Abstract: Cardiac resident macrophages are pivotal in heart development, homeostasis, and disease response. Recent studies have shown that macrophages enhance cardiomyocyte (CM) function in cardiac organoids through various mechanisms. In this study, we generated cardiac organoids using human pluripotent stem cell (hPSC)-derived cardiomyocytes and macrophages. Integrative transcriptomic and epigenomic analyses revealed that the cardiac tissue environment reprograms macrophages to express muscle-specific genes, while macrophages, in turn, promote CM maturation, contractile strength, and connectivity. Notably, macrophage-derived HBEGF activates ERBB4 signaling in CMs, further enhancing their functional properties. These findings highlight the bidirectional reprogramming between CMs and macrophages, leading to the generation of cardiac organoids that more closely resemble in vivo tissue, offering improved models for studying cardiac physiology and disease.
Funding Source: This work was supported by the National Key R&D Program of China Grants 2022YFA1103103 and 2023YFA1800302 and the National Natural Science Foundation of China (NSFC) Grants 32270784 and 31970819 to Jie Na.
