Takayama Kazuo, Mizuguchi Hiroyuki
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan; The Keihanshin Consortium for Fostering the Next Generation of Global Leaders in Research (K-CONNEX), Kyoto University, Kyoto 606-8302, Japan; PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan; Laboratory of Hepatocyte Regulation, National Institute of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan.
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan; Laboratory of Hepatocyte Regulation, National Institute of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Global Center for Medical Engineering and Informatics, Osaka University, Osaka 565-0871, Japan.
Drug Metab Pharmacokinet. 2017 Feb;32(1):12-20. doi: 10.1016/j.dmpk.2016.10.408. Epub 2016 Oct 26.
Because drug-induced liver injury is one of the main reasons for drug development failures, it is important to perform drug toxicity screening in the early phase of pharmaceutical development. Currently, primary human hepatocytes are most widely used for the prediction of drug-induced liver injury. However, the sources of primary human hepatocytes are limited, making it difficult to supply the abundant quantities required for large-scale drug toxicity screening. Therefore, there is an urgent need for a novel unlimited, efficient, inexpensive, and predictive model which can be applied for large-scale drug toxicity screening. Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are able to replicate indefinitely and differentiate into most of the body's cell types, including hepatocytes. It is expected that hepatocyte-like cells generated from human ES/iPS cells (human ES/iPS-HLCs) will be a useful tool for drug toxicity screening. To apply human ES/iPS-HLCs to various applications including drug toxicity screening, homogenous and functional HLCs must be differentiated from human ES/iPS cells. In this review, we will introduce the current status of hepatocyte differentiation technology from human ES/iPS cells and a novel method to predict drug-induced liver injury using human ES/iPS-HLCs.
由于药物性肝损伤是药物研发失败的主要原因之一，因此在药物研发早期进行药物毒性筛选非常重要。目前，原代人肝细胞在预测药物性肝损伤方面应用最为广泛。然而，原代人肝细胞的来源有限，难以满足大规模药物毒性筛选所需的大量供应。因此，迫切需要一种新型的、无限的、高效的、廉价的且具有预测性的模型，可用于大规模药物毒性筛选。人胚胎干细胞（ES细胞）和诱导多能干细胞（iPS细胞）能够无限复制，并分化为包括肝细胞在内的大多数人体细胞类型。预计从人ES/iPS细胞产生的肝细胞样细胞（人ES/iPS-HLCs）将成为药物毒性筛选的有用工具。为了将人ES/iPS-HLCs应用于包括药物毒性筛选在内的各种应用，必须从人ES/iPS细胞中分化出同质且有功能的HLCs。在这篇综述中，我们将介绍从人ES/iPS细胞分化肝细胞技术的现状，以及一种使用人ES/iPS-HLCs预测药物性肝损伤的新方法。
