UC Irvine

Current preclinical methods to evaluate drug safety fail to accurately predict cardiotoxicity, the leading cause of drug withdrawal from the market. Human stem cell-derived cardiomyocytes represent an intriguing new source of cells for the development of in vitro drug screening platforms. However, questions of phenotypic immaturity, lack of analytical tools to monitor critical cardiomyocyte functions and simplicity of current cardiac tissue models, have delayed the acceptance of these new stem cell-based testing platforms. In this work, we surveyed the many aspects of the stem cell-derived cardiomyocyte phenotype and contrasted them to adult cardiomyocytes. Phasor fluorescent lifetime imaging microscopy (FLIM) analysis monitors metabolism of cells in a nondestructive and noninvasive manner. Phasor FLIM analysis was used to assess the transient metabolic signature of cardiac spheroids and to characterize the acute effect of cyanide poisoning on cardiomyocyte metabolism. Future cardiac drug testing platforms can be used in conjunction with phasor FLIM analysis to elucidate the metabolic effect of drugs. Finally, the effect of interstitial flow on a model of vascularized cardiac tissue was examined. Increased interstitial flow rates enhanced vascular network formation and significantly increased cardiomyocyte growth in cardiac tissues. Methods to increase the complexity and maturity of cardiac tissue can potentially improve the predictive capability of stem cell-based drug testing platforms, and ultimately prevent unnecessary mortality by cardiac drug side effects.