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Fibroblast growth factor 10 (FGF10) is well established as a mesenchyme-derived growth factor and a critical regulator of fetal organ development in mice and humans. Using a single-cell RNA sequencing (RNA-seq) atlas of salivary gland (SG) and a tamoxifen inducible Fgf10 CreERT2 :R26-tdTomato mouse, we show that FGF10pos cells are exclusively mesenchymal until postnatal day 5 (P5) but, after P7, there is a switch in expression and only epithelial FGF10pos cells are observed after P15. Further RNA-seq analysis of sorted mesenchymal and epithelial FGF10pos cells shows that the epithelial FGF10pos population express the hallmarks of ancient ionocyte signature Forkhead box i1 and 2 (Foxi1 , Foxi2), Achaete-scute homolog 3 (Ascl3), and the cystic fibrosis transmembrane conductance regulator (Cftr). We propose that epithelial FGF10pos cells are specialized SG ionocytes located in ducts and important for the ionic modification of saliva. In addition, they maintain FGF10-dependent gland homeostasis via communication with FGFR2bpos ductal and myoepithelial cells. [Display omitted] Our study demonstrates that, during early postnatal development, FGF10 is expressed by mesenchymal fibroblasts and signals to SG epithelium, which contains immature ionocytes expressing Cftr, Ascl3, and Foxi1. Between P5 and P15, the shift of FGF10 expression from mesenchymal to epithelial cells is observed. Importantly, this FGF10 expression shift correlates with ionocyte maturation. The mature FGF10pos ionocytes express more ion channels and participate in the ionic modification of saliva. Ionocyte-derived FGF10 is predicted to signal to myoepithelial cells and basal duct cells. • Unique FGF10-expressing ionocytes have been identified within salivary gland ducts • The FGF10pos ionocytes express the hallmark of ancient ionocyte signature genes • FGF10 expression shifts from fibroblasts to ionocytes between postnatal days 7 and 15 • Salivary gland ionocytes maintain ion homeostasis and act as niche cells Mauduit et al. identified unique FGF10-expressing ionocytes in salivary glands. FGF10 expression shifts from fibroblasts to epithelial ionocytes during postnatal development. Ionocytes play a dual role in salivary gland homeostasis; they maintain specific ion composition in saliva and act as niche cells, providing growth factor support for other epithelial cells. [ABSTRACT FROM AUTHOR]

Summary In the adult salivary glands, the origin of replacement and regenerated acinar cells remains unclear. Although many reports describe the identification of stem cells in adult salivary glands, we have shown that differentiated acinar cells can be maintained and regenerated through self-duplication. Here, we have used genetic mouse models to further investigate acinar cell replacement and regeneration during homeostasis and after injury. Under normal conditions or after duct ligation, replacement of duct and acinar cells occurs through lineage-restricted progenitors. In contrast, after irradiation, in vivo lineage tracing shows that acinar, as well as duct, cells contribute to acinar cell regeneration, revealing that cellular plasticity is involved in salivary gland repair. Our results also indicate that even after radiation damage, several cell populations have regenerative potential for restoring salivary gland function. [ABSTRACT FROM AUTHOR]