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Metabolically-Driven Maturation of hiPSC-Cell Derived Heart-on-a-Chip

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) are a promising in vitro tool for drug development and disease modeling, but their immature electrophysiology limits their diagnostic utility. Tissue engineering approaches involving aligned and 3D culture enhance hiPSC-CM maturation but are insufficient to induce electrophysiological maturation. We hypothesized that recapitulating post-natal switching of the heart’s primary adenosine triphosphate source from glycolysis to fatty acid oxidation could enhance maturation of hiPSC-CM. We combined hiPSC-CM with microfabrication to create 3D cardiac microphysiological systems (MPS) that enhanced immediate microtissue alignment and tissue specific extracellular matrix production. Using Robust Experimental design, we identified a maturation media that allowed the cardiac MPS to correctly assess false positive and negative drug response. Finally, we employed mathematical modeling and gene expression data to explain the observed changes in electrophysiology and pharmacology of MPS exposed to maturation media. In contrast, the same media had no effects on 2D hiPSC-CM monolayers. These results suggest that systematic combination of biophysical stimuli and metabolic cues can enhance the electrophysiological maturation of hiPSC-derived cardiomyocytes.