Aberrant cellular communities underlying disease heterogeneity in chronic obstructive pulmonary disease.

Summary

Using single-nucleus RNA-seq, spatial transcriptomics, and proteomics, this study maps COPD cellular heterogeneity across 141 lungs. It identifies early epithelial regenerative states that wane with progression and expanding profibrotic/remodeling states and immune subsets, defines spatially localized niches, and nominates plasma biomarkers and intercellular networks linked to disease severity.

Key Findings

• Single-nucleus RNA-seq of 1,516,727 nuclei revealed COPD stage-linked shifts in cell composition and emergent states.
• Early epithelial regenerative states declined with progression, while profibrotic/remodeling states and select immune populations expanded.
• Spatial transcriptomics defined localized co-occurring pathological niches; plasma proteomics identified biomarkers tied to extracellular matrix remodeling.
• Mediation and cell–cell communication analyses uncovered networks associated with disease severity.

Clinical Implications

Facilitates patient stratification using plasma biomarkers of pathological cell states and supports designing trials targeting profibrotic/remodeling niches or their signaling networks.

Limitations

• Cross-sectional design limits causal inference and temporal dynamics.
• External prospective validation and functional perturbation studies are needed to confirm therapeutic targets.

Future Directions

Develop and validate blood-based biomarker panels for stratification; test interventions that modulate profibrotic/remodeling cell states and intercellular networks; longitudinal single-cell studies to track trajectories.