Mitochondria Clearance Enables Macrophage-Driven Maturation of iPSC-Derived Cardiomyocyte Metabolism

Generation of functional engineered myocardial tissue remains a challenge, owing in part to lacking maturity of stem cell-derived cardiomyocytes. Current strategies to mature these cells fall short of achieving in vivo-like physiology. Macrophages, members of the innate immune system, reside in the heart and exert positive effects on cardiomyocyte function. We hypothesized that developmentally informed addition of macrophages to cardiomyocytes would improve their maturity. While some recent studies have added macrophages to stem cell-derived models of the human myocardium, these previous approaches do not replicate the early colonization of the heart. Addition of macrophages to developing cardiomyocytes 8 days after the start of differentiation significantly alters cardiomyocyte behavior. We show that macrophages drive improvements in metabolic capabilities of cardiomyocytes. Developing cardiomyocytes shed lowly polarized mitochondria, adopt a new mitochondria network architecture, and develop more active mitophagy programs after >20 days coculture with macrophages. This interaction is dependent on macrophage MerTK reception of cardiomyocyte-derived mitochondria material. These results inform our understanding of the responsibility of macrophages in the development of the myocardium, and we hope that these interactions can be leveraged to produce more physiologically relevant models of the human myocardium.