Long-term chronic toxicity testing using human pluripotent stem cell-derived hepatocytes

• Published in: Drug metabolism and disposition Vol. 42; no. 9; pp. 1401 - 1406
• Main Authors: Holmgren, Gustav, Sjögren, Anna-Karin, Barragan, Isabel, Sabirsh, Alan, Sartipy, Peter, Synnergren, Jane, Björquist, Petter, Ingelman-Sundberg, Magnus, Andersson, Tommy B, Edsbagge, Josefina
• Format: Journal Article
• Language: English
• Published: United States 01.09.2014
• Subjects: Bioinformatics; Bioinformatik; Cell Line, Tumor; CELLS; Clinical Medicine; CYTOCHROMES P450; DIRECT THROMBIN INHIBITOR; Drug Evaluation, Preclinical - methods; DRUG-METABOLISM; Drug-Related Side Effects and Adverse Reactions - etiology; Fatty Liver - chemically induced; Hep G2 Cells; HEPARG CELLS; Hepatocytes - drug effects; HEPATOTOXICITY; HEPG2; HUMAN HEPATOMA-CELL; Humans; IN-VITRO MODEL; INDUCED LIVER-INJURY; Klinisk medicin; Lipidoses - chemically induced; Liver - drug effects; Medicin och hälsovetenskap; Pharmaceutical Preparations - administration & dosage; Pharmacology & Pharmacy; Pluripotent Stem Cells - drug effects; XIMELAGATRAN
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1124/dmd.114.059154

Human pluripotent stem cells (hPSC) have the potential to become important tools for the establishment of new models for in vitro drug testing of, for example, toxicity and pharmacological effects. Late-stage attrition in the pharmaceutical industry is to a large extent caused by selection of drug candidates using nonpredictive preclinical models that are not clinically relevant. The current hepatic in vivo and in vitro models show clear limitations, especially for studies of chronic hepatotoxicity. For these reasons, we evaluated the potential of using hPSC-derived hepatocytes for long-term exposure to toxic drugs. The differentiated hepatocytes were incubated with hepatotoxic compounds for up to 14 days, using a repeated-dose approach. The hPSC-derived hepatocytes became more sensitive to the toxic compounds after extended exposures and, in addition to conventional cytotoxicity, evidence of phospholipidosis and steatosis was also observed in the cells. This is, to the best of our knowledge, the first report of a long-term toxicity study using hPSC-derived hepatocytes, and the observations support further development and validation of hPSC-based toxicity models for evaluating novel drugs, chemicals, and cosmetics.