期刊
JOURNAL OF HEPATOLOGY
卷 57, 期 3, 页码 628-636出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2012.04.038
关键词
FOXA2; HNF1 alpha; Hepatocytes; Adenovirus; Drug screening; Drug metabolism; hESCs; hiPSCs
资金
- Ministry of Health, Labor, and Welfare of Japan
- Japan Research foundation For Clinical Pharmacology
- Nakatomi Foundation
- Uehara Memorial Foundation
- Ministry of Education, Sports, Science and Technology of Japan [20200076]
- Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO)
- Grants-in-Aid for Scientific Research [20200076] Funding Source: KAKEN
Background & Aims: Hepatocyte-like cells differentiated from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) can be utilized as a tool for screening for hepatotoxicity in the early phase of pharmaceutical development. We have recently reported that hepatic differentiation is promoted by sequential transduction of SOX17, HEX, and HNF4 alpha into hESC- or hiPSC-derived cells, but further maturation of hepatocyte-like cells is required for widespread use of drug screening. Methods: To screen for hepatic differentiation-promoting factors, we tested the seven candidate genes related to liver development. Results: The combination of two transcription factors, FOXA2 and HNF1 alpha, promoted efficient hepatic differentiation from hESCs and hiPSCs. The expression profile of hepatocyte-related genes (such as genes encoding cytochrome P450 enzymes, conjugating enzymes, hepatic transporters, and hepatic nuclear receptors) achieved with FOXA2 and HNF1 alpha transduction was comparable to that obtained in primary human hepatocytes. The hepatocyte-like cells generated by FOXA2 and HNF1 alpha transduction exerted various hepatocyte functions including albumin and urea secretion, and the uptake of indocyanine green and low density lipoprotein. Moreover, these cells had the capacity to metabolize all nine tested drugs and were successfully employed to evaluate drug-induced cytotoxicity. Conclusions: Our method employing the transduction of FOXA2 and HNF1 alpha represents a useful tool for the efficient generation of metabolically functional hepatocytes from hESCs and hiPSCs, and the screening of drug-induced cytotoxicity. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.
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