Developing High‐Fidelity Hepatotoxicity Models From Pluripotent Stem Cells

Pluripotent stem cells were differentiated to hepatocytes. Upon hepatic specification, cells were replated onto a synthetic surface, which stabilized cell function for more than 2 weeks in vitro. The goal of these studies was the accurate prediction of cellular toxicity in response to specific pharm...

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Bibliographic Details
Published in:Stem cells translational medicine 2013-07, Vol.2 (7), p.505-509
Main Authors: Medine, Claire N., Lucendo-Villarin, Baltasar, Storck, Christopher, Wang, Faye, Szkolnicka, Dagmara, Khan, Ferdous, Pernagallo, Salvatore, Black, James R., Marriage, Howard M., Ross, James A., Bradley, Mark, Iredale, John P., Flint, Oliver, Hay, David C.
Format: Article
Language:English
Subjects:
Cell culture
Cell differentiation
Cell Line, Transformed
Cell surface
Cell Survival - drug effects
Cell Survival - physiology
Cell-Based Drug Development, Screening, and Toxicology
Chemical and Drug Induced Liver Injury - pathology
Chemical and Drug Induced Liver Injury - physiopathology
Councils
Cytochrome
Cytochrome P-450 Enzyme System - genetics
Cytochrome P-450 Enzyme System - metabolism
Data analysis
Embryonic stem cells
Employment
Enzymes
Gene expression
Gene Expression Regulation, Enzymologic - drug effects
Gene Expression Regulation, Enzymologic - physiology
Hepatocyte differentiation
Hepatocytes
Hepatocytes - cytology
Hepatocytes - drug effects
Hepatocytes - physiology
Hepatotoxicity
Humans
iPS
Liver
Medical research
Metabolism
Metabolites
Nonsteroidal anti-inflammatory drugs
Pharmacovigilance
Pluripotency
Pluripotent Stem Cells - cytology
Pluripotent Stem Cells - drug effects
Pluripotent Stem Cells - physiology
Population studies
Primary Cell Culture
Proteins
Reference Standards
Reproducibility of Results
Stem cell
Stem cells
Stock options
Toxicity
Toxicity Tests - methods
Toxicity Tests - standards
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Summary:Pluripotent stem cells were differentiated to hepatocytes. Upon hepatic specification, cells were replated onto a synthetic surface, which stabilized cell function for more than 2 weeks in vitro. The goal of these studies was the accurate prediction of cellular toxicity in response to specific pharmacological compounds. Importantly, stem cell‐derived hepatocytes displayed equivalence to primary human material. Moreover, this approach was capable of modeling metabolic differences observed in the population. These studies provide robust hepatocyte models which will likely contribute to improvements in drug safety testing. 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.
ISSN:2157-6564
2157-6580
DOI:10.5966/sctm.2012-0138