Human heart-macrophage assembloids mimic immune-cardiac interactions and enable arrhythmia disease modeling
Year: 2025
Type: article
Abstract: Yolk-sac-derived embryonic cardiac tissue-resident macrophages (TRMPs) colonize the heart early in development and are essential for proper heart development, supporting tissue remodeling, angiogenesis, electrical conduction, efferocytosis, and immune regulation. We present here a human heart-macrophage assembloid (hHMA) model by integrating autologous human pluripotent stem cell (hPSC)-derived embryonic monocytes into heart organoids to generate physiologically relevant TRMPs that persist long-term and contribute to cardiogenesis. Using single-cell transcriptomics, live imaging, and proteomics, we demonstrate that TRMPs modulate cardiac paracrine signaling, perform efferocytosis, and regulate extracellular matrix remodeling and electrical conduction. In a proof-of-concept maturated hHMA model of chronic inflammation, TRMPs adopt pro-inflammatory phenotypes that promote arrhythmogenic activity, consistent with atrial fibrillation through activation of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. This system enables detailed mechanistic studies of immune-cardiac interactions and provides a powerful in vitro platform for modeling human heart development and inflammation-driven arrhythmias. • Human heart-macrophage assembloids model embryonic cardiac macrophage integration • Tissue-resident macrophages regulate heart morphogenesis and electrical conduction • Macrophages communicate with cardiac cells via EVs and efferocytosis pathways • Chronic inflammasome activation in matured hHMAs models arrhythmia phenotypes O’Hern et al. present a novel human heart-macrophage assembloid platform generated by integrating hPSC-derived embryonic monocytes into heart organoids. These tissue-resident macrophages regulate cardiac development and conduction and, under chronic inflammation, recapitulate atrial fibrillation features, offering a powerful model to study immune-cardiac interactions and arrhythmia mechanisms.
Source: Cell stem cell
Authors: Colin O’Hern, Sammantha Caywood, Shakhlo Aminova, Artem Kiselev, Brett Volmert, Weiheng Cao, Fei Wang, Mia Dionise, Merlinda-Loriane Sewavi, Milana Skoric, Hussain Basrai, Freyda Mannering, Priyadharshni Muniyandi, Mirel Popa, George Boulos, Kyle Wolf, Izabelle Brown, Isabel Nuñez-Regueiro, Amanda Huang, Aleksandra Kostina, Lauren Squire, Curtis Wilkerson, Nagib Chalfoun, Sangbum Park, Nureddin Ashammakhi, Chao Zhou, Christopher Contag, Aitor Aguirre
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: Corewell Health Foundation Southwest Michigan, National Science Foundation, American Heart Association, Alternatives Research and Development Foundation, Beaumont Health System, Saving Tiny Hearts Society, Murray State University, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Biomedical Imaging and Bioengineering
Awards: Lipid signaling in cardiac development and disease, Macrophage type 2-derived extracellular vesicle and O2 generating patch for the treatment of ischemic heart, G3022526764, G4265488674, High throughput optical coherence tomography (OCT)-based imaging platform for label-free, non-invasive characterization of 3D tumor spheroids., High-throughput integrated live imaging and optogenetic pacing platform to assess hypoxia responsiveness in the fly heart, G6308160924, An artificial biological pump for failing Fontan circulation, G8094057358, G9000076839, Understanding immune-epithelial interactions during wound repair in live mammals
OpenAlex ID: W4415610473