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Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data

Journal article
Authors Gustav Holmgren
P. Sartipy
C. X. Andersson
Anders Lindahl
J. Synnergren
Published in Toxicological Sciences
Volume 163
Issue 1
Pages 182-195
ISSN 1096-6080
Publication year 2018
Published at Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Pages 182-195
Language en
Links doi.org/10.1093/toxsci/kfy012
Keywords human pluripotent stem cells, cardiomyocytes, proteomics, multi-omics data, doxorubicin, toxicity, anthracycline-induced cardiotoxicity, cross-platform microarray, heart-failure, quantitative proteomics, big data, fibroblasts, biomarkers, micrornas, toxicity, therapy
Subject categories Biochemistry and Molecular Biology

Abstract

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 this 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 2 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.

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