FGFR signaling establishes spatial gradients of secretory cell identities along the airway proximal-distal axis.

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.