Academic Journal
Developmental dynamics of ovine lung in health and cystic fibrosis at single-cell resolution.
| Τίτλος: | Developmental dynamics of ovine lung in health and cystic fibrosis at single-cell resolution. |
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| Συγγραφείς: | Tkachenko S; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA., Leir SH; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA., Van Wettere AJ; Department of Veterinary Clinical and Life Sciences, Utah State University, Logan, UT, USA., Perisse IV; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA., Mustafa Y; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA., Marriott CM; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA., Patrick T; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA., Liu Y; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA., White KL; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA., Polejaeva IA; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA., Harris A; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA. ann.harris@case.edu. |
| Πηγή: | Functional & integrative genomics [Funct Integr Genomics] 2026 Jul 31; Vol. 26 (1). Date of Electronic Publication: 2026 Jul 31. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Springer Country of Publication: Germany NLM ID: 100939343 Publication Model: Electronic Cited Medium: Internet ISSN: 1438-7948 (Electronic) Linking ISSN: 1438793X NLM ISO Abbreviation: Funct Integr Genomics Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Berlin : Springer, c2000- |
| Ιατρικοί όροι (MeSH): | Lung*/metabolism , Lung*/growth & development , Lung*/embryology , Lung*/pathology , Cystic Fibrosis*/genetics , Cystic Fibrosis*/pathology , Cystic Fibrosis*/metabolism, Sheep/genetics ; Sheep/growth & development ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Animals ; Single-Cell Analysis ; Female ; Mutation |
| Περίληψη: | The sheep lung has long been used to model aspects of the human lung, both its normal development and pathological changes that occur in ovine models of lung disease. The similarities between the two species provide an opportunity to investigate phases of lung development that are not accessible for investigation in humans, for example later in gestation. Here we use single cell (sc) RNA-seq to investigate the developmental dynamics of the sheep proximal and distal lung from mid gestation (80 days) through late gestation (120 days) and term (147 days). We identify changes in cell identity and abundance between the time points that illustrate many key features of mesenchymal, endothelial, and epithelial differentiation. Lastly we compare the single cell profiles through development of wildtype (WT) sheep with those of animals of the same breed engineered to have a loss-of-function mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Mutations in CFTR cause cystic fibrosis (CF) and the CFTR-/- sheep exhibit many features of CF in humans. The results identify cellular signatures in the CFTR-/- lung before birth that may facilitate the understanding of clinical features of CF in early postnatal life. (© 2026. The Author(s).) |
| Competing Interests: | Declarations. Competing interests: The authors declare no competing interests. |
