Kai-Ting Chen1, Kelig Pernelle2, Yuan-Hau Tsai3, Yu-Hsuan Wu3, Jui-Yu Hsieh3, Ko-Hsun Liao3, Christiane Guguen-Guillouzo4, Hsei-Wei Wang5. 1. Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan. 2. Inserm UMR 991, Université de Rennes 1, Faculté de médecine, F-35043 Rennes cedex, France. 3. Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. 4. Inserm UMR 991, Université de Rennes 1, Faculté de médecine, F-35043 Rennes cedex, France; Biopredic international, Parc d'activité Bretèche batA4, 35760 Saint-Grégoire, France. 5. Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan; Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; YM-VGH Genome Research Center, National Yang-Ming University, Taipei, Taiwan; Department of Education and Research, Taipei City Hospital, Taipei, Taiwan. Electronic address: hwwang@ym.edu.tw.
Abstract
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.
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 immunodeficientmouse 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.
Authors: Laia Tolosa; Jérôme Caron; Zara Hannoun; Marc Antoni; Silvia López; Deborah Burks; Jose Vicente Castell; Anne Weber; Maria-Jose Gomez-Lechon; Anne Dubart-Kupperschmitt Journal: Stem Cell Res Ther Date: 2015-12-12 Impact factor: 6.832
Authors: Latifa Bakiri; Rainer Hamacher; Osvaldo Graña; Ana Guío-Carrión; Ramón Campos-Olivas; Lola Martinez; Hans P Dienes; Martin K Thomsen; Sebastian C Hasenfuss; Erwin F Wagner Journal: J Exp Med Date: 2017-03-29 Impact factor: 14.307
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