Micro-Engineered Heart Tissues on-Chip with Heterotypic Cell Composition Display Self-Organization and Improved Cardiac Function.

Advanced in vitro models that recapitulate the structural organization and function of the human heart are highly needed for accurate disease modeling, more predictable drug screening and safety pharmacology. Conventional 3D Engineered Heart Tissues (EHTs) lack heterotypic cell complexity and culture under flow, whereas microfluidic Heart-on-Chip (HoC) models in general lack the 3D configuration and accurate contractile readouts. In this study, an innovative and user-friendly HoC model is developed to overcome these limitations, by culturing human pluripotent stem cell (hPSC)-derived cardiomyocytes, endothelial- and smooth muscle cells, together with human cardiac fibroblasts, under flow, leading to self-organized miniaturized micro-EHTs (μEHTs) with a cardiomyocyte-endothelial cell interface reminiscent of the physiological capillary lining. μEHTs cultured under flow display enhanced contractile performance and conduction velocity. In addition, the presence of the endothelial cell layer altered drug responses in μEHT contraction. This observation suggests a potential barrier-like function of endothelial cells, which may affect the availability of drugs to the cardiomyocytes. These cardiac models with increased physiological complexity, will pave the way to screen for therapeutic targets and predict drug efficacy. This article is protected by copyright. All rights reserved.