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In vitro toxicity testing using human pluripotent stem cell derivatives
Sahlgrenska Academy at University of Gothenburg. (Bioinformatics)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
University of Gothenburg, 2016. , p. 82
Keywords [en]
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: urn:nbn:se:his:diva-13340ISBN: 978-91-629-0001-4 (print)ISBN: 978-91-629-0002-1 (electronic)OAI: oai:DiVA.org:his-13340DiVA, id: diva2:1068929
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: 2018-07-31Bibliographically approved
List of papers
1. Long-term chronic toxicity testing using human pluripotent stem cell-derived hepatocytes
Open this publication in new window or tab >>Long-term chronic toxicity testing using human pluripotent stem cell-derived hepatocytes
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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
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-10212 (URN)10.1124/dmd.114.059154 (DOI)000341254300005 ()24980256 (PubMedID)2-s2.0-84906846876 (Scopus ID)
Available from: 2014-11-22 Created: 2014-11-22 Last updated: 2018-07-31Bibliographically approved
2. MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity
Open this publication in new window or tab >>MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity
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2016 (English)In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 34, p. 26-34Article in journal (Refereed) Published
Abstract [en]

Anthracyclines, such as doxorubicin, are well-established, highly efficient anti-neoplastic drugs used for treatment of a variety of cancers, including solid tumors, leukemia, lymphomas, and breast cancer. The successful use of doxorubicin has, however, been hampered by severe cardiotoxic side-effects. In order to prevent or reverse negative side-effects of doxorubicin, it is important to find early biomarkers of heart injury and drug-induced cardiotoxicity. The high stability under extreme conditions, presence in various body fluids, and tissue-specificity, makes microRNAs very suitable as clinical biomarkers. The present study aimed towards evaluating the early and late effects of doxorubicin on the microRNA expression in cardiomyocytes derived from human pluripotent stem cells. We report on several microRNAs, including miR-34a, miR-34b, miR-187, miR-199a, miR-199b, miR-146a, miR-15b, miR-130a, miR-214, and miR-424, that are differentially expressed upon, and after, treatment with doxorubicin. Investigation of the biological relevance of the identified microRNAs revealed connections to cardiomyocyte function and cardiotoxicity, thus supporting the findings of these microRNAs as potential biomarkers for drug-induced cardiotoxicity.

Place, publisher, year, edition, pages
Elsevier, 2016
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-12339 (URN)10.1016/j.tiv.2016.03.009 (DOI)000379273800004 ()27033315 (PubMedID)2-s2.0-84962362050 (Scopus ID)
Available from: 2016-06-08 Created: 2016-06-08 Last updated: 2018-07-31Bibliographically approved
3. Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells
Open this publication in new window or tab >>Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells
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2015 (English)In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 328, p. 102-111Article in journal (Refereed) Published
Abstract [en]

Doxorubicin is a chemotherapeutic agent indicated for the treatment of a variety of cancer types, including leukaemia, lymphomas, and many solid tumours. The use of doxorubicin is, however, associated with severe cardiotoxicity, often resulting in early discontinuation of the treatment. Importantly, the toxic symptoms can occur several years after the termination of the doxorubicin administration. In this study, the toxic effects of doxorubicin exposure have been investigated in cardiomyocytes derived from human embryonic stem cells (hESC). The cells were exposed to different concentrations of doxorubicin for up to 2 days, followed by a 12 day recovery period. Notably, the cell morphology was altered during drug treatment and the cells showed a reduced contractile ability, most prominent at the highest concentration of doxorubicin at the later time points. A general cytotoxic response measured as Lactate dehydrogenase leakage was observed after 2 days' exposure compared to the vehicle control, but this response was absent during the recovery period. A similar dose-dependant pattern was observed for the release of cardiac specific troponin T (cTnT) after 1 day and 2 days of treatment with doxorubicin. Global transcriptional profiles in the cells revealed clusters of genes that were differentially expressed during doxorubicin exposure, a pattern that in some cases was sustained even throughout the recovery period, suggesting that these genes could be used as sensitive biomarkers for doxorubicin-induced toxicity in human cardiomyocytes. The results from this study show that cTnT release can be used as a measurement of acute cardiotoxicity due to doxorubicin. However, for the late onset of doxorubicin-induced cardiomyopathy, cTnT release might not be the most optimal biomarker. As an alternative, some of the genes that we identified as differentially expressed after doxorubicin exposure could serve as more relevant biomarkers, and may also help to explain the cellular mechanisms behind the late onset apoptosis associated with doxorubicin-induced cardiomyopathy.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Biomarkers, Cardiomyocytes, Doxorubicin, Human pluripotent stem cells, Toxicity
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-11417 (URN)10.1016/j.tox.2014.12.018 (DOI)000349881500013 ()25529476 (PubMedID)2-s2.0-84920119624 (Scopus ID)
Available from: 2015-08-25 Created: 2015-08-25 Last updated: 2018-07-31Bibliographically approved

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Holmgren, Gustav

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