Research ArticleTOXICITY SCREENING

High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells

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Science Translational Medicine  15 Feb 2017:
Vol. 9, Issue 377, eaaf2584
DOI: 10.1126/scitranslmed.aaf2584

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  • Cardiotoxicity testing in human cardiac cells and tissue
    • Peter P Rainer, Cardiologist-Scientist, Division of Cardiology, Medical University of Graz, Austria
    • Other Contributors:
      • Ewald Kolesnik, Research Fellow, Division of Cardiology, Medical University of Graz, Austria
      • Markus Wallner, Postdoctoral Fellow, Temple University School of Medicine, Philadelphia PA, USA
      • Christopher Schneider, Research Fellow, Division of Cardiology, Medical University of Graz, Austria
      • Dirk von Lewinski, Cardiologist - Scientist, Division of Cardiology, Medical University of Graz, Austria
      • Martin Pichler, Oncologist, Division of Oncology, Medical University of Graz, Austria

    We read Sharma et al.’s manuscript(1) with great interest and congratulate the authors for establishing high throughput cardiotoxicity screening of novel anti-cancer agents using human induced pluripotent stem cell (hiPSC) cardiac cells.
    We would like to point out an established and complementary approach. That is the use of human multicellular trabecular preparations for contractility and calcium cycling assessment. In contrast to hiPSC derived CMs (Fig. 1B in manuscript) these tissues contain completely differentiated, mechanically and electrically coupled, rod-shaped cardiomyocytes. They also contain non-cardiomyocyte cardiac cells. In addition, field-stimulated auxotonically contracting multicellular muscle strips are exposed to load, which is crucial to assess physiology and contractile properties in muscle. These tissues originate from human myocardium that is routinely excised at the time of cardiac surgery, is readily available, and otherwise discarded. The underlying method has been in use for decades(2) due to the high translational value of studies in human differentiated heart tissue.
    Our results with using this approach are consistent with Sharma et al.’s. Sunitinib elicited pronounced acute negative inotropy at concentrations consistent with values that have been found in hiPSC-CMs (Fig. 2C in manuscript, in our own data starting at 1µM for sunitinib(3). This is in line with Sharma et al. and supports the use of hiPSC-CMs for cardiotoxicity testi...

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    Competing Interests: None declared.