Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α

• Published in: Journal of hepatology 2014-12, Vol.61 (6), p.1276-1286
• Main Authors: Chen, Kai-Ting, Pernelle, Kelig, Tsai, Yuan-Hau, Wu, Yu-Hsuan, Hsieh, Jui-Yu, Liao, Ko-Hsun, Guguen-Guillouzo, Christiane, Wang, Hsei-Wei
• Format: Article
• Language: English
• Subjects: Animals; Carbon Tetrachloride - adverse effects; Cell Differentiation - physiology; Cell Line; Cell Transplantation; Disease Models, Animal; Gastroenterology and Hepatology; HepaRG progenitor cell; Hepatocyte Nuclear Factor 4 - physiology; Hepatocytes - cytology; Hepatocytes - physiology; Hepatogenesis; HNF4A; Humans; In Vitro Techniques; Life Sciences; Liver Failure - chemically induced; Liver Failure - therapy; Liver Regeneration - physiology; Liver X Receptors; LXRα/NR1H3; Mice; Mice, Inbred NOD; Mice, SCID; Orphan Nuclear Receptors - physiology; Stem Cells - cytology; Stem Cells - physiology
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2014.07.025

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 α (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 HNF4α-dependent reciprocal network. This contributes to hepatogenesis and is therapeutically beneficial to liver disease.