Human heart assembloids with autologous tissue-resident macrophages recreate physiological immuno-cardiac...

Area of Science:

• Cardiovascular Biology
• Developmental Immunology
• Stem Cell Biology

Background:

• Cardiac development relies on immune system interactions, crucial for homeostasis.
• Existing human pluripotent stem cell (hPSC)-derived organoids lack essential tissue-resident immune cells.
• Disruptions in heart-immune interactions are linked to various cardiovascular diseases.

Purpose of the Study:

• To introduce a novel human heart-macrophage assembloid (hHMA) model.
• To investigate the role of cardiac tissue-resident macrophages (MPs) in heart development and function.
• To establish a platform for studying inflammation-driven cardiac diseases and arrhythmias.

Main Methods:

• Generation of hHMA by integrating autologous cardiac MPs with human heart organoids (hHOs).
• Multi-omic analyses to characterize MP phenotype and viability within the assembloid.
• Development of a platform to induce and study cardiac arrhythmias using pro-inflammatory factors.

Main Results:

• MPs were phenotypically similar to embryonic cardiac MPs and viable long-term in hHMAs.
• MPs significantly influenced cardiac cellular composition, communication, ECM remodeling, and sarcomeric maturation.
• The hHMA model successfully replicated inflammasome-mediated atrial fibrillation features.

Conclusions:

• The hHMA model provides a robust platform for studying immune cell roles in cardiac development and disease.
• MPs contribute to cardiac homeostasis through efferocytosis, electrical integration, and metabolic support.
• This model advances cardiovascular research, drug discovery, and understanding of inflammation-driven heart conditions.