Cardiotoxicity assessment using 3D vascularized cardiac tissue consisting of human iPSC-derived cardiomyocytes and fibroblasts

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for cardiac safety assessment but have limitations for the evaluation of drug-induced contractility. Threedimensional (3D) cardiac tissues are similar to native tissue and valuable for the assessment of contractility. However, a longer time and specialized equipment are required to generate 3D tissues. We previously developed a simple method to generate 3D tissue in a short period by coating the cell surfaces with extracellular matrix proteins. We hypothesized that this 3D cardiac tissue could be used for simultaneous evaluation of drug-induced repolarization and contractility. In the present work, we examined the effects of several compounds with different mechanisms of action by cell motion imaging. Consequently, human ether-ago-go-related gene (HERG) channel blockers with high arrhythmogenic risk caused prolongation of contraction-relaxation duration and arrhythmia-like waveforms. Positive inotropic drugs, which increase intracellular Ca 2+ levels or myocardial Ca 2+ sensitivity, caused an increase in maximum contraction speed (MCS) or average deformation distance (ADD) (ouabain, 138% for MCS at 300 nM; pimobendane, 132% for ADD at 3 mM). For negative inotropic drugs, verapamil reduced both MCS and ADD (61% at 100 nM). Thus, this 3D cardiac tissue detected the expected effects of various cardiovascular drugs, suggesting its usefulness for cardiotoxicity evaluation.

Validating the Arrhythmogenic Potential of High-, Intermediate-, and Low-Risk Drugs in a Human-Induced Pluripotent Stem Cell-Derived Cardiac Microphysiological System

“…Where applicable, we compared our own findings to results obtained in other 3D cardiac tissue culture systems (Table ). However, few systems were directly comparable to our data since they either used different drug compounds, different metrics (such as structural metrics or mechanical analysis ,, ), or both . We did not find 3D studies with comparable metrics for amiodarone and bepridil, and 3D cardiac tissue testing for mexiletine has not been previously published.…”

Universal and Sensitive Drug Assessment Biosensing Platform Using Optimal Mechanical Beating Detection of Single Cardiomyocyte

“…Compared with the control group, nifedipine significantly decreases the mechanical beating amplitude by 23% from 0.0039 ± 0.0003 to 0.0030 ± 0.0003 |Δ Z |/| Z 0 | and reduces the firing rate by 7% from 96.4 ± 3.4 to 89.2 ± 16.3 min –1 , as Figure G,H illustrates. Furthermore, pharmacological assays based on different concentrations of flecainide are performed to evaluate the sensitivity of the biosensing platform, which acts as a Na + channel blocker to reduce the beating rate and amplitude and prolong the contraction, relaxation, beating, and resting period of the cardiomyocytes. − As shown in Figure I, in contrast with the control group, the mechanical beating signals recorded by our platform exhibit a significant reduction in beating rate and amplitude after the administration of 100 nM flecainide. Further analysis demonstrates that the contraction, relaxation, beating, and resting periods prolong from 240.9 ± 5.4 to 269.5 ± 27.6 ms, 350.8 ± 4.6 to 583.6 ± 22.2 ms, 596.4 ± 5.7 to 851.3 ± 24.6 ms, and 322.9 ± 30.6 to 968.4 ± 318.9 ms, respectively (Figure J).…”

A Change of Heart: Human Cardiac Tissue Engineering as a Platform for Drug Development

“…This platform has the additional benefit of microgrooves providing anisotropic cell patterning that more closely represents native myocardium. Other groups have developed methods of coating hPSC-CMs and other cell types with ECM and seeding them into cell sheets that are multiple layers thick [ 44 , 45 ]. Using motion tracking, it was possible to measure the effects of several drug compounds on magnitude of contraction, contraction kinetics, and abnormal beat intervals [ 44 ].…”

“…Other groups have developed methods of coating hPSC-CMs and other cell types with ECM and seeding them into cell sheets that are multiple layers thick [ 44 , 45 ]. Using motion tracking, it was possible to measure the effects of several drug compounds on magnitude of contraction, contraction kinetics, and abnormal beat intervals [ 44 ]. However, shortcomings of cardiac sheets include the difficulty in obtaining direct measurement of force output and the need for additional interventions to facilitate sheet patterning and cellular alignment.…”