Aberrant cellular communities underlying disease heterogeneity in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is clinically and molecularly heterogeneous. To investigate COPD heterogeneity, we profiled lung tissue by single-nucleus RNA sequencing from 141 study participants (1,516,727 nuclei) and identified shifts in cell composition and emergent cell states that correlated with lung function, emphysema and composite symptom scores. Epithelial regenerative states peaked in early COPD and declined thereafter, whereas inflamed nonimmune cells and profibrotic/remodeling states, together with select immune populations, expanded with disease progression. Clustering study participants by the proportion of pathologic cells coupled with spatial transcriptomics identified distinct patterns of cellular co-occurrence within spatially localized niches. Proteomic analyses identified plasma biomarkers of cell states and their impact on the extracellular matrix. Mediation and cell communication analyses revealed cell-autonomous and intercellular communication networks associated with disease. These data define the cellular landscape of COPD heterogeneity, revealing molecular drivers and biomarkers that could inform therapeutic strategies. This study uses single-nucleus RNA sequencing to analyze lung tissue from 141 individuals with chronic obstructive pulmonary disease. Distinct patterns of spatially resolved changes in cell composition and cell states that correlate with clinical features are highlighted.