Olfactory microvillar tuft cells direct neurogenesis during allergic inflammation

Abstract: Integrating single-cell RNA sequencing and immunolocalization we define distinct markers of olfactory neuroepithelial cells, showing that Muc2 uniquely identifies sustentacular cells and Ncam1 is a robust mouse and human marker for OSNs. The enigmatic, transcriptionally uncharacterized subsets of olfactory microvillous cells (MVCs) correspond to nasal tuft cells and ionocytes in both mice and humans. Next we identify three morphologically, molecularly, and spatially distinct subsets of tuft cells: Nrgn+ MVC, Dclk1+ glandular and Gnat3+ respiratory tuft cells. While distinct, these subsets of tuft cells share a core machinery for allergen recognition and generation of the eicosanoid mediators cysteinyl leukotrienes. Single-cell analysis of the response to inhaled allergens revealed robust induction of olfactory stem cell proliferation, which is abolished by tuft cell-specific deletion of Ltc4s, required for cysteinyl leukotriene generation. Together our data provide high resolution characterization of epithelial cell diversity in the nose, uncovering a novel mechanism by which the mucosal response to allergens, specifically tuft cell-derived eicosanoids, regulates stem cell proliferation in the olfactory neuroepithelium.