Spatial single-cell atlas reveals regional variations in healthy and diseased human lung

Firsova, Alexandra B. and Marco, Salas Sergio and Kuemmerle, Louis B. and Abalo, Xesus M. and Sountoulidis, Alexandros and Larsson, Ludvig and Mahbubani, Krishnaa T. and Theelke, Jonas and Andrusivova, Zaneta and Alonso, Galicia Leire and Liontos, Andreas and Balassa, Tamás and Kovács, Ferenc and Horváth, Péter and Chen, Yuexin and Gote-Schniering, Janine and Stoleriu, Mircea-Gabriel and Behr, Jurgen and Meyer, Kerstin B. and Timens, Wim and Schiller, Herbert B. and Luecken, Malte D. and Theis, Fabian J. and Lundeberg, Joakim and Nilsson, Mats and Nawijn, Martijn C. and Samakovlis, Christos (2025) Spatial single-cell atlas reveals regional variations in healthy and diseased human lung. NATURE COMMUNICATIONS, 16 (1). No. -9745. ISSN 2041-1723

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Abstract

Integration of scRNA-seq 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, constantly exposed to external agents, it is crucial to understand the influence of lung tissue topography or external factors on gene expression variability within cell types. Here, we apply 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 gene expression variability within and across cell types, and (iii) reveal distinct cellular neighborhoods in specific anatomical regions and examine gene expression variations in them. We thus provide a spatially resolved tissue reference atlas 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 chronic obstructive pulmonary disease lungs. Our topographic atlas enables a precise description of characteristic regional cellular responses upon experimental perturbations or during disease progression.

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