Cellular imbalance in proximal and distal lung of CFTR −/− sheep in utero and at birth
Abstract Background The Lung is the major focus of therapeutic approaches for the inherited disorder cystic fibrosis (CF) as without treatment lung disease is life-limiting. However, the initiating events that predispose the CF lung to cycles of infection, inflammation and resultant tissue damage ar...
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2025-06-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01266-7 |
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| author | Shih-Hsing Leir Svyatoslav Tkachenko Alekh Paranjapye Arnaud J. Van Wettere Jenny L. Kerschner Iuri Viotti Perisse Cheyenne M. Marriott Tayler Patrick Ying Liu Kenneth L. White Irina A. Polejaeva Ann Harris |
| author_facet | Shih-Hsing Leir Svyatoslav Tkachenko Alekh Paranjapye Arnaud J. Van Wettere Jenny L. Kerschner Iuri Viotti Perisse Cheyenne M. Marriott Tayler Patrick Ying Liu Kenneth L. White Irina A. Polejaeva Ann Harris |
| author_sort | Shih-Hsing Leir |
| collection | DOAJ |
| description | Abstract Background The Lung is the major focus of therapeutic approaches for the inherited disorder cystic fibrosis (CF) as without treatment lung disease is life-limiting. However, the initiating events that predispose the CF lung to cycles of infection, inflammation and resultant tissue damage are still unclear. Inflammation may occur in the CF lung prior to birth in human and several large animal models suggesting an in utero origin for the disease and encouraging further studies prior to birth. Methods Here we used the sheep model of CF (CFTR −/− ) and age-matched wild-type (WT) sheep of the same breed to investigate the single cell transcriptomes of proximal and distal lung tissue at 80 days and 120 days of gestation and at term (147 days). Single cell RNA-seq was performed on tissues from 4 to 7 animals of each genotype (WT and CFTR −/− ) at each time point. Results At term, FOXJ1-expressing ciliated cells are overrepresented in both lung regions from CFTR −/− lambs, while secretory epithelial and basal cells are underrepresented in proximal lung, as are T cells and monocytes in distal lung. The imbalance in ciliated and basal cells was confirmed by immunohistochemistry. At 120 days of gestation, lymphoid cells are slightly more abundant in proximal and distal lung from CFTR −/− animals compared to WT, consistent with the transient CF-associated inflammatory response in utero. At 80 days of gestation, T and B cells are underrepresented in both lung regions. Conclusions The differences in epithelial cell abundance observed in the CFTR −/− lambs at term may reflect sequelae from the loss of CFTR on lung development and differentiation in utero. These findings provide novel insights into the cellular mechanisms of pathology and may be relevant to the design of new therapeutic approaches for CF lung disease. |
| format | Article |
| id | doaj-art-14a4d68cf4564e3494db6026b181a9fa |
| institution | DOAJ |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj-art-14a4d68cf4564e3494db6026b181a9fa2025-08-20T03:21:03ZengBMCMolecular Medicine1528-36582025-06-0131112410.1186/s10020-025-01266-7Cellular imbalance in proximal and distal lung of CFTR −/− sheep in utero and at birthShih-Hsing Leir0Svyatoslav Tkachenko1Alekh Paranjapye2Arnaud J. Van Wettere3Jenny L. Kerschner4Iuri Viotti Perisse5Cheyenne M. Marriott6Tayler Patrick7Ying Liu8Kenneth L. White9Irina A. Polejaeva10Ann Harris11Department of Genetics and Genome Sciences, Case Western Reserve University School of MedicineDepartment of Genetics and Genome Sciences, Case Western Reserve University School of MedicineDepartment of Genetics and Genome Sciences, Case Western Reserve University School of MedicineDepartment of Animal, Dairy and Veterinary Sciences, Utah State UniversityDepartment of Genetics and Genome Sciences, Case Western Reserve University School of MedicineDepartment of Animal, Dairy and Veterinary Sciences, Utah State UniversityDepartment of Animal, Dairy and Veterinary Sciences, Utah State UniversityDepartment of Animal, Dairy and Veterinary Sciences, Utah State UniversityDepartment of Animal, Dairy and Veterinary Sciences, Utah State UniversityDepartment of Animal, Dairy and Veterinary Sciences, Utah State UniversityDepartment of Animal, Dairy and Veterinary Sciences, Utah State UniversityDepartment of Genetics and Genome Sciences, Case Western Reserve University School of MedicineAbstract Background The Lung is the major focus of therapeutic approaches for the inherited disorder cystic fibrosis (CF) as without treatment lung disease is life-limiting. However, the initiating events that predispose the CF lung to cycles of infection, inflammation and resultant tissue damage are still unclear. Inflammation may occur in the CF lung prior to birth in human and several large animal models suggesting an in utero origin for the disease and encouraging further studies prior to birth. Methods Here we used the sheep model of CF (CFTR −/− ) and age-matched wild-type (WT) sheep of the same breed to investigate the single cell transcriptomes of proximal and distal lung tissue at 80 days and 120 days of gestation and at term (147 days). Single cell RNA-seq was performed on tissues from 4 to 7 animals of each genotype (WT and CFTR −/− ) at each time point. Results At term, FOXJ1-expressing ciliated cells are overrepresented in both lung regions from CFTR −/− lambs, while secretory epithelial and basal cells are underrepresented in proximal lung, as are T cells and monocytes in distal lung. The imbalance in ciliated and basal cells was confirmed by immunohistochemistry. At 120 days of gestation, lymphoid cells are slightly more abundant in proximal and distal lung from CFTR −/− animals compared to WT, consistent with the transient CF-associated inflammatory response in utero. At 80 days of gestation, T and B cells are underrepresented in both lung regions. Conclusions The differences in epithelial cell abundance observed in the CFTR −/− lambs at term may reflect sequelae from the loss of CFTR on lung development and differentiation in utero. These findings provide novel insights into the cellular mechanisms of pathology and may be relevant to the design of new therapeutic approaches for CF lung disease.https://doi.org/10.1186/s10020-025-01266-7Cystic fibrosis (CF)In uteroLung developmentScRNA-seqCiliated cells |
| spellingShingle | Shih-Hsing Leir Svyatoslav Tkachenko Alekh Paranjapye Arnaud J. Van Wettere Jenny L. Kerschner Iuri Viotti Perisse Cheyenne M. Marriott Tayler Patrick Ying Liu Kenneth L. White Irina A. Polejaeva Ann Harris Cellular imbalance in proximal and distal lung of CFTR −/− sheep in utero and at birth Molecular Medicine Cystic fibrosis (CF) In utero Lung development ScRNA-seq Ciliated cells |
| title | Cellular imbalance in proximal and distal lung of CFTR −/− sheep in utero and at birth |
| title_full | Cellular imbalance in proximal and distal lung of CFTR −/− sheep in utero and at birth |
| title_fullStr | Cellular imbalance in proximal and distal lung of CFTR −/− sheep in utero and at birth |
| title_full_unstemmed | Cellular imbalance in proximal and distal lung of CFTR −/− sheep in utero and at birth |
| title_short | Cellular imbalance in proximal and distal lung of CFTR −/− sheep in utero and at birth |
| title_sort | cellular imbalance in proximal and distal lung of cftr sheep in utero and at birth |
| topic | Cystic fibrosis (CF) In utero Lung development ScRNA-seq Ciliated cells |
| url | https://doi.org/10.1186/s10020-025-01266-7 |
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