Abstract
While cardiomyocytes differentiated from human induced pluripotent stems cells (hiPSCs) hold great promise for drug screening, the electrophysiological properties of these cells can be variable and immature, producing results that are significantly different from their human adult counterparts. Here, we describe a computational framework to address this limitation, and show how in silico methods, applied to measurements on immature cardiomyocytes, can be used to both identify drug action and to predict its effect in mature cells. Our synthetic and experimental results indicate that optically obtained waveforms of voltage and calcium from microphysiological systems can be inverted into information on drug ion channel blockage, and then, through assuming functional invariance of proteins during maturation, this data can be used to predict drug induced changes in mature ventricular cells. Together, this pipeline of measurements and computational analysis could significantly improve the ability of hiPSC derived cardiomycocytes to predict dangerous drug side effects.
Highlights
The discovery of human induced pluripotent stem cells has started a new era in biological science and medicine
The overall applicability of human induced pluripotent stems cells (hiPSCs)-CMs to find unwanted side effects of drugs for adult cardiomyocytes remains limited by the fact that only relatively immature cells are available for analysis
We present a mathematical analysis framework to define the electrophysiologic mechanisms of drug action in mature human cardiomyocytes using only optical recordings of membrane potential and calcium in hiPSC-CMs
Summary
The discovery of human induced pluripotent stem cells (hiPSCs) has started a new era in biological science and medicine. These reprogrammed somatic cells can be differentiated into a wide variety of cell lineages, and allow in vitro examination of cellular properties at the level of the human individual This technology has large implications in drug development, moving us away from well studied but often unrepresentative animal models towards direct testing of compounds in specific human phenotypes and genotypes. HiPSCs can be used to create specialized human cells and tissues, these rapidly grown cells and tissues may have significant proteomic and structural differences to, and are often more fetal-like than, their adult in vivo counterparts This is especially true in hiPSC derived cardiomyocytes (hiPSC-CMs), where the adult cells they are intended to represent have undergone decades of growth and development under cyclical physiological loading and stimulation.
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