FGFR signaling establishes spatial gradients of secretory cell identities along the airway proximal-distal axis
Journal article, 2026
Secretory cells are major structural and functional constituents of the lung airways. Their heterogeneity, spatial organization and specification mechanisms are partially understood. Here, we analyze secretory lung cell-types at single-cell resolution. In the airway epithelium, we find opposing, partially overlapping gene-expression gradients along the proximal-distal airway axis superimposed on a general gene program encoding detoxification. One graded program is elevated proximally and relates to innate immunity, whereas the other is enriched distally, encoding lipid metabolism and antigen presentation. Intermediately positioned cells express moderate levels of both graded programs creating a differentiation continuum towards each end. Lineage tracing analysis during development reveals the sequential establishment of the gradients in common epithelial progenitors postnatally. We show that Fgfr2b regulates the airway patterning by inducing and maintaining high levels of lipid biosynthesis and vesicle trafficking in distal airways and down-regulating innate-immunity genes in vivo and in airway organoids. Our analysis offers a framework for studying epithelial and lung tissue organization to better understand cellular roles in tissue-level pathology.
Author
Alexandros Sountoulidis
Stockholm University
Jonas Theelke
Stockholm University
Andreas Liontos
Stockholm University
Alexandra B. Firsova
Stockholm University
Orane Eliot
Stockholm University
Janine Koepke
Univ Giessen & Marburg Lung Ctr
Pamela Millar-Buchner
Univ Giessen & Marburg Lung Ctr
Louise Manneras-Holm
University of Gothenburg
Åsa Björklund
Chalmers, Life Sciences, Systems and Synthetic Biology
Athanasios Fysikopoulos
Univ Giessen & Marburg Lung Ctr
Antonia Kelm
Stockholm University
Eleni Bouloukou
Univ Giessen & Marburg Lung Ctr
Konstantin Gaengel
Uppsala University
Fredrik Backhed
University of Gothenburg
Christer Betsholtz
Uppsala University
Karolinska Institutet
Werner Seeger
Univ Giessen & Marburg Lung Ctr
Saverio Bellusci
Univ Giessen & Marburg Lung Ctr
Christos Samakovlis
Stockholm University
Univ Giessen & Marburg Lung Ctr
Nature Communications
2041-1723 (ISSN) 20411723 (eISSN)
Vol. 17 1 2651Subject Categories (SSIF 2025)
Cell and Molecular Biology
Respiratory Medicine and Allergy
Immunology in the Medical Area
DOI
10.1038/s41467-026-70842-0
PubMed
41851103