Abstract
Introduction: Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) form spontaneously beating syncytia in-vitro. We evaluated whether hiPSC-CM are a compelling model of human cardiac pharmacology useful for early drug development. Methods: We measured hiPSC-CM beating frequency using Ca-sensitive dyes and a high-throughput screening system. We quantified the effects of 640 drugs with various structures and pharmacologies. Results: When tested at 1 μM, most drugs without direct effects on heart rhythm or with effects at high concentrations do not change frequency, indicating specificity. In contrast, the preparation detects compounds with direct activity on heart rhythm, demonstrating sensitivity. In particular, β-adrenergic agonists increase frequency and the model differentiates β2 from β1 agonists, as well as partial from full agonists. Phosphodiesterase inhibitors have subtype-specific actions and PDE4 is particularly important in controlling frequency. The preparation is sensitive to cardiac ion channel blockers: L-type calcium channel blockers, Class-I and Class-III antiarrhythmics change frequency but drugs acting on KATP channels do not. The assay detects compounds blocking the cardiac rapid delayed-rectifier K channel and is an alternative to the classic “hERG test”. Conclusion: hiPSC-CM are a useful in-vitro cardiac model in drug development since they respond appropriately to drugs that modify heart rate in humans.
Highlights
Cardiomyocytes derived from human induced pluripotent stem cells form spontaneously beating syncytia in-vitro
These Human induced pluripotent stem cells (hiPSC)-derived cardiomyocytes are likely to provide an ideal source of human cells to generate models for drug development, when questions arise regarding cardiac effects that may be seen when a drug is administered to humans
After 2 - 3 days in culture, hiPSC-CMs establish spontaneously-beating syncytia with a uniform rhythm that evolves with days in culture, starting slow (~10 bpm), accelerating progressively during 10 12 days, remaining stable up to 28 days
Summary
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) form spontaneously beating syncytia in-vitro. These hiPSC-derived cardiomyocytes (hiPSC-CM) are likely to provide an ideal source of human cells to generate models for drug development, when questions arise regarding cardiac effects that may be seen when a drug is administered to humans. The acquisition frequency (8 Hz) is at the lower limit when trying to record accurately beating rates that can reach 120 bpm (2 Hz) under stimulated conditions and it is too low to extract additional information (e.g., slope or duration) To overcome these limitations, we developed a similar method using a faster reader (up to 30 Hz) with improved temperature control (Hamamatsu FDSS7000)
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