Journal
JOURNAL OF HEPATOLOGY
Volume 61, Issue 6, Pages 1276-1286Publisher
ELSEVIER
DOI: 10.1016/j.jhep.2014.07.025
Keywords
Hepatogenesis; LXR alpha/NR1H3; HNF4A; HepaRG progenitor cell
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Funding
- Taiwan Ministry of Science and Technology [NSC101-2321-B-010-011, NSC101-2320-B-010-059-MY3, NSC101-2627-B-010-003, NSC102-2622-B-010-002]
- Taipei City Hospital [10201-62-070]
- National Health Research Institutes [NHRI-EX102-10254SI]
- UST-UCSD International Center of Excellence in Advanced Bioengineering - Taiwan Ministry of Science and Technology I-RiCE Program [NSC102-2911-I-009-101]
- National Yang-Ming University (Ministry of Education)
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Background & Aims: Hepatocyte-like cells, differentiated from different stem cell sources, are considered to have a range of possible therapeutic applications, including drug discovery, metabolic disease modelling, and cell transplantation. However, little is known about how stem cells differentiate into mature and functional hepatocytes. Methods: Using transcriptomic screening, a transcription factor, liver X receptor a (NR1H3), was identified as increased during HepaRG cell hepatogenesis; this protein was also upregulated during embryonic stem cell and induced pluripotent stem cell differentiation. Results: Overexpressing NR1H3 in human HepaRG cells promoted hepatic maturation; the hepatocyte-like cells exhibited various functions associated with mature hepatocytes, including cytochrome P450 (CYP) enzyme activity, secretion of urea and albumin, upregulation of hepatic-specific transcripts and an increase in glycogen storage. Importantly, the NR1H3-derived hepatocyte-like cells were able to rescue lethal fulminant hepatic failure using a non-obese diabetic/severe combined immunodeficient mouse model. Conclusions: In this study, we found that NR1H3 accelerates hepatic differentiation through an HNF4 alpha-dependent reciprocal network. This contributes to hepatogenesis and is therapeutically beneficial to liver disease. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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