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Long-term chronic toxicity testing using human pluripotent stem cell-derived hepatocytes
University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. (Bioinformatics)ORCID iD: 0000-0002-0402-1437
Department of Discovery Safety, Drug Safety and Metabolism, AstraZeneca RandD, Mölndal, Sweden.
Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Department of Bioscience, Cardiovascular and Metabolic Diseases, AstraZeneca RandD, Mölndal, Sweden.
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2014 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 42, no 9, p. 1401-1406Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society for Pharmacology and Experimental Therapeutics , 2014. Vol. 42, no 9, p. 1401-1406
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:his:diva-10212DOI: 10.1124/dmd.114.059154ISI: 000341254300005PubMedID: 24980256Scopus ID: 2-s2.0-84906846876OAI: oai:DiVA.org:his-10212DiVA, id: diva2:765348
Available from: 2014-11-22 Created: 2014-11-22 Last updated: 2017-12-05Bibliographically approved
In thesis
1. In vitro toxicity testing using human pluripotent stem cell derivatives
Open this publication in new window or tab >>In vitro toxicity testing using human pluripotent stem cell derivatives
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
University of Gothenburg, 2016. p. 82
Keyword
toxicity testing, human pluripotent stem cells, cardiomyocytes, hepatocytes, microarray, quantitative proteomics, bioinformatics, transcriptomics, microRNA
National Category
Bioinformatics and Systems Biology Cell Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical sciences
Identifiers
urn:nbn:se:his:diva-13340 (URN)978-91-629-0001-4 (ISBN)978-91-629-0002-1 (ISBN)
Public defence
2016-12-15, 09:00 (English)
Opponent
Supervisors
Note

I avhandlingen ingår även:

Holmgren, G., Sartipy, P., Andersson, C.X., Lindahl, A., and Synnergren, J. Expression profiling of human pluripotent stem cell-derived cardiomyocytes exposed to doxorubicin – integration and visualization of multi omics data Manuscript

Available from: 2017-11-27 Created: 2017-01-26 Last updated: 2017-11-27Bibliographically approved

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Holmgren, GustavSartipy, PeterSynnergren, Jane

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