Microbial-derived lithocholic acid and vitamin K2 drive the metabolic maturation of pluripotent stem cells-derived and fetal hepatocytes
Abstract
Unlabelled The liver is the main organ responsible for the modification, clearance, and transformational toxicity of most xenobiotics owing to its abundance in cytochrome P450 (CYP450) enzymes. However, the scarcity and variability of primary hepatocytes currently limits their utility. Human pluripotent stem cells (hPSCs) represent an excellent source of differentiated hepatocytes; however, current protocols still produce fetal-like hepatocytes with limited mature function. Interestingly, fetal hepatocytes acquire mature CYP450 expression only postpartum, suggesting that nutritional cues may drive hepatic maturation. We show that vitamin K2 and lithocholic acid, a by-product of intestinal flora, activate pregnane X receptor (PXR) and subsequent CYP3A4 and CYP2C9 expression in hPSC-derived and isolated fetal hepatocytes. Differentiated cells produce albumin and apolipoprotein B100 at levels equivalent to primary human hepatocytes, while demonstrating an 8-fold induction of CYP450 activity in response to aryl hydrocarbon receptor (AhR) agonist omeprazole and a 10-fold induction in response to PXR agonist rifampicin. Flow cytometry showed that over 83% of cells were albumin and hepatocyte nuclear factor 4 alpha (HNF4α) positive, permitting high-content screening in a 96-well plate format. Analysis of 12 compounds showed an R(2) correlation of 0.94 between TC50 values obtained in stem cell-derived hepatocytes and primary cells, compared to 0.62 for HepG2 cells. Finally, stem cell…
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The PSC-to-liver bud differentiation system was significantly more rapid and yielded higher expression of liver bud markers compared to four extant liver differentiation methods.
“Finally, this PSC-to-liver bud differentiation system was significantly more rapid and yielded higher expression of liver bud markers, compared to four extant liver differentiation methods (Avior et al., 2015; Carpentier et al., 2016; Chen et al., 2012; Si-Tayeb et al., 2010; Zhao et al., 2013) (Figures 3A–3C and S3C).”
From A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells (2018) · cites this paper as Avior et al., 2015
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A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells
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“Based on Avior et al., 2015 and Chen et al., 2012, human ESCs were treated with 100ng/mL ACTIVIN, 50ng/mL WNT3A and 10ng/mL HGF for 3 days in 2% B27 RPMI supplemented with 1mM Glutamax.”
BackgroundMethodResultInfluentialChallenges and Opportunities in the Design of Liver-on-Chip Microdevices
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Substrate stiffness modulates the maturation of human pluripotent stem-cell-derived hepatocytes
Mittal, N., Tasnim, F., Yue, C., Qu, Y., Phan, D., Choudhury, Y., Tan, M.-H., & Yu, H. (2016) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.6b00475 · Cited by 25 · see citing works
- Authors
- Avior, Y., Levy, G., Zimerman, M., Kitsberg, D., Schwartz, R., Sadeh, R., Moussaieff, A., Cohen, M., Itskovitz‐Eldor, J., & Nahmias, Y.
- Affiliations
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Nahmias, Yaakov
- Venue
- Hepatology
- Published
- 2015-04-22
- Volume
- 62
- Issue
- 1
- Pages
- 265-278
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- OpenAlex
- W2120456698
- Cited by
- 88
- References
- 5
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 11 · 2021: 10 · 2020: 12 · 2019: 11 · 2018: 9 · 2017: 5 · 2016: 14 · 2015: 3 · 2014: 1
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hebrew University of Jerusalem
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- lithocholic acid, vitamin K2, fetal hepatocytes, hepatic maturation, pregnane X receptor, CYP3A4, CYP2C9, aryl hydrocarbon receptor, omeprazole, rifampicin, HNF4α, albumin, apolipoprotein B-100, hepatotoxicity, steatosis, cholestasis, apoptosis, high-content screening, predictive toxicology, gut microbiota, cytochrome P450
- MeSH terms
- Pregnane X Receptor, Cell Differentiation, Cells, Cultured, Humans, Lithocholic Acid, Receptors, Steroid, Sequence Analysis, RNA, Cell Culture Techniques, Hepatocytes, Toxicity Tests, Acute, Vitamin K 2, Pluripotent Stem Cells, Cytochrome P-450 CYP3A, Embryonic Stem Cells, Cytochrome P-450 CYP2C9
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