Abstract
Although hepatocyte-like cells derived from human pluripotent stem cells (hPSC-HLCs) are considered a promising model for predicting hepatotoxicity, their application has been restricted because of the low activity of drug metabolizing enzymes (DMEs). Here we found that the low expression of xenobiotic receptors (constitutive androstane receptor, CAR; and pregnane X receptor, PXR) contributes to the low activity of DMEs in hPSC-HLCs. Most CAR- and PXR-regulated DMEs and transporters were transcriptionally down-regulated in hPSC-HLC. Transcriptional expression of CAR and PXR was highly repressed in hPSC-HLCs, whereas mRNA levels of aryl hydrocarbon receptor (AHR) were comparable to those of adult liver. Furthermore, ligand-induced transcriptional activation was observed only at AHR in hPSC-HLCs. Bisulfite sequencing analysis demonstrated that promoter hypermethylation of CAR and PXR was associated with diminished transcriptional activity in hPSC-HLCs. Treatment with AHR-selective ligands increased the transcription of AHR-dependent target genes by direct AHR-DNA binding at the xenobiotic response element. In addition, an antagonist of AHR significantly inhibited AHR-dependent target gene expression. Thus, AHR may function intrinsically as a xenosensor as well as a ligand-dependent transcription factor in hPSC-HLCs. Our results indicate that hPSC-HLCs can be used to screen toxic substances related to AHR signaling and to identify potential AHR-targeted therapeutics.
Highlights
Enable the prediction of inter-individual differences in drug metabolism and susceptibility on the basis of single nucleotide polymorphisms of cytochrome P450 (CYP) genes[11]
Minor differences were observed in marker gene expression and albumin secretion between hESC- and hiPSC-HLCs, the overall results indicate that both hESCs and hiPSCs were efficiently differentiated into hepatocyte-like cells
Recent progress in technology and in the understanding of stem cell biology has enabled significant progress towards establishing alternative in vitro models based on hPSC-HLCs for drug safety and toxicology applications[6,31,32]
Summary
Enable the prediction of inter-individual differences in drug metabolism and susceptibility on the basis of single nucleotide polymorphisms of cytochrome P450 (CYP) genes[11] These findings of the predictive capacities of hPSC-HLCs wholly rely on the expression and functional activity of drug metabolizing enzymes (DMEs) and related drug transporters. A number of ligand-activated transcription factors, mostly nuclear receptors, exhibit miscellaneous xenobiotic binding capabilities and function as sensors of endogenous toxic metabolites and xenobiotics[16,17]. These receptors can induce the majority of genes involved in xenobiotic metabolism and transport by recognition of various ligands and are termed xenobiotic receptors. The transcriptional activity of AHR was reproducible in hPSC-HLCs, which was tightly regulated by AHR-specific agonistic and antagonistic xenobiotics
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