Human heart-macrophage assembloids mimic immune-cardiac interactions and enable arrhythmia disease modeling

Area of Science:

• Cardiovascular Biology
• Immunology
• Stem Cell Biology

Background:

• Embryonic cardiac tissue-resident macrophages (TRMPs) are crucial for heart development, supporting functions like remodeling, angiogenesis, and immune regulation.
• Existing models lack the complexity to fully study immune-cardiac interactions during development and disease.

Purpose of the Study:

• To create a human heart-macrophage assembloid (hHMA) model using human pluripotent stem cell (hPSC)-derived monocytes.
• To investigate the role of TRMPs in cardiogenesis, cardiac function, and inflammation-induced arrhythmias.

Main Methods:

• Generation of hHMA by integrating hPSC-derived embryonic monocytes into human heart organoids.
• Utilized single-cell transcriptomics, live imaging, and proteomics to analyze TRMP function.
• Developed a chronic inflammation model within the hHMA to study arrhythmogenic activity.

Main Results:

• hHMA successfully generated physiologically relevant TRMPs that persisted long-term and contributed to cardiogenesis.
• TRMPs were shown to modulate cardiac paracrine signaling, perform efferocytosis, and regulate extracellular matrix and electrical conduction.
• In an inflammation model, TRMPs adopted pro-inflammatory phenotypes, activating the NLRP3 inflammasome and promoting arrhythmogenic activity linked to atrial fibrillation.

Conclusions:

• The hHMA model provides a powerful in vitro platform for studying human heart development and immune-cardiac interactions.
• This model enables mechanistic studies of inflammation-driven arrhythmias, offering insights into conditions like atrial fibrillation.