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Cellular responses in the airway ciliary microenvironment from mouse models of primary ciliary dyskinesia with central pair apparatus defects

ABSTRACT: Dysfunction of motile cilia can impair mucociliary clearance in the airway and result in primary ciliary dyskinesia (PCD), a pediatric syndrome characterized by chronic respiratory infection and bronchiectasis, as well as infertility, laterality defects, and occasionally hydrocephalus due to defects in cilia in other organ systems. We have previously shown that mutations in genes encoding components of the ciliary central pair apparatus (CPA) perturb ciliary motility and result in PCD in mouse models. However, little is known about how epithelial cell types in the ciliary microenvironment of the upper airway respond to defects in ciliary motility and mucociliary clearance. In this study, we have used a single-cell RNA sequencing (scRNA-seq) approach to investigate the effects of ciliary dysfunction on the tracheal epithelial cells from mouse models with mutations in CPA genes Cfap221 (also known as Pcdp1), Cfap54, and Spef2. Expected cell types were identified in the tracheal epithelial samples, including basal cells, suprabasal cells, secretory cells, deuterosomal cells, ciliated cells, tuft cells, ionocytes, and neuroendocrine cells, as well as an unidentified cell type that does not express markers of typical airway cells. The deuterosomal cells were found to exist in two states that differ largely in expression of genes involved in differentiation into the ciliated cell type. Differentially expressed genes (DEGs) were identified for each cell type, and functional enrichment analysis revealed a variety of important cellular functions altered in mutant cells. Overlapping DEGs shed light on general cellular responses to cilia dysfunction, while unique DEGs indicate that some responses may be specific to the individual mutation and ciliary defect. These analyses uncover new information about cellular responses to mucociliary clearance defects in the airway and pathogenesis of PCD.

ORGANISM(S): Mus musculus

PROVIDER: GSE254100 | GEO | 2024/11/14

REPOSITORIES: GEO

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Project description:Study Smoking and COPD are associated with decreased mucociliary clearance and healthy smokers have shorter cilia in the large airway than nonsmokers. Intraflagellar transport (IFT) is the process by which cilia are produced and maintained. We assessed expression of IFT-related genes in smokers and nonsmokers and evaluated cilia length in the large and small airway of nonsmokers, healthy smokers, and smokers with COPD. Methods Airway epithelium was obtained via bronchoscopic brushing. Affymetrix microarrays were used to evaluate IFT gene expression in 2 independent data sets from large and small airway. Cilia length was assessed by measuring 100 cilia (10 cilia on each of 10 cells) per subject. Results All 40 IFT genes were expressed in the human large and small airway epithelium. In the large airway, 10 IFT genes were down-regulated and 1 up-regulated in smokers. In the small airway, 11 genes were down-regulated and 3 up-regulated in smokers. A set of 8 IFT genes was down-regulated in both data sets. In the large and small airway epithelium, cilia were significantly shorter in healthy smokers than nonsmokers, and significantly shorter in COPD smokers than in both healthy smokers and nonsmokers. Answer to the Question These results support the concept that loss of cilia length contributes to defective mucociliary clearance in COPD, and that smoking-induced changes in expression of IFT genes may be one mechanism of abnormally short cilia in smokers. Strategies to normalize cilia length may be an important avenue for novel COPD therapies. Gene expression was assessed for 40 intraflagellar transport related genes in the LAE of nonsmokers (n=21) and healthy smokers (n=31) and the SAE of an independent group of nonsmokers (n=28) and healthy smokers (n=69). Cilia length was assessed in a total of 228 airway epithelium samples, including 120 LAE samples and 108 SAE samples; a subset of the 228 samples is represented among the 149 samples in this Series.

Project description:We have established a consortium of 7 geographically-dispersed clinical research sites that are designed to study rare diseases of the airways, which involve defects in clearance of mucus secretions from the airways (defective "mucociliary clearance"). These sites will collaborate in diagnostic, genetic, and other studies in patients with impairments of mucociliary clearance, including primary ciliary dyskinesia (PCD), variant cystic fibrosis (CF), and pseudohypoaldosteronism (PHA). These disorders reflect genetic defects in airway host-defense, and typically result in chronic infection of the airways. Patients with these disorders of the conducting airways and sinuses have delayed (or incorrect) diagnoses, because diagnostic tests are not readily available. These patients may also have sub-optimal management of their clinical disease, because the cause of these disorders is not well-defined, and treatment regimens are usually not driven by evidence-based medicine. This current protocol is designed to employ a systematic approach to the diagnostic evaluation of these patients with chronic airways disease, which will yield precise diagnoses in individual patients, and will be associated with development of better diagnostic techniques, including genetic testing. In addition, we will compare/contrast clinical features (phenotype) across these disorders. A rigorous cross-sectional comparison of the clinical features will provide better understanding of the clinical disease of these disorders; in turn, this will lead not only to a better standard of clinical care, but will also assist in the identification of novel therapeutic approaches. The patient population for these studies includes individuals carrying a tentative diagnosis of the three disorders (PCD, variant CF or PHA), plus individuals suspected to have one of these disorders, but with inadequate or inconclusive diagnostic tests. Individuals in this latter category must have a preliminary clinical evaluation to evaluate for other more common disorders that may have similar manifestations including classical CF, immunodeficiency, asthma, and severe gastroesophageal reflux. We have an informal agreement with a network of pulmonologists across the United States to perform clinically-indicated (not research) preliminary clinical testing, if not directly available to patients who inquire about these studies. Blood will be collected for DNA to test for genetic mutations. The blood samples will be processed to establish a cell line (lymphocyte transformation) for a source of DNA for future genetic studies, in participants with disease. For participants unable to provide a blood sample, a buccal sample will be obtained for DNA.

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Cellular responses in the airway ciliary microenvironment from mouse models of primary ciliary dyskinesia with central pair apparatus defects

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