Metabolically-Driven Maturation of hiPSC-Cell Derived Cardiac Chip

摘要: Abstract 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 diagnostic utility. Tissue engineering approaches involving aligned 3D cultures enhance hiPSC-CM structural maturation insufficient to induce mature electrophysiology. We hypothesized that mimicking post-natal switching of the heart’s primary ATP source from glycolysis fatty acid oxidation could electrophysiological hiPSC-CM. combined with microfabricated culture chambers form cardiac microphysiological systems (MPS) enhanced immediate microtissue alignment tissue specific extracellular matrix (ECM) production. Using Robust Experimental design, we identified media improved calcium handling MPS two genetically distinct hiPSC sources. Although metabolic were both genotypes, there was divergent effect on action potential duration (APD): started abnormally prolonged APD exhibited shorter response media, whereas same aberrantly short APD. Importantly, genotypes brought near range 270-300ms observed human left ventricular cardiomyocytes. Mathematical modeling explained these phenotypes, further predicted matured drugs known pro-arrhythmic effects. These results suggest systematic combination biophysical stimuli cues can hiPSC-derived However, they also reveal maturation-inducing have differential effects depending baseline phenotype In silico models provide valuable predicting how changes cellular will manifest responsiveness.