| References: | Barry JS, Anthony RV (2008) The pregnant sheep as a model for human pregnancy. Theriogenology 69:55–67. (PMID: 10.1016/j.theriogenology.2007.09.02117976713) Basil MC, Cardenas-Diaz FL, Kathiriya JJ, Morley MP, Carl J, Brumwell AN, Katzen J, Slovik KJ, Babu A, Zhou S, Kremp MM, McCauley KB, Li S, Planer JD, Hussain SS, Liu X, Windmueller R, Ying Y, Stewart KM, Oyster M, Christie JD, Diamond JM, Engelhardt JF, Cantu E, Rowe SM, Kotton DN, Chapman HA, Morrisey EE (2022) Human distal airways contain a multipotent secretory cell that can regenerate alveoli. Nature 604:120–126. (PMID: 10.1038/s41586-022-04552-0353550139297319) Burri PH (1984) Fetal and postnatal development of the lung. Annu Rev Physiol 46:617–628. (PMID: 10.1146/annurev.ph.46.030184.0031536370120) Cao S, Feng H, Yi H, Pan M, Lin L, Zhang YS, Feng Z, Liang W, Cai B, Li Q, Xiong Z, Shen Q, Ke M, Zhao X, Chen H, He Q, Min M, Cai Q, Liu H, Wang J, Pei D, Chen J, Ma Y (2023) Single-cell RNA sequencing reveals the developmental program underlying proximal-distal patterning of the human lung at the embryonic stage. Cell Res 33:421–433. (PMID: 10.1038/s41422-023-00802-63708573210119843) Carraro G, Langerman J, Sabri S, Lorenzana Z, Purkayastha A, Zhang G, Konda B, Aros CJ, Calvert BA, Szymaniak A, Wilson E, Mulligan M, Bhatt P, Lu J, Vijayaraj P, Yao C, Shia DW, Lund AJ, Israely E, Rickabaugh TM, Ernst J, Mense M, Randell SH, Vladar EK, Ryan AL, Plath K, Mahoney JE, Stripp BR, Gomperts BN (2021) Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition. Nat Med 7:806–814. (PMID: 10.1038/s41591-021-01332-7) Deprez M, Zaragosi LE, Truchi M, Becavin C, Ruiz Garcia S, Arguel MJ, Plaisant M, Magnone V, Lebrigand K, Abelanet S, Brau F, Paquet A, Pe’er D, Marquette CH, Leroy S, Barbry P (2020) A single-cell atlas of the human healthy airways. Am J Respir Crit Care Med 202:1636–1645. (PMID: 10.1164/rccm.201911-2199OC32726565) Fan Z, Perisse IV, Cotton CU, Regouski M, Meng Q, Domb C, Van Wettere AJ, Wang Z, Harris A, White KL, Polejaeva IA (2018) A sheep model of cystic fibrosis generated by CRISPR/Cas9 disruption of the CFTR gene. JCI Insight 3:e123529. (PMID: 10.1172/jci.insight.123529302828316237476) Firsova AB, Marco Salas S, Kuemmerle LB, Abalo XM, Sountoulidis A, Larsson L, Mahbubani KT, Theelke J, Andrusivova Z, Alonso Galicia L, Liontos A, Balassa T, Kovacs F, Horvath P, Chen Y, Gote-Schniering J, Stoleriu MG, Behr J, Meyer KB, Timens W, Schiller HB, Luecken MD, Theis FJ, Lundeberg J, Nilsson M, Nawijn MC, Samakovlis C (2025) Spatial single-cell atlas reveals regional variations in healthy and diseased human lung. Nat Commun 16:9745. (PMID: 10.1038/s41467-025-65704-04119346812589588) Hao Y, Hao S, Andersen-Nissen E, Mauck WM 3rd, Zheng S, Butler A, Lee MJ, Wilk AJ, Darby C, Zager M, Hoffman P, Stoeckius M, Papalexi E, Mimitou EP, Jain J, Srivastava A, Stuart T, Fleming LM, Yeung B, Rogers AJ, McElrath JM, Blish CA, Gottardo R, Smibert P, Satija R (2021) Integrated analysis of multimodal single-cell data. Cell 184:3573–87 e29. (PMID: 10.1016/j.cell.2021.04.048340621198238499) He P, Lim K, Sun D, Pett JP, Jeng Q, Polanski K, Dong Z, Bolt L, Richardson L, Mamanova L, Dabrowska M, Wilbrey-Clark A, Madissoon E, Tuong ZK, Dann E, Suo C, Goh I, Yoshida M, Nikolic MZ, Janes SM, He X, Barker RA, Teichmann SA, Marioni JC, Meyer KB, Rawlins EL (2022) A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates. Cell 185(4841–60):e25. Nikolic MZ, Sun D, Rawlins EL (2018) Human lung development: recent progress and new challenges. Development 145(16):dev163485. Kadur Lakshminarasimha Murthy P, Sontake V, Tata A, Kobayashi Y, Macadlo L, Okuda K, Conchola AS, Nakano S, Gregory S, Miller LA, Spence JR, Engelhardt JF, Boucher RC, Rock JR, Randell SH, Tata PR (2022) Human distal lung maps and lineage hierarchies reveal a bipotent progenitor. Nature 604:111–119. (PMID: 10.1038/s41586-022-04541-3353550189169066) Kerschner JL, Paranjapye A, Schacht M, Meckler F, Huang F, Bebek G, Van Wettere AJ, Regouski M, Perisse IV, White KL, Polejaeva IA, Leir SH, Harris A (2023) Transcriptomic analysis of lung development in wildtype and CFTR(-/-) sheep suggests an early inflammatory signature in the CF distal lung. Funct Integr Genomics 23:135. (PMID: 10.1007/s10142-023-01050-y3708573310121546) Leir SH, Tkachenko S, Paranjapye A, Meckler F, Van Wettere AJ, Kerschner JL, Kuznetsov E, Schacht M, Gillurkar P, Regouski M, Viotti Perisse I, Marriott CM, Liu Y, Bunderson I, White KL, Polejaeva IA, Harris A (2024) Stellate cells are in utero markers of pancreatic disease in cystic fibrosis. Mol Med 30:115. (PMID: 10.1186/s10020-024-00871-23911296511304907) Leir SH, Tkachenko S, Paranjapye A, Van Wettere AJ, Kerschner JL, Perisse IV, Marriott CM, Patrick T, Liu Y, White KL, Polejaeva IA, Harris A (2025) Cellular imbalance in proximal and distal lung of CFTR(-/-) sheep in utero and at birth. Mol Med 31:231. (PMID: 10.1186/s10020-025-01266-74049513512153128) Meckler F, Van Wettere AJ, Umrigar A, Bebek G, Leir SH, Viotti Perisse I, Lovrenert K, White KL, Polejaeva IA, Harris A (2025) Molecular phenotypes in early gallbladder and liver disease in the CFTR(-/-)sheep highlight aspects of CF-relevant hepatobiliary disease. Physiol Genomics 57(12):682-94. Meeusen EN, Snibson KJ, Hirst SJ, Bischof RJ (2009) Sheep as a model species for the study and treatment of human asthma and other respiratory diseases. Drug Discov Today Dis Model. https://doi.org/10.1016/j.ddmod.2009.12.002. (PMID: 10.1016/j.ddmod.2009.12.002) Miller AJ, Yu Q, Czerwinski M, Tsai YH, Conway RF, Wu A, Holloway EM, Walker T, Glass IA, Treutlein B, Camp JG, Spence JR (2020) In vitro and in vivo development of the human airway at single-cell resolution. Dev Cell 53:117–28 e6. (PMID: 10.1016/j.devcel.2020.01.033321093867396815) Miller SA, Policastro RA, Sriramkumar S, Lai T, Huntington TD, Ladaika CA, Kim D, Hao C, Zentner GE, O’Hagan HM (2021) LSD1 and aberrant DNA methylation mediate persistence of enteroendocrine progenitors that support BRAF-mutant colorectal cancer. Can Res 81:3791–3805. (PMID: 10.1158/0008-5472.CAN-20-3562) Montoro DT, Haber AL, Biton M, Vinarsky V, Lin B, Birket SE, Yuan F, Chen S, Leung HM, Villoria J, Rogel N, Burgin G, Tsankov AM, Waghray A, Slyper M, Waldman J, Nguyen L, Dionne D, Rozenblatt-Rosen O, Tata PR, Mou H, Shivaraju M, Bihler H, Mense M, Tearney GJ, Rowe SM, Engelhardt JF, Regev A, Rajagopal J (2018) A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 560:319–324. (PMID: 10.1038/s41586-018-0393-7300690446295155) Plasschaert LW, Zilionis R, Choo-Wing R, Savova V, Knehr J, Roma G, Klein AM, Jaffe AB (2018) A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature 560:377–381. (PMID: 10.1038/s41586-018-0394-6300690466108322) Scheerlinck JP, Snibson KJ, Bowles VM, Sutton P (2008) Biomedical applications of sheep models: from asthma to vaccines. Trends Biotechnol 26:259–266. (PMID: 10.1016/j.tibtech.2008.02.00218353472) Sountoulidis A, Marco Salas S, Braun E, Avenel C, Bergenstrahle J, Theelke J, Vicari M, Czarnewski P, Liontos A, Abalo X, Andrusivova Z, Mirzazadeh R, Asp M, Li X, Hu L, Sariyar S, Martinez Casals A, Ayoglu B, Firsova A, Michaelsson J, Lundberg E, Wahlby C, Sundstrom E, Linnarsson S, Lundeberg J, Nilsson M, Samakovlis C (2023) A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung. Nat Cell Biol 25:351–365. (PMID: 10.1038/s41556-022-01064-x366467919928586) Sun X, Perl AK, Li R, Bell SM, Sajti E, Kalinichenko VV, Kalin TV, Misra RS, Deshmukh H, Clair G, Kyle J, Crotty Alexander LE, Masso-Silva JA, Kitzmiller JA, Wikenheiser-Brokamp KA, Deutsch G, Guo M, Du Y, Morley MP, Valdez MJ, Yu HV, Jin K, Bardes EE, Zepp JA, Neithamer T, Basil MC, Zacharias WJ, Verheyden J, Young R, Bandyopadhyay G, Lin