Cellular and molecular architecture of submucosal glands in wild-type and cystic fibrosis pigs

• Published in: Proceedings of the National Academy of Sciences - PNAS 2022-01, Vol.119 (4), p.1
• Main Authors: Yu, Wenjie, Moninger, Thomas O, Thurman, Andrew L, Xie, Yuliang, Jain, Akansha, Zarei, Keyan, Powers, Linda S, Pezzulo, Alejandro A, Stoltz, David A, Welsh, Michael J
• Format: Article
• Language: English
• Subjects: Abnormalities; Acinar Cells - metabolism; Animals; Antimicrobial agents; Biological Sciences; Biomarkers; Cystic fibrosis; Cystic Fibrosis - etiology; Cystic Fibrosis - genetics; Cystic Fibrosis - metabolism; Cystic Fibrosis - pathology; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Disease Models, Animal; Fluorescent Antibody Technique; Gene Expression; Gene Knockdown Techniques; Gene sequencing; Genetic Predisposition to Disease; Hybridization; Immunohistochemistry; Ion transport; Lung diseases; Molecular structure; mRNA; Mucin; Mucins; Mucins - metabolism; Mucociliary Clearance; Mucus; Mucus - metabolism; Mutation; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; Spatial distribution; Swine; Transcription
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2119759119

Submucosal glands (SMGs) protect lungs but can also contribute to disease. For example, in cystic fibrosis (CF), SMGs produce abnormal mucus that disrupts mucociliary transport. CF is an ion transport disease, yet knowledge of the ion transporters expressed by SMG acini, which produce mucus, and SMG ducts that carry it to the airway lumen is limited. Therefore, we isolated SMGs from newborn pigs and used single-cell messenger RNA sequencing, immunohistochemistry, and in situ hybridization to identify cell types, gene expression, and spatial distribution. Cell types and transcript levels were the same in non-CF and CF SMGs, suggesting that loss of epithelial anion secretion rather than an intrinsic cell defect causes CF mucus abnormalities. Gene signatures of acinar mucous and acinar serous cells revealed specialized functions in producing mucins and antimicrobials, respectively. However, surprisingly, these two cell types expressed the same ion transporters and neurohumoral receptors, suggesting the importance of balancing mucin and liquid secretion to produce optimal mucus properties. SMG duct cell transcripts suggest that they secrete HCO and Cl , and thus have some similarity to pancreatic ducts that are also defective in CF. These and additional findings suggest the functions of the SMG acinus and duct and provide a baseline for understanding how environmental and genetic challenges impact their contribution to lung disease.