ArticleToxicological sciences : an official journal of the Society of Toxicology2014
Aggregate culture of human embryonic stem cell-derived hepatocytes in suspension are an improved in vitro model for drug metabolism and toxicity testing.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 46 citations in OpenAlex.
- A comprehensive transcriptomic comparison of hepatocyte model systems improves selection of models for experimental use.Communications biology · 2022Pooled it
- Three-Dimensional Cell Cultures: The Bridge between In Vitro and In Vivo Models.International journal of molecular sciences · 2023Review
- Bioengineering liver microtissues for modeling non-alcoholic fatty liver disease.EXCLI journal · 2023Review
- iPSC-derived hepatocytes generated from NASH donors provide a valuable platform for disease modeling and drug discovery.Biology open · 2020Article
- Real-time fluorometric evaluation of hepatoblast proliferation in vivo and in vitro using the expression of CYP3A7 coding for human fetus-specific P450.Pharmacology research & perspectives · 2020Article
- Sustained release and protein stabilization reduce the growth factor dosage required for human pluripotent stem cell expansion.Biomaterials · 2020Article
- Co-culture with mouse embryonic fibroblasts improves maintenance of metabolic function of human small hepatocyte progenitor cells.Current research in toxicology · 2020Article
- Transplantation of mesenchymal stem cells and their derivatives effectively promotes liver regeneration to attenuate acetaminophen-induced liver injury.Stem cell research & therapy · 2020Review
- Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration.Cells · 2020Review
- Novel in vitro dynamic metabolic system for predicting the human pharmacokinetics of tolbutamide.Acta pharmacologica Sinica · 2018Article
- Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.Hepatology (Baltimore, Md.) · 2017Review
- CYP3A5 Mediates Effects of Cocaine on Human Neocorticogenesis: Studies using an In Vitro 3D Self-Organized hPSC Model with a Single Cortex-Like Unit.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2017Article
- The Use of Induced Pluripotent Stem Cells for the Study and Treatment of Liver Diseases.Current protocols in toxicology · 2016Review
- Collagen density regulates xenobiotic and hypoxic response of mammary epithelial cells.Environmental toxicology and pharmacology · 2015Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Early phase drug development relies on primary human hepatocytes for studies of drug metabolism, cytotoxicity, and drug-drug interactions. However, primary human hepatocytes rapidly lose metabolic functions ex vivo and are refractory to expansion in culture and thus are limited in quantity. Hepatocytes derived from human pluripotent stem cells (either embryonic stem (ES) or induced pluripotent stem (iPS) cells), have the potential to overcome many of the limitations of primary human hepatocytes, but to date the use of human pluripotent stem cell-derived hepatocytes has been limited by poor enzyme inducibility and immature metabolic function. Here, we present a simple suspension culture of aggregates of ES cell-derived hepatocytes that compared to conventional monolayer adherent culture significantly increases induction of CYP 1A2 by omeprazole and 3A4 by rifampicin. Using liquid chromatography-tandem mass spectrometry, we further show that ES cell-derived hepatocytes in aggregate culture convert omeprazole and rifampicin to their human-specific metabolites. We also show that these cells convert acetaminophen (APAP) to its cytotoxic metabolite (N-acetyl-p-benzoquinone imine (NAPQI)), although they fail to perform APAP glucuronidation. In summary, we show that human pluripotent stem cell-derived hepatocytes in aggregate culture display improved enzymatic inducibility and metabolic function and is a promising step toward a simple, scalable system, but nonetheless will require further improvements to completely replace primary human hepatocytes in drug development.
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Registered trials
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