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

Pubmed ID: 41578022

Pubmed Central ID: PMC12900648

Journal: Nature genetics

Publication Date: Feb. 1, 2026

MeSH Terms: Humans, Male, Female, Aged, Middle Aged, Disease Progression, Lung, Pulmonary Disease, Chronic Obstructive, Proteomics, Biomarkers, Transcriptome, Cell Communication

Grants: R01 HL141852, R01 HL127349, UH3 TR002445, S10 OD018034, T32 GM086287, P30 DA018343, R21 HL173512, S10 OD019967, F30 HL162459, R01 HL149744, R01 HL155948, R21 HL161723, U01 HL145567, R01 LM014087, R01 HL145372

Authors: Zhang Y, Liu J, Zhang X, Wang W, Wei H, Yan X, Kaminski N, Herzog EL, Nouws J, Jiang W, Brewster RM, Nguyen JP, Liang S, Pass SM, Collin F, Oill AT, Kim SH, Siller SS, Zhao AY, Hansbro P, Dela Cruz C, Britto C, Gomez J, Cloonan SM, Lam TT, Banovich NE, Raredon MSB, Mangiola S, Homer RJ, McDonough J, Polverino F, Sauler M

Cite As: Zhang Y, Wei H, Nouws J, Jiang W, Brewster RM, Nguyen JP, Liang S, Pass SM, Wang W, Collin F, Oill AT, Kim SH, Siller SS, Liu J, Zhao AY, Hansbro P, Dela Cruz C, Britto C, Gomez J, Cloonan SM, Herzog EL, Lam TT, Banovich NE, Raredon MSB, Zhang X, Mangiola S, Homer RJ, Kaminski N, McDonough J, Polverino F, Yan X, Sauler M. Aberrant cellular communities underlying disease heterogeneity in chronic obstructive pulmonary disease. Nat Genet 2026 Feb;58(2):376-391. Epub 2026 Jan 23.

Studies:

Abstract

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.