Holmgren Gustav, Sjögren Anna-Karin, Barragan Isabel, Sabirsh Alan, Sartipy Peter, Synnergren Jane, Björquist Petter, Ingelman-Sundberg Magnus, Andersson Tommy B, Edsbagge Josefina
Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden (G.H., P.S., J.S.); Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (G.H.); Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D, Mölndal, Sweden (A.-K.S.); Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B., T.B.A., M.I.-S.); Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (A.S.); NovaHep AB, Gothenburg, Sweden (P.B.); Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Mölndal, Sweden (T.B.A.); and Cellectis AB, Gothenburg, Sweden (P.S., P.B., J.E.)
Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden (G.H., P.S., J.S.); Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (G.H.); Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D, Mölndal, Sweden (A.-K.S.); Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (I.B., T.B.A., M.I.-S.); Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca R&D, Mölndal, Sweden (A.S.); NovaHep AB, Gothenburg, Sweden (P.B.); Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D, Mölndal, Sweden (T.B.A.); and Cellectis AB, Gothenburg, Sweden (P.S., P.B., J.E.).
Drug Metab Dispos. 2014 Sep;42(9):1401-6. doi: 10.1124/dmd.114.059154. Epub 2014 Jun 30.
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.
人类多能干细胞（hPSC）有潜力成为建立新模型的重要工具，用于体外药物测试，例如毒性和药理作用测试。制药行业后期的药物研发失败在很大程度上是由于使用了与临床无关的非预测性临床前模型来筛选候选药物。当前的肝脏体内和体外模型存在明显局限性，尤其是在慢性肝毒性研究方面。基于这些原因，我们评估了使用hPSC衍生的肝细胞长期暴露于有毒药物的潜力。采用重复给药方法，将分化的肝细胞与肝毒性化合物孵育长达14天。长时间暴露后，hPSC衍生的肝细胞对有毒化合物变得更加敏感，并且除了传统的细胞毒性外，在细胞中还观察到了磷脂沉积和脂肪变性的迹象。据我们所知，这是首次使用hPSC衍生的肝细胞进行长期毒性研究的报告，这些观察结果支持进一步开发和验证基于hPSC的毒性模型，以评估新型药物、化学品和化妆品。
