TY - JOUR
T1 - Human heart-macrophage assembloids mimic immune-cardiac interactions and enable arrhythmia disease modeling
AU - O'Hern, Colin
AU - Caywood, Sammantha
AU - Aminova, Shakhlo
AU - Kiselev, Artem
AU - Volmert, Brett
AU - Cao, Weiheng
AU - Wang, Fei
AU - Dionise, Mia
AU - Sewavi, Merlinda Loriane
AU - Skoric, Milana
AU - Basrai, Hussain
AU - Mannering, Freyda
AU - Muniyandi, Priyadharshni
AU - Popa, Mirel
AU - Boulos, George
AU - Wolf, Kyle
AU - Brown, Izabelle
AU - Nuñez-Regueiro, Isabel
AU - Huang, Amanda
AU - Kostina, Aleksandra
AU - Squire, Lauren
AU - Wilkerson, Curtis
AU - Chalfoun, Nagib
AU - Park, Sangbum
AU - Ashammakhi, Nureddin
AU - Zhou, Chao
AU - Contag, Christopher
AU - Aguirre, Aitor
N1 - Publisher Copyright:
© 2025 The Author(s)
PY - 2025/11/6
Y1 - 2025/11/6
N2 - 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.
AB - 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.
KW - assembloid
KW - atrial fibrillation
KW - cardiac development
KW - disease modeling
KW - embryonic monocyte
KW - human heart organoid
KW - inflammasome
KW - pluripotent stem cell
KW - tissue-resident macrophage
UR - https://www.scopus.com/pages/publications/105020398227
U2 - 10.1016/j.stem.2025.09.011
DO - 10.1016/j.stem.2025.09.011
M3 - Article
C2 - 41151577
AN - SCOPUS:105020398227
SN - 1934-5909
VL - 32
SP - 1671-1690.e13
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 11
ER -