Early developmental phenotypes in the cystic fibrosis sheep model

The precise molecular events initiating human lung disease are often poorly characterized. Investigating prenatal events that may underlie lung disease in later life is challenging in man, but insights from the well-characterized sheep model of lung development are valuable. Here, we determine the transcriptomic signature of lung development in wild-type sheep (WT) and use a sheep model of cystic fibrosis (CF) to characterize disease associated changes in gene expression through the pseudoglandular, canalicular, saccular, and alveolar stages of lung growth and differentiation. Using gene ontology process enrichment analysis of differentially expressed genes at each developmental time point, we define changes in biological processes (BP) in proximal and distal lung from WT or CF animals. We also compare divergent BP in WT and CF animals at each time point. Next, we establish the developmental profile of key genes encoding components of ion transport and innate immunity that are pivotal in CF lung disease and validate transcriptomic data by RT-qPCR. Consistent with the known pro-inflammatory phenotype of the CF lung after birth, we observe upregulation of inflammatory response processes in the CF sheep distal lung during the saccular stage of prenatal development. These data suggest early commencement of therapeutic regimens may be beneficial.

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Transcriptomic analysis of lung development in wildtype and CFTR−/− sheep suggests an early inflammatory signature in the CF distal lung

Kerschner

Paranjapye

Schacht

et al. 2023

Funct Integr Genomics

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A retrospective analysis of sheep generated by somatic cell nuclear transfer

Liu,

Stott,

Regouski

et al. 2024

Theriogenology

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Endocrine pathology in young rabbits with cystic fibrosis

Liang,

Hou,

Chen

et al. 2024

egastro

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BackgroundCystic fibrosis (CF) is an autosomal recessive genetic disorder caused by loss-of-function mutations in the CF transmembrane conductance regulator gene. CF-related pancreatic lesions are known to cause exocrine dysfunctions such as pancreatic insufficiency, and endocrine dysfunctions, including CF-related diabetes. In a previous study, we generated rabbits with CF using CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9)-mediated gene editing.MethodsRabbits with CF were subjected to histological analysis with a focus on CF-associated pancreatic lesions. Endocrine function-related assays were conducted to evaluate CF-related pancreatic endocrine disorders in these animals.ResultsWe report that rabbits with CF develop spontaneous pancreatic lesions at a young age, characterised by pancreatic inflammation and fibrosis, vacuolar degeneration, epithelium mucus-secretory cell metaplasia and pancreatic duct dilation. The size of the pancreatic islets in the rabbits with CF is significantly smaller than that of the wild-type animals. Consistent with these pathological findings, young rabbits with CF exhibited signs of pancreatic endocrine-related disorders such as lower insulin levels and impaired glucose metabolism.ConclusionsOur results suggest that the CF rabbit could serve as a valuable model for translational research on CF-related pancreatic endocrine dysfunction.

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Early developmental phenotypes in the cystic fibrosis sheep model

Cited by 4 publications

References 37 publications

Transcriptomic analysis of lung development in wildtype and CFTR−/− sheep suggests an early inflammatory signature in the CF distal lung

Transcriptomic analysis of lung development in wildtype and CFTR−/− sheep suggests an early inflammatory signature in the CF distal lung

A retrospective analysis of sheep generated by somatic cell nuclear transfer

Endocrine pathology in young rabbits with cystic fibrosis

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