Macrophages enhance contractile force in iPSC-derived human engineered cardiac tissue

Resident cardiac macrophages are critical mediators of cardiac function. Despite their known importance to cardiac electrophysiology and tissue maintenance, there are currently no stem-cell derived models of human engineered cardiac tissues (hECT) that include resident macrophages. In this study, we made an iPSC-derived hECT model with a resident population of macrophages (iM0) to better recapitulate the native myocardium, and characterized their impact on tissue function. Macrophage retention within the hECTs was confirmed via immunofluorescence after 28 days of cultivation. Inclusion of iM0 significantly impacted hECT function, increasing contractile force production. A potential mechanism underlying these changes was revealed by interrogation of calcium signaling, which demonstrated modulation of ß-adrenergic signaling in +iM0 hECTs. Collectively, these findings demonstrate that macrophages significantly enhance cardiac function in iPSC-derived hECT models, emphasizing the need to further explore their contributions not only in healthy hECT models, but also in the contexts of disease and injury. Overall design: To investigate the impact of iPSC-derived macrophages (iM0) on human engineered cardiac tissues, iM0 were added to the tissue composition at formation. Tissues with iM0 (+iM0) were compared to control tissues without iM0 (-iM0), which only contained iPSC-derived cardiomyocytes and iPSC-derived cardiac fibroblasts. We performed comparative gene expression profiling analysis of bulk RNA-seq data from n=3 +iM0 tissues and n=3 -iM0 tissues collected at one timepoint of 28 days of culture.