A spatially resolved atlas of the human lung characterizes a gland-associated immune niche

Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, researchers from the Wellcome Sanger Institute profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org ). Using computational data integration and analysis, the researchers extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. They identify and implicate peribronchial fibroblasts in lung disease. Importantly, the researchers discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). They show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new ‘gland-associated immune niche’ has implications for respiratory health.

Spatial multi-omics atlas of the human lung allows
the identification of cell types and their location

a, Multi-omics spatial lung atlas experimental design included fresh and frozen sampling from five locations for scRNA-seq (seven donors), sc VDJ-seq (four donors), snRNA-seq (seven donors) and Visium ST (seven donors). Five donors (D) from the frozen samples were pooled into five reactions, each containing different locations (Loc) from donors. b, UMAP of all scRNA-seq/snRNA-seq from 193,108 cells/nuclei in total from ten donors. Cells from all major subsets were captured. c, cell2location mapping on Visium ST from a bronchi section shows matching of cell types to expected structures. H&E staining and cell abundance estimated by cell2location (density score) for ciliated, basal epithelium, AT1, AT2 and chondrocyte cell types with histology image in the background. Dotted lines circle the epithelium (pink), parenchyma (green) and cartilage (brown). d, Cell type groups are enriched in expected micro-anatomical tissue environments on Visium ST across sections from five donors. Cell type loadings are represented by both dot size and color for cell types annotated in b across the manually annotated micro-environments in the Visium data. e, Cell type capture is affected by protocol and location. Cell type proportion analysis with fold changes and LTSR score for all cell type groups with regard to the material, protocol and location. Dashed boxes highlight the greatest changes. AT1, alveolar type 1; AT2, alveolar type 2; LE, lymphatic endothelium; VE, vascular endothelium.

Availability – The processed scRNA-seq, snRNA-seq and Visium ST data are available for browsing and download via our website www.lungcellatlas.org.