameters such as field potential duration, beat period, and spike amplitude were different between the 2 groups. Overall, these results emphasize that applying matured hPSC-CMs to the field of preclinical cardiotoxicity evaluation, which has become an essential procedure for new drug development, is necessary.
摘要：
随着体外心脏毒性评估和心脏疾病建模的研究变得越来越重要，人类多能干细胞来源的心肌细胞(hPSC-CM)的需求正在增加.然而,IthasbeenreportedthatdifferentiatedhPSC-CMareinaphysiologicalinmaturestatecomparedtoinvivoadultCMs.SinceimmaturityofhPSC-CMcanleadtopoordrugresponseandlossofacquiredheartdiseasemodeling,已经尝试了各种方法来促进CM的成熟。在这里，我们证实过氧化物酶体增殖物激活受体α（PPARα），CM代谢和心脏保护作用的代表性机制之一也影响CM的成熟。我们用非诺贝特（Feno）治疗hPSC-CM，一种用于临床高脂血症治疗的PPARα激动剂，并证明了这种结构，线粒体介导的代谢，hPSC-CM基于电生理的功能均已成熟。此外，作为多电极阵列（MEA）心脏毒性评估的结果，对照组和Feno组根据心律失常诱导药物治疗，药物反应在剂量依赖性方面相似.然而,主要参数，如场电位持续时间，节拍期,两组之间的尖峰幅度不同。总的来说,这些结果强调了将成熟的hPSC-CM应用于临床前心脏毒性评估领域，这已经成为新药开发的重要程序，是必要的。
