Liver X receptor α (LXRα/NR1H3) regulates differentiation of hepatocyte-like cells via reciprocal regulation of HNF4α
Résumé
BACKGROUND & AIMS: Hepatocyte-like cells differentiated from different stem cell source are considered to have a range of possible therapeutic applications, including drug discovery, metabolism disease modeling and cell transplantation. However, little is known about how stem cells differentiate into mature and functional hepatocytes. METHODS: Using transcriptomic screening, a transcriptional factor, liver x receptor α (NR1H3) was identified as increased during HepaRG cell hepatogenesis; this protein is also up-regulated during embryonic stem cells and induced pluripotent stem cells differentiation. RESULTS: Overexpressing NR1H3 in human HepaRG cells promoted hepatic maturation, and these hepatocyte-like cells exhibit various functions associated with mature hepatocytes, including cytochrome P450 (CYP) enzyme activity, the secretion of urea and albumin, up regulation of hepatic-specific transcripts and an increase in glycogen storage. Importantly, the NR1H3-derived hepatocyte-like cells were able to rescued lethal fulminant hepatic failure using a non-obese diabetic severe combined immunodeficient mouse model. CONCLUSIONS: In this study, we found out that NR1H3 accelerates hepatic differentiation through a HNF4α-dependent reciprocal network. This contribute in hepatogenesis and is therapeutically beneficial to liver disease.
Domaines
Sciences du Vivant [q-bio]
Origine : Fichiers produits par l'(les) auteur(s)
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