title: Developing high-fidelity hepatotoxicity models from pluripotent stem cells.
abstract: Faithfully recapitulating human physiology "in a dish" from a renewable source remains a holy grail for medicine and pharma. Many procedures have been described that, to a limited extent, exhibit human tissue-specific function in vitro. In particular, incomplete cellular differentiation and/or the loss of cell phenotype postdifferentiation play a major part in this void. We have developed an interdisciplinary approach to address this problem, using skill sets in cell biology, materials chemistry, and pharmacology. Pluripotent stem cells were differentiated to hepatocytes before being replated onto a synthetic surface. Our approach yielded metabolically active hepatocyte populations that displayed stable function for more than 2 weeks in vitro. Although metabolic activity was an important indication of cell utility, the accurate prediction of cellular toxicity in response to specific pharmacological compounds represented our goal. Therefore, detailed analysis of hepatocellular toxicity was performed in response to a custom-built and well-defined compound set and compared with primary human hepatocytes. Importantly, stem cell-derived hepatocytes displayed equivalence to primary human material. Moreover, we demonstrated that our approach was capable of modeling metabolic differences observed in the population. In conclusion, we report that pluripotent stem cell-derived hepatocytes will model toxicity predictably and in a manner comparable to current gold standard assays, representing a major advance in the field.
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Claire N
authors.initials: CN
authors.lastname: Medine
authors.forename: Baltasar
authors.initials: B
authors.lastname: Lucendo-Villarin
authors.forename: Christopher
authors.initials: C
authors.lastname: Storck
authors.forename: Faye
authors.initials: F
authors.lastname: Wang
authors.forename: Dagmara
authors.initials: D
authors.lastname: Szkolnicka
authors.forename: Ferdous
authors.initials: F
authors.lastname: Khan
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pernagallo
authors.forename: James R
authors.initials: JR
authors.lastname: Black
authors.forename: Howard M
authors.initials: HM
authors.lastname: Marriage
authors.forename: James A
authors.initials: JA
authors.lastname: Ross
authors.forename: Mark
authors.initials: M
authors.lastname: Bradley
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
authors.forename: Oliver
authors.initials: O
authors.lastname: Flint
authors.forename: David C
authors.initials: DC
authors.lastname: Hay
mesh_terms: D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology* / Q000503:physiopathology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006801:Humans; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D061251:Primary Cell Culture; D012015:Reference Standards; D015203:Reproducibility of Results; D018675:Toxicity Tests / Q000379:methods* / Q000592:standards*
chemical_list: D003577:Cytochrome P-450 Enzyme System
keywords: Embryonic stem cells; Hepatocyte differentiation; Stem cell; Toxicity; iPS