Poster: 148Airway glandular myoepithelial cells mediate airway regeneration and exhibit distinct CFTR functional profiles in a ferret model of cystic fibrosis

Y. Ma; L. Yang; Z. Hu; C. Wang; X. Liu; J. Engelhardt

doi:10.1016/j.jcf.2026.07.179

Airway submucosal glands (SMGs) are essential for maintaining respiratory health by secreting fluid, mucus, and antimicrobial compounds into the airways. In cystic fibrosis (CF), impaired CFTR function in both SMGs and the surface epithelium contributes to defective mucus clearance and airway obstruction. Although murine studies have identified tracheal glandular myoepithelial cells (GMECs) as reserve stem cells, rodents lack cartilage and SMGs in their intrapulmonary bronchial airways and do not spontaneously develop CF-like lung disease, limiting their translational relevance. Like humans, ferrets have abundance of SMGs throughout their extrapulmonary and intrapulmonary airways and spontaneously develop muco-obstructive lung disease and bacterial infections. To define the role of GMECs in airway development, repair, and CF-related remodeling, we generated ACTA2-CreER::ROSA-mTmG transgenic ferrets to lineage trace αSMA-expressing GMECs and their progeny. Tamoxifen was administered during postnatal gland development, during CF disease progression, or prior to polidocanol-induced airway epithelial injury in adult ferrets. Lineage-labeled GMECs were isolated and evaluated in organoid and air-liquid interface (ALI) cultures. CFTR-dependent epithelial function was assessed by forskolin-induced swelling (FIS) and Ussing chamber analysis. Lineage tracing showed that ferret GMECs are multipotent progenitors that contribute to both glandular mucous and serous lineages during SMG development and regenerate multiple surface airway epithelial cell types after severe injury. Lineage-labeled cells were also detected in MUC5B+ mucus cells and lysozyme+ serous cells in adult glands, including those from CF ferrets, supporting a role for GMECs in glandular remodeling and pathological SMG hyperplasia. Invitro, GMEC-derived cells formed organoids and ALI epithelia containing major airway epithelial cell types, including FOXI1+ ionocytes. Functional analyses showed that GMEC-derived epithelia were capable of CFTR-mediated ion transport and fluid secretion; however, compared with non-GMEC-derived glandular epithelia, they exhibited reduced CFTR expression and function, together with a bias toward secretory differentiation and CFTR-Low ionocytes. These CFTR-dependent functions were further impaired in epithelia derived from GMECs isolated from CFTR-G551D CF ferrets. Together, these findings demonstrate that ferret GMECs are multipotent progenitors involved in SMG development, airway repair, and pathological gland remodeling. They also establish GMECs as a clinically relevant cell population and potential therapeutic target in CF and other obstructive airway diseases that involve glandular remodeling. Importantly, these findings suggest that remodeling processes can directly influence airway CFTR function by mobilizing stem cell compartments with intrinsic biases toward specific cellular specification programs, thereby reshaping the CFTR-dependent functional properties of the regenerated airway epithelium.

Poster: 148Airway glandular myoepithelial cells mediate airway regeneration and exhibit distinct CFTR functional profiles in a ferret model of cystic fibrosis

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