Profiling Cardio-Active Compound Response Between High-Throughput 2D-Monolayers, Aniosotropic and 3-Dimensional Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) have become a prominent tool in safety pharmacology, toxicology studies and disease modeling. However, in traditional 2D monolayers hiPSC-CMs typically display an abnormal sub-cellular structural organization with reported features of cellular immaturity. Micro-engineered high-density screening platforms with mechanical cues to promote cardiomyocyte alignment generate anisotropic cultures with readily identifiable, correctly patterned myofibrils along the cell body, intercalated disc components targeted to the distal ends of the cells and more elongated nuclei. Directional contraction patterns of hiPSC-CM preparations were observed to become markedly uniform in this platform. Parallelly, complex 3D cultures of cardiomyocytes, fibroblasts and endothelial cells have been reported to promote more physiological contraction patterns, with positive increases in the force-frequency relationship in response to ionotropic compounds. Here we compared cardiomyocytes cultured as 2D monolayers, anisotropic cultures and 3D cardiomyocyte spheroids in high throughput screening formats for their ability to respond to cardioactive compounds. Interestingly, our observations indicate that the different systems can display marked differences in their response to compounds of interest. Examples of compounds with clear differential response include the potassium channel blocker Dofetilide, the beta-adrenergic agonist dobutamine and a cocktail of hypertrophic stimuli.

Altogether the results obtained in this study highlight that specific hiPSC-CM based platforms present advantages and limitations which need to be weighed in to ensure suitability to their context of use.

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