A Tunable Pulmonary Organoid Model Demonstrates Compositionally Driven Epithelial Plasticity and Immune Polarization

Area of Science:

• Pulmonary Medicine
• Regenerative Biology
• Cellular Biology

Background:

• Chronic lung diseases like idiopathic pulmonary fibrosis (IPF) and COPD involve abnormal epithelial repair and immune responses.
• The precise role of cellular context in directing these aberrant regenerative processes remains unclear.

Purpose of the Study:

• To investigate how varying immune, epithelial, and mesenchymal cell compositions influence lung epithelial plasticity and macrophage polarization.
• To model context-specific regenerative mechanisms in chronic lung diseases.

Main Methods:

• Development of a tunable, primary rat-derived lung organoid model.
• Systematic variation of immune, epithelial, and mesenchymal cell inputs.
• Analysis of emergent cell states, macrophage polarization, and multicellular signaling networks.

Main Results:

• Observed spontaneous emergence of disease-relevant transitional epithelial cell states (e.g., Sox9+ progenitors, RAS/AT0-like intermediates, hillock-like cells).
• Identified distinct macrophage activation profiles correlating with different cellular contexts.
• Mesenchyme-rich contexts promoted inflammatory signaling and persistence; immune-dominant contexts favored alveolar repair or squamous remodeling.
• Hillock-like cells exhibited context-specific immune-regulatory functions, potentially orchestrating inflammatory responses.

Conclusions:

• Lung organoid composition dictates epithelial plasticity and macrophage polarization, driving distinct regenerative outcomes.
• Multicellular signaling networks integrate stress, immune coordination, and epithelial fate to determine regenerative trajectories.
• This model offers a platform for studying context-dependent lung repair and developing targeted therapies for chronic lung diseases.