Early developmental phenotypes in the cystic fibrosis sheep model
Abstract Highly effective modulator therapies for cystic fibrosis (CF) make it a treatable condition for many people. However, although CF respiratory illness occurs after birth, other organ systems particularly in the digestive tract are damaged before birth. We use an ovine model of CF to investig...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-01-01
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| Series: | FASEB BioAdvances |
| Subjects: | |
| Online Access: | https://doi.org/10.1096/fba.2022-00085 |
| _version_ | 1797955825445109760 |
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| author | Arnaud J. Van Wettere Shih‐Hsing Leir Calvin U. Cotton Misha Regouski Iuri Viotti Perisse Jenny L. Kerschner Alekh Paranjapye Zhiqiang Fan Ying Liu Makayla Schacht Kenneth L. White Irina A. Polejaeva Ann Harris |
| author_facet | Arnaud J. Van Wettere Shih‐Hsing Leir Calvin U. Cotton Misha Regouski Iuri Viotti Perisse Jenny L. Kerschner Alekh Paranjapye Zhiqiang Fan Ying Liu Makayla Schacht Kenneth L. White Irina A. Polejaeva Ann Harris |
| author_sort | Arnaud J. Van Wettere |
| collection | DOAJ |
| description | Abstract Highly effective modulator therapies for cystic fibrosis (CF) make it a treatable condition for many people. However, although CF respiratory illness occurs after birth, other organ systems particularly in the digestive tract are damaged before birth. We use an ovine model of CF to investigate the in utero origins of CF disease since the sheep closely mirrors critical aspects of human development. Wildtype (WT) and CFTR ‐/‐ sheep tissues were collected at 50, 65, 80, 100, and 120 days of gestation and term (147 days) and used for histological, electrophysiological, and molecular analysis. Histological abnormalities are evident in CFTR‐/‐ ‐/‐ animals by 80 days of gestation, equivalent to 21 weeks in humans. Acinar and ductal dilation, mucus obstruction, and fibrosis are observed in the pancreas; biliary fibrosis, cholestasis, and gallbladder hypoplasia in the liver; and intestinal meconium obstruction, as seen at birth in all large animal models of CF. Concurrently, cystic fibrosis transmembrane conductance regulator (CFTR)‐dependent short circuit current is present in WT tracheal epithelium by 80 days gestation and is absent from CFTR ‐/‐ tissues. Transcriptomic profiles of tracheal tissues confirm the early expression of CFTR and suggest that its loss does not globally impair tracheal differentiation. |
| first_indexed | 2024-04-10T23:39:11Z |
| format | Article |
| id | doaj.art-43c1be17a98f465c84755dd90b13f12b |
| institution | Directory Open Access Journal |
| issn | 2573-9832 |
| language | English |
| last_indexed | 2024-04-10T23:39:11Z |
| publishDate | 2023-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | FASEB BioAdvances |
| spelling | doaj.art-43c1be17a98f465c84755dd90b13f12b2023-01-11T11:53:18ZengWileyFASEB BioAdvances2573-98322023-01-0151132610.1096/fba.2022-00085Early developmental phenotypes in the cystic fibrosis sheep modelArnaud J. Van Wettere0Shih‐Hsing Leir1Calvin U. Cotton2Misha Regouski3Iuri Viotti Perisse4Jenny L. Kerschner5Alekh Paranjapye6Zhiqiang Fan7Ying Liu8Makayla Schacht9Kenneth L. White10Irina A. Polejaeva11Ann Harris12Department of Animal, Dairy and Veterinary Sciences Utah State University Logan Utah USADepartment of Genetics and Genome Sciences Case Western Reserve University School of Medicine Cleveland Ohio USADepartments of Pediatrics, Physiology and Biophysics Case Western Reserve University School of Medicine Cleveland Ohio USADepartment of Animal, Dairy and Veterinary Sciences Utah State University Logan Utah USADepartment of Animal, Dairy and Veterinary Sciences Utah State University Logan Utah USADepartment of Genetics and Genome Sciences Case Western Reserve University School of Medicine Cleveland Ohio USADepartment of Genetics and Genome Sciences Case Western Reserve University School of Medicine Cleveland Ohio USADepartment of Animal, Dairy and Veterinary Sciences Utah State University Logan Utah USADepartment of Animal, Dairy and Veterinary Sciences Utah State University Logan Utah USADepartment of Genetics and Genome Sciences Case Western Reserve University School of Medicine Cleveland Ohio USADepartment of Animal, Dairy and Veterinary Sciences Utah State University Logan Utah USADepartment of Animal, Dairy and Veterinary Sciences Utah State University Logan Utah USADepartment of Genetics and Genome Sciences Case Western Reserve University School of Medicine Cleveland Ohio USAAbstract Highly effective modulator therapies for cystic fibrosis (CF) make it a treatable condition for many people. However, although CF respiratory illness occurs after birth, other organ systems particularly in the digestive tract are damaged before birth. We use an ovine model of CF to investigate the in utero origins of CF disease since the sheep closely mirrors critical aspects of human development. Wildtype (WT) and CFTR ‐/‐ sheep tissues were collected at 50, 65, 80, 100, and 120 days of gestation and term (147 days) and used for histological, electrophysiological, and molecular analysis. Histological abnormalities are evident in CFTR‐/‐ ‐/‐ animals by 80 days of gestation, equivalent to 21 weeks in humans. Acinar and ductal dilation, mucus obstruction, and fibrosis are observed in the pancreas; biliary fibrosis, cholestasis, and gallbladder hypoplasia in the liver; and intestinal meconium obstruction, as seen at birth in all large animal models of CF. Concurrently, cystic fibrosis transmembrane conductance regulator (CFTR)‐dependent short circuit current is present in WT tracheal epithelium by 80 days gestation and is absent from CFTR ‐/‐ tissues. Transcriptomic profiles of tracheal tissues confirm the early expression of CFTR and suggest that its loss does not globally impair tracheal differentiation.https://doi.org/10.1096/fba.2022-00085CF developmentCFTRCF GI tractCF liverCF lungCF pancreas |
| spellingShingle | Arnaud J. Van Wettere Shih‐Hsing Leir Calvin U. Cotton Misha Regouski Iuri Viotti Perisse Jenny L. Kerschner Alekh Paranjapye Zhiqiang Fan Ying Liu Makayla Schacht Kenneth L. White Irina A. Polejaeva Ann Harris Early developmental phenotypes in the cystic fibrosis sheep model FASEB BioAdvances CF development CFTR CF GI tract CF liver CF lung CF pancreas |
| title | Early developmental phenotypes in the cystic fibrosis sheep model |
| title_full | Early developmental phenotypes in the cystic fibrosis sheep model |
| title_fullStr | Early developmental phenotypes in the cystic fibrosis sheep model |
| title_full_unstemmed | Early developmental phenotypes in the cystic fibrosis sheep model |
| title_short | Early developmental phenotypes in the cystic fibrosis sheep model |
| title_sort | early developmental phenotypes in the cystic fibrosis sheep model |
| topic | CF development CFTR CF GI tract CF liver CF lung CF pancreas |
| url | https://doi.org/10.1096/fba.2022-00085 |
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