S, Ansong C, Adkins J, Salomonis N, Aronow BJ, Xu Y, Pryhuber G, Whitsett J, Morrisey EE, Nhlbi LungMAP Consortium (2022) A census of the lung: CellCards from LungMAP. Dev Cell 57:112–45.e2. (PMID: 10.1016/j.devcel.2021.11.00734936882) Travaglini KJ, Nabhan AN, Penland L, Sinha R, Gillich A, Sit RV, Chang S, Conley SD, Mori Y, Seita J, Berry GJ, Shrager JB, Metzger RJ, Kuo CS, Neff N, Weissman IL, Quake SR, Krasnow MA (2020) A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature 587:619–625. (PMID: 10.1038/s41586-020-2922-4332089467704697) Vieira Braga FA, Kar G, Berg M, Carpaij OA, Polanski K, Simon LM, Brouwer S, Gomes T, Hesse L, Jiang J, Fasouli ES, Efremova M, Vento-Tormo R, Talavera-Lopez C, Jonker MR, Affleck K, Palit S, Strzelecka PM, Firth HV, Mahbubani KT, Cvejic A, Meyer KB, Saeb-Parsy K, Luinge M, Brandsma CA, Timens W, Angelidis I, Strunz M, Koppelman GH, van Oosterhout AJ, Schiller HB, Theis FJ, van den Berge M, Nawijn MC, Teichmann SA (2019) A cellular census of human lungs identifies novel cell states in health and in asthma. Nat Med 25:1153–1163. (PMID: 10.1038/s41591-019-0468-531209336) Viotti Perisse I, Fan Z, Van Wettere A, Liu Y, Leir SH, Keim J, Regouski M, Wilson MD, Cholewa KM, Mansbach SN, Kelley TJ, Wang Z, Harris A, White KL, Polejaeva IA (2021) Sheep models of F508del and G542X cystic fibrosis mutations show cellular responses to human therapeutics. FASEB Bioadv 3:841–854. (PMID: 10.1096/fba.2021-00043346323188493969) Van Wettere AJ, Leir SH, Cotton CU, Regouski M, Perisse IV, Kerschner JL, Paranjapye A, Fan ZQ, Liu Y, Schacht M, White KL, Polejaeva IA, Harris A (2022) Early developmental phenotypes in the cystic fibrosis sheep model. Faseb Bioadvances 5:13–26. (PMID: 10.1096/fba.2022-00085366438959832529) Sikkema L, Ramirez-Suastegui C, Strobl DC, Gillett TE, Zappia L, Madissoon E, Markov NS, Zaragosi LE, Ji Y, Ansari M, Arguel MJ, Apperloo L, Banchero M, Becavin C, BergM, Chichelnitskiy E, Chung MI, Collin A, Gay ACA, Gote-Schniering J, Hooshiar Kashani B, Inecik K, Jain M, Kapellos TS, Kole TM, Leroy S, Mayr CH, Oliver AJ, von Papen M, Peter L, Taylor CJ, Walzthoeni T, Xu C, Bui LT, De Donno C, Dony L, Faiz A, Guo M, Gutierrez AJ, HeumosL, Huang N, Ibarra IL, Jackson ND, Kadur Lakshminarasimha Murthy P, Lotfollahi M, Tabib T, Talavera-Lopez C, Travaglini KJ, Wilbrey-Clark A, Worlock KB, Yoshida M, Consortium Lung Biological Network, van den Berge M, Bosse Y, Desai TJ, Eickelberg O, Kaminski N, Krasnow MA, Lafyatis R, Nikolic MZ, Powell JE, Rajagopal J, Rojas M, Rozenblatt-Rosen O, Seibold MA, Sheppard D, Shepherd DP, Sin DD, Timens W, Tsankov AM, Whitsett J, Xu Y, Banovich NE, Barbry P, Duong TE, Falk CS, Meyer KB, Kropski JA, Pe’er D, Schiller HB, Tata PR, Schultze JL, Teichmann SA, Misharin AV, Nawijn MC, Luecken MD, Theis FJ (2023) An integrated cell atlas of the lung in health and disease. Nat Med 29:1563–1577. |
| Grant Information: | Poleja23P0 Cystic Fibrosis Foundation; Harris 21G0, Harris 23P0 Cystic Fibrosis Foundation; W4171 US Department of Agriculture Multistate Project; Project 1343 Utah Agricultural Experiment Station |
| Contributed Indexing: | Keywords: CFTR; Cystic fibrosis (CF); Lung development; ScRNA-seq; Sheep |
| Substance Nomenclature: | 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) |
| Entry Date(s): | Date Created: 20260730 Date Completed: 20260731 Latest Revision: 20260802 |
| Update Code: | 20260802 |
| PubMed Central ID: | PMC13424028 |
| DOI: | 10.1007/s10142-026-01981-2 |
| PMID: | 42533177 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1438-7948 |
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| DOI: | 10.1007/s10142-026-01981-2 |