# Biology of Submucosal Gland Stem Cells in the Airway

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $751,354

## Abstract

Project Summary
Airway submucosal glands (SMGs) are known to contain reserve stem cells for the surface airway epithelium
(SAE). In mice, this niche serves only the trachea; however, in larger mammals such as humans, pigs and ferrets,
SMGs are present throughout the intralobar cartilaginous airways and may serve the broader function of
maintaining the proximal conducting airway epithelium in the setting of disease. During the previous six funding
cycles, this grant has used mouse and ferret genetic models to address multiple aspects of airway SMG biology,
SMG stem/progenitor cell biology, and cystic fibrosis (CF) lung pathogenesis. This proposal aims to identify the
subpopulations of glandular myoepithelial cells (GMECs) that participate in airway repair, as well as the Wnt-
regulated mechanisms that control their behavior following injury. Based on our preliminary data, we hypothesize
that Lef-1 and Sox9 transcription factors differentially control Wnt-responsive GMEC states that orchestrate the
commitment, renewal, migration, and proliferative expansion of GMECs on the airway surface. Aim 1 will define
the biology of tracheal GMECs in mice and utilize an array of transgenic lines (intersectional lineage tracing,
conditional knockout, Wnt-reporters, Dox-inducible H2B-GFP) to study the involvement of Lef-1 and Sox9 in
regulating processes that control GMEC commitment, renewal, migration, and proliferation. Aim 2 will use
intersectional lineage tracing in ferrets to define the participation of GMEC subtypes and gland ductal cells in
maintaining the extralobar and intralobar SAE at homeostasis and following injury. We hypothesize that gland
ducts are a site for GMEC maturation to a pre-basal cell state, and that this underlying hierarchical relationship
is disturbed in chronic airway diseases such as CF. Aim 3 will test this hypothesis by identifying disturbances in
GMEC and gland duct niches in the setting of mild and severe CF lung disease, using VX-770-responsive
CFTRG551D ferrets. Novel aspects of these studies include the first non-rodent fate mapping in a species (ferret)
that closely models CF lung disease and SMG biology of humans, and supporting fate mapping data
demonstrating that ferret GMECs (ACTA2CreER) and gland ductal cells (KRT7CreER) participate in SAE repair. This
research will also shed light on differences in the behavior of SMG stem cell compartments in the extralobar and
intralobar cartilaginous airways, which cannot be addressed in mice because they lack SMGs in the intralobar
airways. This project is designed to enhance our understanding of stem cell phenotypes in airway SMGs and
the mechanisms that regulate their participation in SMG and surface airway repair. Given that GMECs can
regenerate both glandular and surface airway cell types, they are an attractive target for gene editing in CF and
such efforts will be enhanced by knowledge gained from this proposal. Furthermore, this work will delineate
disease-associated change...

## Key facts

- **NIH application ID:** 10833178
- **Project number:** 5R01HL165404-34
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** JOHN F ENGELHARDT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $751,354
- **Award type:** 5
- **Project period:** 2022-06-20 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833178

## Citation

> US National Institutes of Health, RePORTER application 10833178, Biology of Submucosal Gland Stem Cells in the Airway (5R01HL165404-34). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10833178. Licensed CC0.

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