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In vitro toxicity testing using human pluripotent stem cell derivatives
Sahlgrenska Academy at University of Gothenburg. (Bioinformatics)ORCID-id: 0000-0002-0402-1437
2016 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
sted, utgiver, år, opplag, sider
University of Gothenburg, 2016. , s. 82
Emneord [en]
toxicity testing, human pluripotent stem cells, cardiomyocytes, hepatocytes, microarray, quantitative proteomics, bioinformatics, transcriptomics, microRNA
HSV kategori
Forskningsprogram
Medicin; Bioinformatik
Identifikatorer
URN: urn:nbn:se:his:diva-13340ISBN: 978-91-629-0001-4 (tryckt)ISBN: 978-91-629-0002-1 (digital)OAI: oai:DiVA.org:his-13340DiVA, id: diva2:1068929
Disputas
2016-12-15, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2017-11-27 Laget: 2017-01-26 Sist oppdatert: 2023-05-02bibliografisk kontrollert
Delarbeid
1. Long-term chronic toxicity testing using human pluripotent stem cell-derived hepatocytes
Åpne denne publikasjonen i ny fane eller vindu >>Long-term chronic toxicity testing using human pluripotent stem cell-derived hepatocytes
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2014 (engelsk)Inngår i: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 42, nr 9, s. 1401-1406Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
University of Illinois Press, 2014
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-10212 (URN)10.1124/dmd.114.059154 (DOI)000341254300005 ()24980256 (PubMedID)2-s2.0-84906846876 (Scopus ID)
Tilgjengelig fra: 2014-11-22 Laget: 2014-11-22 Sist oppdatert: 2019-11-25bibliografisk kontrollert
2. MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity
Åpne denne publikasjonen i ny fane eller vindu >>MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity
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2016 (engelsk)Inngår i: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 34, s. 26-34Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Elsevier, 2016
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-12339 (URN)10.1016/j.tiv.2016.03.009 (DOI)000379273800004 ()27033315 (PubMedID)2-s2.0-84962362050 (Scopus ID)
Tilgjengelig fra: 2016-06-08 Laget: 2016-06-08 Sist oppdatert: 2018-07-31bibliografisk kontrollert
3. Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells
Åpne denne publikasjonen i ny fane eller vindu >>Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells
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2015 (engelsk)Inngår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 328, s. 102-111Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Elsevier, 2015
Emneord
Biomarkers, Cardiomyocytes, Doxorubicin, Human pluripotent stem cells, Toxicity
HSV kategori
Forskningsprogram
Bioinformatik
Identifikatorer
urn:nbn:se:his:diva-11417 (URN)10.1016/j.tox.2014.12.018 (DOI)000349881500013 ()25529476 (PubMedID)2-s2.0-84920119624 (Scopus ID)
Merknad

CC BY-NC-ND 4.0

Tilgjengelig fra: 2015-08-25 Laget: 2015-08-25 Sist oppdatert: 2023-07-18bibliografisk kontrollert
4. Expression profiling of human pluripotent stem cell-derived cardiomyocytes exposed to doxorubicin - integration and visualization of multi omics data
Åpne denne publikasjonen i ny fane eller vindu >>Expression profiling of human pluripotent stem cell-derived cardiomyocytes exposed to doxorubicin - integration and visualization of multi omics data
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2018 (engelsk)Inngår i: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 163, nr 1, s. 182-195Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Anthracyclines, such as doxorubicin, are highly efficient chemotherapeutic agents against a variety of cancers. However, anthracyclines are also among the most cardiotoxic therapeutic drugs presently on the market. Chemotherapeutic-induced cardiomyopathy is one of the leading causes of disease and mortality in cancer survivors. The exact mechanisms responsible for doxorubicin-induced cardiomyopathy are not completely known, but the fact that the cardiotoxicity is dose-dependent and that there is a variation in time-to-onset of toxicity, and gender- and age differences suggests that several mechanisms may be involved.In the present study, we investigated doxorubicin-induced cardiotoxicity in human pluripotent stem cell-derived cardiomyocytes using proteomics. In addition, different sources of omics data (protein, mRNA, and microRNA) from the same experimental setup were further combined and analyzed using newly developed methods to identify differential expression in data of various origin and types. Subsequently, the results were integrated in order to generate a combined visualization of the findings.In our experimental model system, we exposed cardiomyocytes derived from human pluripotent stem cells to doxorubicin for up to two days, followed by a wash-out period of additionally 12 days. Besides an effect on the cell morphology and cardiomyocyte functionality, the data show a strong effect of doxorubicin on all molecular levels investigated. Differential expression patterns that show a linkage between the proteome, transcriptome, and the regulatory microRNA network, were identified. These findings help to increase the understanding of the mechanisms behind anthracycline-induced cardiotoxicity and suggest putative biomarkers for this condition.

sted, utgiver, år, opplag, sider
Oxford University Press, 2018
Emneord
Human pluripotent stem cells, cardiomyocytes, doxorubicin, multi-omics data, proteomics, toxicity
HSV kategori
Forskningsprogram
Bioinformatik; INF502 Biomarkörer; INF501 Integrering av -omicsdata
Identifikatorer
urn:nbn:se:his:diva-14745 (URN)10.1093/toxsci/kfy012 (DOI)000432299900018 ()29385562 (PubMedID)2-s2.0-85046994085 (Scopus ID)
Merknad

© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology

Tilgjengelig fra: 2018-02-14 Laget: 2018-02-14 Sist oppdatert: 2023-01-03bibliografisk kontrollert

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