Journal article
Ferret Glandular Myoepithelial Cells Are Multipotent Airway Progenitors with a Secretory Lineage Bias
American journal of respiratory cell and molecular biology
09/28/2026
DOI: 10.1093/ajrcmb/aanag191
PMID: 42804731
Abstract
Airway submucosal glands (SMGs) play a key role in pulmonary defense by producing mucus and antimicrobial secretions; their dysfunction underlies diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease. Murine studies have identified tracheal glandular myoepithelial cells (GMECs) as reserve stem cells, but CFTR-deficient mice lack the intrapulmonary airway glands required to model CF lung disease. In contrast, CFTR-deficient ferrets possess intrapulmonary airway glands, thereby closely recapitulating human CF lung pathology, yet we currently lack models to trace these cells in vivo.
We generated an ACTA2 CreER::ROSA mTmG transgenic ferret model to lineage-trace ACTA2-expressing GMECs. We examined GMEC contributions to glandular development and surface airway epithelium (SAE) regeneration following polidocanol injury. Single-cell transcriptomics, organoid, and air-liquid interface (ALI) cultures were utilized to evaluate epithelial differentiation and CFTR-mediated ion transport.
Single-cell trajectory models and lineage tracing revealed that ferret GMECs are high-potency multipotent progenitors contributing to the basal, serous, and mucous lineages during gland development. After severe adult airway injury, GMECs recruited to the SAE and regenerated multiple epithelial cell types with a bias towards secretory cells. Despite robust FOXI1+ ionocyte formation, GMEC-derived epithelia exhibited reduced CFTR expression, function, and fluid secretion compared to non-GMEC-derived glandular epithelia.
Ferret GMECs are multipotent progenitors and contribute to gland development and airway repair. However, their descendants demonstrate bias toward the specification of secretory cells and CFTRLow ionocytes. This suggests that GMEC-driven repair may result in structurally restored yet functionally compromised epithelia, potentially contributing to mucus retention in muco-obstructive airway diseases.
Details
- Title: Subtitle
- Ferret Glandular Myoepithelial Cells Are Multipotent Airway Progenitors with a Secretory Lineage Bias
- Creators
- Yabo Ma - University of Alabama at BirminghamMiao Yu - University of IowaYoshihiko Kobayashi - Duke UniversityThomas Whitlow - Duke UniversityZheqing Hu - University of Alabama at BirminghamLiyuan Yang - University of Alabama at BirminghamAleksandra Tata - Duke UniversityYaling Yi - University of Alabama at BirminghamPreetish Kadur Lakshminarasimha Murthy - University of Illinois ChicagoPin-Yi Lee - University of Alabama at BirminghamZiying Yan - University of Alabama at BirminghamXingshen Sun - University of Alabama at BirminghamPurushothama Rao Tata - Duke UniversityXiaoming Liu - University of Alabama at BirminghamJohn F Engelhardt - University of Alabama at Birmingham
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory cell and molecular biology
- DOI
- 10.1093/ajrcmb/aanag191
- PMID
- 42804731
- NLM abbreviation
- Am J Respir Cell Mol Biol
- ISSN
- 1535-4989
- eISSN
- 1535-4989
- Publisher
- Oxford University Press
- Language
- English
- Electronic publication date
- 09/28/2026
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9985240281802771
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