Human heart-macrophage assembloids mimic immune-cardiac interactions and enable arrhythmia disease modeling
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.
Authors
- Fei Wang (ORCID: https://orcid.org/0000-0002-0890-4595)
- Aleksandra Kostina (ORCID: https://orcid.org/0000-0002-1983-4609)
- Chao Zhou (ORCID: https://orcid.org/0000-0002-8679-3413)
- Amanda Huang
- Sang‐Bum Park (ORCID: https://orcid.org/0000-0001-8329-5104)
- Artem Kiselev (ORCID: https://orcid.org/0000-0002-5524-6900)
- Milana Skoric
- Colin O’Hern (ORCID: https://orcid.org/0000-0002-5896-2101)
- Brett Volmert (ORCID: https://orcid.org/0000-0002-5209-4833)
- Freyda L. Mannering
- Nagib Chalfoun (ORCID: https://orcid.org/0000-0001-5757-7773)
- Aitor Aguirre (ORCID: https://orcid.org/0000-0002-1383-2792)
- Lyle Squire
- Shakhlo Aminova (ORCID: https://orcid.org/0000-0002-4944-7650)
- Priyadharshni Muniyandi (ORCID: https://orcid.org/0000-0003-2028-842X)
- Curtis G. Wilkerson (ORCID: https://orcid.org/0000-0003-0503-1546)
- Kyle J. Wolf (ORCID: https://orcid.org/0000-0003-4874-2911)
- Nureddin A. Ashammakhi (ORCID: https://orcid.org/0000-0003-0181-6055)
- Christopher H. Contag (ORCID: https://orcid.org/0000-0002-1011-8278)
- Mirel Adrian Popa
- Ivan W. Brown
- Weiheng Cao
- George Boulos
- Isabel Nuñez-Regueiro
- Sammantha Caywood
- Merlinda-Loriane Sewavi
- Mia Dionise
- Hussain F. Basrai
Institutions
- Washington University in St. Louis (US)
- Romanian Academy (RO)
- Michigan State University (US)
Publication Details
- Journal
- Cell stem cell
- Published
- 2025-10-28
- DOI
- https://doi.org/10.1016/j.stem.2025.09.011
- Citations
- 10
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 13.88