Fig. 1: Cellular shifts in endothelial, epithelial and fibroblast populations in COPD.

a, UMAP of endothelial cells (left) and cell states (right), including artery (n = 2,891), vein (n = 2,171), systemic circulation endothelial cells (systemic, n = 1,523), lymphatic (n = 7,925), cycling endothelial cells (Endo_div, n = 127), gCap (n = 9,131) and aerocytes (n = 8,001). Cell states including control (aerocyte_c, gCap_c, artery_c) and inflamed (aerocyte_i, gCap_i, artery_i) endothelial cells and angiogenic tip cells (gCap_tip). b, Dot plot of endothelial marker genes. Size represents the proportion of expressing cells; color denotes scaled expression. c, Pathway enrichment analysis across inflamed cell states; x axis shows NES, dot size shows −log₁₀(P) and color shows cell state; only pathways with FDR < 0.05 are shown (Benjamini–Hochberg, two-sided permutation tests). d, UMAP of epithelial populations, including goblet (n = 9,544), basal (n = 2,570), ABCs (n = 5,001), SCGB1A1⁺ secretory (n = 8,655), SCGB3A2⁺ secretory (n = 25,704) and AT2 subtypes—AT2_div (n = 1,326), AT2_SCGB3A2 (n = 23,375), AT2_i (n = 148,699), AT2_b (n = 330,033) and AT2_s (n = 98,751). e, Dot plot of epithelial marker genes. Size represents proportion of expressing cells; color denotes scaled expression. f, UMAP of fibroblast subsets, including alv. (n = 36,968), adv. (n = 6,294), CTHRC1⁺ fibroblasts (n = 2,734), IR (n = 739), FRC (n = 524), PB (n = 953) and myofibroblasts (n = 1,057). Alv. and adv. fibroblasts further stratified into control (fibroblast_c) and inflamed (fibroblast_i) cell states. g, Dot plot of fibroblast marker genes. Size represents proportion of expressing cells; color denotes scaled expression. h, Heatmap of normalized gene expression in adv. and adv. fibroblasts, clustered by cell state and study participant. i–k, Immunofluorescence of NF-κB (red) and DAPI (blue), with (i) PECAM1 (green) in inflamed endothelial-enriched tissue (j), pro-SFTPC (pSFTPC; green) in AT2_i-rich tissue and (k) AGER (green) in AT1_i-rich tissue; scale bars = 100 μm. l–n, Proportion of inflamed cell states across GOLD stages identified after deconvolution of spatial transcriptomic data in the Baylor cohort—(l) gCap_i, (m) AT2_i and (n) alv. fibroblast_i (no COPD, n = 11; GOLD stage I/II, n = 10; GOLD stage III/IV, n = 12). o, Feature plots of scaled LAMP3 and SCGB3A2 expression in epithelial cells. p, Immunofluorescence of KRT17 (red), CPA6 (green) and DAPI (blue); scale bar = 100 μm. q, Immunofluorescence of CTHRC1 (red), KRT17 (green) and DAPI (blue); scale bar = 50 μm. r, Proportion of CTHRC1⁺ fibroblasts (proportion of all fibroblasts) across GOLD stages in the Baylor cohort identified after deconvolution of spatial transcriptomic data (no COPD, n = 11; GOLD stage I/II, n = 10; GOLD stage III/IV, n = 12). All images representative of five participants per group (i–k,p,q). Group differences tested by Kruskal–Wallis with two-sided Wilcoxon post hoc tests and Benjamini–Hochberg FDR correction (l–n,r). Box plots depict the median (centerline), IQR (box) and 1.5× IQR whiskers. UMAP, Uniform Manifold Approximation and Projection; NES, normalized enrichment score; IFNγ, interferon-γ; gCap, general capillaries; alv, alveolar; adv, adventitial; IR, immune reticular; PB, peribronchial; expr, expression.