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Updated: Apr 7, 2026
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Generation of 3D Whole Lung Organoids from Induced Pluripotent Stem Cells for Modeling Lung Developmental Biology and Disease
Published on: April 12, 2021
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Pulmonary organoid models demonstrate compositionally driven epithelial plasticity and immune polarization.
Sophie E Edelstein1,2, Satoshi Mizoguchi1,2,3, Maria Tomàs Gracia1,2,4
1Department of Anesthesiology, Yale School of Medicine, New Haven, CT 06520, USA.
Iscience
|April 6, 2026
Summary
Chronic lung diseases involve abnormal epithelial repair and immune responses. This study uses a lung organoid model to show how different cell types influence lung regeneration and inflammation.
Area of Science:
- Pulmonary Medicine
- Regenerative Biology
- Immunology
Background:
- Chronic lung diseases like idiopathic pulmonary fibrosis and COPD feature abnormal epithelial regeneration and immune remodeling.
- The precise influence of cellular context on these regenerative processes remains unclear.
Purpose of the Study:
- To investigate how varying immune, epithelial, and mesenchymal cell compositions in a lung organoid model affect epithelial plasticity and macrophage polarization.
- To understand the role of cellular crosstalk in driving regenerative outcomes in chronic lung disease contexts.
Main Methods:
- Development of a lung organoid model with adjustable immune, epithelial, and mesenchymal cell inputs.
- Analysis of condition-dependent cell state transitions and macrophage activation profiles.
- Investigation of epithelial-immune-mesenchymal crosstalk and multicellular signaling networks.
Main Results:
- Observed emergence of transitional epithelial cell states (Sox9+ progenitors, RAS-like intermediates, hillock-like cells) and distinct macrophage activation profiles.
- Mesenchyme-rich contexts promoted inflammatory signaling and stabilized transitional cells; immune-dominant contexts favored ATI-like repair and squamous remodeling.
- Hillock-like cells exhibited context-dependent activation and expressed immune-regulatory genes, potentially acting as epithelial orchestrators.
Conclusions:
- Lung organoid composition critically dictates epithelial plasticity and macrophage polarization, influencing regenerative trajectories.
- Multicellular signaling networks integrating stress, immunity, and resilience govern regenerative outcomes.
- This model provides a platform for studying milieu-specific regeneration and developing strategies to modify epithelial fate in chronic lung diseases.
