Compound Safety Prediction, Pfizer, Inc., Groton, Connecticut 06340, USA.
Toxicol Sci. 2013 Jan;131(1):292-301. doi: 10.1093/toxsci/kfs282. Epub 2012 Sep 14.
Cardiotoxicity is one of the leading causes of drug attrition. Current in vitro models insufficiently predict cardiotoxicity, and there is a need for alternative physiologically relevant models. Here we describe the gene expression profile of human-induced pluripotent stem cell-derived cardiocytes (iCC) postthaw over a period of 42 days in culture and compare this profile to human fetal and adult as well as adult cynomolgus nonhuman primate (NHP, Macaca fascicularis) heart tissue. Our results indicate that iCC express relevant cardiac markers such as ion channels (SCN5A, KCNJ2, CACNA1C, KCNQ1, and KCNH2), tissue-specific structural markers (MYH6, MYLPF, MYBPC3, DES, TNNT2, and TNNI3), and transcription factors (NKX2.5, GATA4, and GATA6) and lack the expression of stem cell markers (FOXD3, GBX2, NANOG, POU5F1, SOX2, and ZFP42). Furthermore, we performed a functional evaluation of contractility of the iCC and showed functional and pharmacological correlations with myocytes isolated from adult NHP hearts. These results suggest that stem cell-derived cardiocytes may represent a novel in vitro model to study human cardiac toxicity with potential ex vivo and in vivo translation.
心脏毒性是导致药物淘汰的主要原因之一。目前的体外模型不能充分预测心脏毒性，因此需要替代具有生理相关性的模型。在这里，我们描述了人诱导多能干细胞衍生的心肌细胞（iCC）在解冻后 42 天的基因表达谱，并将其与人类胎儿和成人以及成年食蟹猴（Macaca fascicularis）心脏组织进行了比较。我们的结果表明，iCC 表达了相关的心脏标志物，如离子通道（SCN5A、KCNJ2、CACNA1C、KCNQ1 和 KCNH2）、组织特异性结构标志物（MYH6、MYLPF、MYBPC3、DES、TNNT2 和 TNNI3）和转录因子（NKX2.5、GATA4 和 GATA6），并且缺乏干细胞标志物（FOXD3、GBX2、NANOG、POU5F1、SOX2 和 ZFP42）的表达。此外，我们还对 iCC 的收缩功能进行了功能评估，并显示出与成年食蟹猴心脏分离的心肌细胞之间的功能和药理学相关性。这些结果表明，干细胞衍生的心肌细胞可能代表一种新型的体外模型，可用于研究人类心脏毒性，并具有潜在的离体和体内转化。
