Generation of induced alveolar assembloids with functional alveolar-like macrophages.

Summary

This study establishes human induced alveolar assembloids that couple pluripotent stem cell-derived alveolar epithelium with induced macrophages. The system recapitulates key functions (GM-CSF production by AT2-like cells; macrophage secretion of IL-1β/IL-6, surfactant metabolism gene expression) and models injury responses, lipid uptake, and bacterial/M. tuberculosis challenges, mirroring human respiratory defense.

Key Findings

• Human induced alveolar assembloids integrate PSC-derived alveolar epithelium with induced macrophages.
• AT2-like cells produced GM-CSF supporting macrophage tissue adaptation.
• Macrophage-like cells secreted IL-1β and IL-6, expressed surfactant metabolism genes, cleared damaged cells, and absorbed oxidized lipids.
• Exposure to bacterial components or Mycobacterium tuberculosis elicited defense responses mirroring human respiratory immunity.

Clinical Implications

While preclinical, assembloids can accelerate target discovery and screening for respiratory infections (e.g., M. tuberculosis), surfactant disorders, and epithelial injury responses, potentially improving the translational pipeline.

Limitations

• In vitro system lacks full vascular, neuronal, and systemic immune components
• Donor variability and scalability to high-throughput disease modeling require further study

Future Directions

Integrate vasculature and additional immune subsets, apply to viral/bacterial co-infections and fibrosis models, and use for preclinical drug screening and personalized medicine.