Developing High‐Fidelity Hepatotoxicity Models From Pluripotent Stem Cells

• 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 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
• ISSN: 2157-6564; 2157-6580
• DOI: 10.5966/sctm.2012-0138

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.