Article

Manipulation-free cultures of human iPSC-derived cardiomyocytes offer a novel screening method for cardiotoxicity

Authors: Sheeja RAJASINGH1, Dona Greta ISAI2, Saheli SAMANTA1, Zhi-gang ZHOU1, Buddhadeb DAWN1, William H KINSEY2, Andras CZIROK2, Johnson RAJASINGH3,4
1 Cardiovascular Research Institute, Division of Cardiovascular Diseases, Department of Internal Medicine, Kansas City, KS, USA
2 Department of Anatomy and Cell Biology, Kansas City, KS, USA
3 Cardiovascular Research Institute, Division of Cardiovascular Diseases, Department of Internal Medicine
4 Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA
Correspondence to: Andras CZIROK: aczirok@gmail.com, Johnson RAJASINGH: rjohnson9@kumc.edu,
DOI: 10.1038/aps.2017.183
Received: 1 August 2017
Accepted: 31 December 2017
Advance online: 5 April 2018

Abstract

Induced pluripotent stem cell (iPSC)-based cardiac regenerative medicine requires the efficient generation, structural soundness and proper functioning of mature cardiomyocytes, derived from the patient’s somatic cells. The most important functional property of cardiomyocytes is the ability to contract. Currently available methods routinely used to test and quantify cardiomyocyte function involve techniques that are labor-intensive, invasive, require sophisticated instruments or can adversely affect cell vitality. We recently developed optical flow imaging method analyses and quantified cardiomyocyte contractile kinetics from video microscopic recordings without compromising cell quality. Specifically, our automated particle image velocimetry (PIV) analysis of phase-contrast video images captured at a high frame rate yields statistical measures characterizing the beating frequency, amplitude, average waveform and beat-to-beat variations. Thus, it can be a powerful assessment tool to monitor cardiomyocyte quality and maturity. Here we demonstrate the ability of our analysis to characterize the chronotropic responses of human iPSC-derived cardiomyocytes to a panel of ion channel modulators and also to doxorubicin, a chemotherapy agent with known cardiotoxic side effects. We conclude that the PIV-derived beat patterns can identify the elongation or shortening of specific phases in the contractility cycle, and the obtained chronotropic responses are in accord with known clinical outcomes. Hence, this system can serve as a powerful tool to screen the new and currently available pharmacological compounds for cardiotoxic effects.
Keywords: iPSCs; stem cells; cardiomyocytes; contractility; optical flow imaging method; cardiotoxicity; ion channel modulator; doxorubicin

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