This article introduces a novel human heart-macrophage assembloid (hHMA) platform, which integrates pluripotent stem cell-derived embryonic monocytes into heart organoids to mimic natural immune-cardiac interactions during development. The researchers demonstrate that these tissue-resident macrophages (TRMPs) successfully integrate, persist long-term, and regulate vital cardiac functions, including morphogenesis, efferocytosis, and electrical conduction. Furthermore, the hHMAs provide a powerful in vitro model for disease by demonstrating that chronic activation of the NLRP3 inflammasome in the assembloids induces arrhythmogenic features consistent with atrial fibrillation (AF). The study uses various advanced techniques like single-cell transcriptomics and proteomics to characterize the TRMPs and their role in modulating cell signaling, including the release of SPP1-positive extracellular vesicles (EVs). Overall, the work establishes a sophisticated platform for studying human heart development and inflammation-driven arrhythmias, offering potential for future mechanistic and preclinical drug screening.

References:

• O’Hern C, Caywood S, Aminova S, et al. Human heart-macrophage assembloids mimic immune-cardiac interactions and enable arrhythmia disease modeling[J]. Cell Stem Cell, 2025.