# Salivary gland ionocyte organization and function during homeostasis, repair, and disease

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $581,508

## Abstract

The salivary glands are exocrine glands that produce saliva. An adequate supply of
saliva is critical to the maintenance of oral tissue. Saliva is composed of a variety of electrolytes
and also contains immunoglobulins, proteins, enzymes and mucins, suggesting that saliva has a
complex function. An important function of salivary gland ducts is to regulate ion
homeostasis[1]. Dysfunction of epithelial ion homeostasis can lead to several human
diseases[2, 3]. Our lineage tracing experiments using a tamoxifen inducible FGF10CreERT2:R26-
Tomato mouse identified new epithelial populations of the Fgf10 expressing cells in the striated
(SD), granular (GCT) and excretory ducts (ED) of submandibular (SMG) and parotid (PG)
glands. Importantly Fgf10 lineage tracing shows that until postnatal day 7 (P7) only
mesenchymal Fgf10 expressing cells are present, however after P10, Fgf10 expression in the
mesenchyme shuts down, while a subset of ductal epithelial cells starts to express Fgf10. Using
Fluorescence Activated Cell Sorting (FACS) we isolated both mesenchymal and epithelial
populations of Fgf10+ cells and performed RNA sequencing (RNA-seq). Analysis of this RNA-
seq data combined with analysis of single cell RNA-Seq (scRNAseq) data from P1 and adult
SMGs showed that epithelial Fgf10+ populations overlap with the known duct population marked
by Ascl3. Moreover, these epithelial Fgf10+ cells expressed many gene characteristics for an
ancient type of ionocyte cell: Bsnd, Foxi1, Foxi2, Asgr1, Stap1, several subunits of the H+-
ATPase (V-ATPase) and markers of SLC12A1/2 and Slc9a4 transporters. Most importantly
Fgf10+ cells expressed cystic fibrosis transmembrane conductance regulator (Cftr) that plays a
key role in exocrine secretion, including in salivary glands. We propose that these epithelial
Fgf10+/Ascl3+/Cftr+ cells are specialized duct salivary gland ionocytes. Moreover, using two
models of Sjogrens syndrome: the NOD.B10Sn-H2b/J and the thrombospondin-1 null (TSP1-/-)
mice, we showed a significant decrease in Fgf10+ expression and the number of ionocytes with
disease progression. We also showed that epithelial Fgf10+ cells isolated from the SMG are
able to maintain proliferation and growth of progenitor and myoepithelial cells, suggesting an
additional role for ionocytes in ductal maintenance. In this application we will determine the role
of Fgf10 signaling in SMG regeneration and ionocyte function, define factors that control
ionocyte differentiation and determine how chronic inflammation affects ionocyte function. In
addition, in collaboration with Dr. Hoffman's group using bulk RNA-seq and scRNA-seq data we
will investigate whether salivary glands have one type or several types of ionocytes. Our
proposed study will provide a starting platform for future studies of ionocytes in basic biology
and clinical research.

## Key facts

- **NIH application ID:** 10471333
- **Project number:** 5R01DE031044-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Helen P. Makarenkova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $581,508
- **Award type:** 5
- **Project period:** 2021-08-18 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10471333

## Citation

> US National Institutes of Health, RePORTER application 10471333, Salivary gland ionocyte organization and function during homeostasis, repair, and disease (5R01DE031044-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10471333. Licensed CC0.

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