A topographic lung cell atlas reveals regional variation in cell-type specific gene programs and identifies healthy and diseased cellular neighborhoods

Integration of single cell mRNA sequencing data from millions of cells revealed a high diversity of cell types in the healthy and diseased human lung. In a large and complex organ, which is also constantly exposed to external agents, it is crucial to understand the influence of lung tissue topography or external factors on gene expression variability within each cell type. Here, we applied three spatial transcriptomics approaches, to: (i) localize the majority of lung cell types, including rare epithelial cells within the tissue topography, (ii) describe consistent anatomical and regional variability in gene expression within and across cell types, and (iii) reveal distinct cellular neighborhoods for specific anatomical regions and examine gene expression variations in them. We thus provide a spatially resolving tissue reference atlas including cell type composition and gene expression variations in three representative regions of the healthy human lung. We further demonstrate its utility by defining previously unknown imbalances of epithelial cell type compositions in diseased tissue from patients with stage II COPD. Our topographic atlas enables a precise description of characteristic regional cellular responses upon experimental perturbations or during disease progression.