Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University.
Drug Metab Pharmacokinet. 2014;29(3):237-43. doi: 10.2133/dmpk.dmpk-13-rg-104. Epub 2013 Dec 10.
The use of human induced pluripotent stem (iPS) cells would be of great value for a variety of applications involving drug development studies. Several reports have been published on the differentiation of human iPS cells into hepatocyte-like cells; however, the cells were insufficient for application in drug metabolism studies. In this study, we aimed to establish effective methods for differentiation of human iPS cells into hepatocytes. Two human iPS cell lines were differentiated by addition of activin A, dimethyl sulfoxide, hepatocyte growth factor, oncostatin M, and dexamethasone. The differentiated cells expressed hepatocyte markers and drug-metabolizing enzymes, revealing that the human iPS cells were differentiated into hepatocyte-like cells. Expression of CYP3A4 and UGT1A1 mRNAs increased with treatment with typical inducers of the enzymes, and the response of the cells against the inducers was similar to that of human hepatocytes. Furthermore, the drug-metabolizing activity of CYP3A4, as monitored by testosterone 6β-hydroxylase activity, was elevated by these inducers. In conclusion, we established methods for differentiation of hepatocyte-like cells expressing drug metabolizing activity from human iPS cells. The hepatocyte-like cells derived from human iPS cells will be useful for drug metabolism studies.
人诱导多能干细胞（iPS）的应用将在涉及药物开发研究的各种应用中具有重要价值。已经有几篇关于将人 iPS 细胞分化为肝样细胞的报道；然而，这些细胞不足以用于药物代谢研究的应用。在这项研究中，我们旨在建立将人 iPS 细胞分化为肝细胞的有效方法。通过添加激活素 A、二甲基亚砜、肝细胞生长因子、肿瘤坏死因子-α和地塞米松，将两种人 iPS 细胞系分化。分化的细胞表达肝细胞标志物和药物代谢酶，表明人 iPS 细胞已分化为肝样细胞。CYP3A4 和 UGT1A1 mRNA 的表达随着酶的典型诱导剂的处理而增加，并且细胞对诱导剂的反应与人类肝细胞相似。此外，CYP3A4 的药物代谢活性，如通过睾酮 6β-羟化酶活性监测，被这些诱导剂升高。总之，我们建立了从人 iPS 细胞分化表达药物代谢活性的肝样细胞的方法。源自人 iPS 细胞的肝样细胞将可用于药物代谢研究。
