Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
J Mol Cell Biol. 2010 Oct;2(5):276-83. doi: 10.1093/jmcb/mjq022. Epub 2010 Aug 27.
Cardiotoxicity testing is a key activity in the pharmaceutical industry in order to detect detrimental effects of new drugs. A reliable human in vitro model would both be beneficial in selection of lead compounds and be important for reducing animal experimentation. However, the human heart is a complex organ composed of many distinct types of cardiomyocytes, but cardiomyocyte clusters (CMCs) derived from human embryonic stem cells could be an option for a cellular model. Data on functional properties of CMCs demonstrate similarities to their in vivo analogues in human. However, development of an in vitro model requires a more thorough comparison of CMCs to human heart tissue. Therefore, we directly compared individually isolated CMCs to human fetal, neonatal, adult atrial and ventricular heart tissues. Real-time qPCR analysis of mRNA levels and protein staining of ion channels and cardiac markers showed in general a similar expression pattern in CMCs and human heart. Moreover, a significant decrease in beat frequency was noted after addition of Zatebradine, a blocker to I(f) involved in regulation of spontaneous contraction in CMCs. The results underscore the similarities of CMCs to human cardiac tissue, and further support establishment of novel cardiotoxicity assays based on the CMCs in drug discovery.
心脏毒性测试是制药行业的一项关键活动，目的是检测新药的有害影响。一个可靠的人类体外模型不仅有利于先导化合物的选择，而且对于减少动物实验也很重要。然而，人类心脏是一个由许多不同类型的心肌细胞组成的复杂器官，但来源于人类胚胎干细胞的心肌细胞簇（CMCs）可能是一种细胞模型的选择。关于 CMCs 的功能特性的数据表明，它们与人类体内的类似物具有相似性。然而，体外模型的开发需要更彻底地比较 CMCs 和人类心脏组织。因此，我们直接将单独分离的 CMCs 与人类胎儿、新生儿、成人心房和心室心脏组织进行了比较。实时 qPCR 分析 mRNA 水平和离子通道和心脏标志物的蛋白染色表明，CMCs 和人类心脏的表达模式总体上相似。此外，在添加 Zatebradine（一种参与调节 CMCs 中自发性收缩的 I(f) 阻滞剂）后，搏动频率显著下降。这些结果强调了 CMCs 与人类心脏组织的相似性，并进一步支持在药物发现中基于 CMCs 建立新的心脏毒性检测方法。
