Drug Discovery Service: Cardiotoxicity Testing with Human iPSC-derived Cardiomyocytes

iCell^® Cardiomyocytes² are high-purity cardiomyocytes derived from human-induced pluripotent stem cells (hiPSCs) produced by FUJIFILM Cellular Dynamics, Inc. with proprietary differentiation technologies.　They recapitulate functions of native human cardiomyocytes. With over 800 peer-reviewed publications, iCell^® Cardiomyocytes² are a valuable tool for pharmacology, safety pharmacology and basic research across multiple assay platforms. Atrial, nodal, and ventricular cardiomyocytes with spontaneous electrical activity possess typical biochemical, electrophy​siological​,​ and mechanical properties of native cardiomyocytes, as well as higher expression levels of critical genes, including ion-channels, as compared to hiPSC-derived cardiomyocytes from other sources.

　

Basic Property as Cardiomyocytes

• High purity of cTNT positive cells¹
• Sarcomere structure²
• Cardiac action potential²
• Expression of major cardiac ion channels (Na_V1.5, Ca_V1.2, hERG) comparable to human heart²

　

High-Quality Extracellular Field Potential to Assess Proarrhythmic Potential

The extracellular field potential of hiPSC-cardiomyocytes is a validated biomarker for assessing the proarrhythmic potential of drugs. It can be obtained using a multielectrode array (MEA) system^{3, 4}. iCell^® Cardiomyocytes is one of the cells used for international validation studies.

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We established a robust protocol to obtain high quality extracellular field potential from iCell Cardiomyocytes² by using MEA system (Maestro Pro, Axion Biosystems). Our proprietary cell culture protocol ensures optimal electrode coverage to enable the acquisition of high-quality extracellular field potential data that satisfies the analysis criteria for all wells. We can provide potential of test compounds for QT prolongation and proarrhythmia in higher throughput (up to 96well; e.g. 22 compounds at 4 different doses per plate at N=4 each dose).

Identify the electrode that provides highest quality extracellular field potential

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• One electrode is chosen from each well that meets specific criteria for analysis to control quality of the data.

  • Signal amplitude (1^st peak, 2^nd peak)
  • Waveform shape
    (from depolarization to repolarization)

　

Evaluate dose-dependent FPDc prolongation and arrhythmia

　

Visualize the proarrythmic potential of the test compounds

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Predictivity

Results of CiPA compounds⁵

The assay predicts potential risk of proarrhythmia by FPDc prolongation and occurrence of EAD in the system.

The obtained results were consistent with previously reported validation study by CiPA.

　

Robustness

Prolongation and shortening of FPDc, as well as proarrhythmic effects, were accurately detected.
Results are consistent with previous reports, demonstrating assay robustness and repeatability.

1. Ma et al., Am J Physiol Heart Circ Physiol 30 (2011) H2006-H2017
2. Kodama et al., J Pharmacol. Sci. 140 (2019) 325-330<
3. Blinova et al., Cell Reports 24 (2018) 3582-3592
4. Ando et al., Journal of Pharmacological and Toxicological Methods 84 (2017) 111-127
5. Blinova et al., Cell Reports 24 (2018) 3582-3592
6. Kitaguchi et al., J Pharmacological and Toxicological Methods 78 (2016) 93-102
7. Nozaki et al., Regulatory Toxicology and Pharmacology 77 (2016) 75-86

MEA system (Axion BioSystems, Inc.）

• Maestro Pro and Cytoview MEA™ plate

Cells and regents (FUJIFILM Cellular Dynamics, Inc.）

• Cells: iCell^® Cardiomyocytes²
• Media: iCell^® CM Plating Medium, iCell^® CM Maintainance Medium

End Point

• FPD/FPDc
• Proarrhythmic Potential
  (Occurrence of EAD, Cardiac Arrest, Abnormal)
• Beat Rate