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May 15, 2010 (Vol. 30, No. 10)

iPSC-Derived Human Cardiomyocytes

Stem Cell Technology Can Facilitate Quick & Early Failure of Toxic or Ineffective NCEs

  • Electrophysiological and Biochemical Responses Mimic In Vivo Cells

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    Figure 1. Prolongation of the iCell Cardiomyocytes field potential duration in response to increasing concentrations of the hERG channel antagonist E-4031 was recorded using MEA platform technology. Y-axis is percent change in field potential duration relative to control conditions, while the x-axis illustrates experimental time. E-4031 additions are illustrated by the arrows, and the inset shows representative field potential waveforms during each application from control to 100 nM.

    Although purified iPSC-derived cardiomyocytes have the physical appearance of cardiomyocytes and aggregations of the cells exhibit synchronous, syncytial, contractile activity (i.e., the cells beat), it was necessary to test the cells’ electrophysiological and biochemical responses to antagonists to determine their utility for drug development and toxicity testing.

    Cardiomyocyte subtypes of the heart have distinctive electrophysiological profiles that can be characterized by, among other items, early depolarization events (phase 4 depolarization) and the duration of the depolarized plateau potential.  Action potentials produced by individual iCell Cardiomyocytes recapitulate the action potentials of native nodal, atrial, and ventricular cardiomyocytes.

    iCell Cardiomyocytes also mimic typical in vivo responses to electrophysiological antagonists. Electrophysiological responses of cardiomyocytes were tested against exposure to E-4031 (Figure 1), a well known blocker of the human cardiac Ether-a-go-go related gene (hERG) potassium channels. Just as hERG channel block prolongs cardiac repolarization in vivo, E-4031 application prolongs, in a dose-dependent manner, the field potential duration generated by iCell Cardiomyocytes as measured on a microelectrode array platform.

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    Figure 2. iCell Cardiomyocytes viability in response to antagonist application: Cell viability in response to application of known cardiotoxicants was assayed with Cell-TiterGlo (Promega). Y-axis is relative luminescence units, while the x-axis is cardiotoxicant concentration.

    iCell Cardiomyocytes also show sensitivity to known cardiotoxic compounds affecting biochemical processes (Figure 2). Cardiomyocytes were exposed to a diverse set of compounds known to have adverse effects on cardiomyocytes over a broad range of EC50 values. Cell viability was subsequently assessed via CellTiter Glo (data courtesy of Chad Zimprich, Promega) and demonstrated an expected sensitivity.

    Cell handling plays a critical role in cell-based assay investigations. iCell Cardiomyocytes, like terminally differentiated native cardiomyocytes, do not divide in culture. Thus, mistakes in plating cannot be undone by simply waiting for the cells to divide and/or splitting and replating. Therefore, cell viability upon thaw from cryopreservation and the plating efficiency, i.e., the ratio of cells added (seeded) into a well over the actual number of cells that attach to the bottom of the well, must be taken into consideration when setting up experiments.

    In the case of iCell Cardiomyocytes, an investigator can either use these two metrics, which are part of the QC program, as supplied by CDI, or they can determine cell viability on their own and combine that result with the supplied QC plating efficiency to determine the appropriate number of cells to place in each well.

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