{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T20:13:02Z","timestamp":1781899982056,"version":"3.54.5"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T00:00:00Z","timestamp":1645488000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>Fetal endoscopic tracheal occlusion (FETO) is an emerging surgical therapy for congenital diaphragmatic hernia (CDH). Ovine and rabbit data suggested altered lung epithelial cell populations after tracheal occlusion (TO) with transcriptomic signatures implicating basal cells. To test this hypothesis, we deconvolved mRNA sequencing (mRNA-seq) data and used quantitative image analysis in fetal rabbit lung TO, which had increased basal cells and reduced ciliated cells after TO. In a fetal mouse TO model, flow cytometry showed increased basal cells, and immunohistochemistry demonstrated basal cell extension to subpleural airways. Nuclear Yap, a known regulator of basal cell fate, was increased in TO lung, and Yap ablation on the lung epithelium abrogated TO-mediated basal cell expansion. mRNA-seq of TO lung showed increased activity of downstream Yap genes. Human lung specimens with congenital and fetal tracheal occlusion had clusters of subpleural basal cells that were not present in the control. TO increases lung epithelial cell nuclear Yap, leading to basal cell expansion.<\/jats:p>","DOI":"10.3389\/fped.2021.780166","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T10:56:08Z","timestamp":1645527368000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Fetal Tracheal Occlusion Increases Lung Basal Cells via Increased Yap Signaling"],"prefix":"10.3389","volume":"9","author":[{"given":"Vincent","family":"Serapiglia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad A.","family":"Stephens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashika","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emrah","family":"Aydin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Oria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Marotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose L.","family":"Peiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian M.","family":"Varisco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1097\/SLA.0000000000001675","article-title":"Fetal Tracheal occlusion for severe pulmonary hypoplasia in isolated congenital diaphragmatic hernia: a systematic review and meta-analysis of survival","volume":"264","author":"Al-Maary","year":"2016","journal-title":"Ann Surg."},{"key":"B2","first-page":"82","article-title":"Prenatally diagnosed severe CDH: mortality and morbidity remain high","author":"Coughlin","year":"2015","journal-title":"J Pediatr Surg."},{"key":"B3","first-page":"174","article-title":"Correction of congenital diaphragmatic hernia in utero. I The model: intrathoracic balloon produces fatal pulmonary hypoplasia","volume":"88","author":"Harrison","year":"1980","journal-title":"Surgery."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e237","DOI":"10.1371\/journal.pmed.0040237","article-title":"Surfactant maturation is not delayed in human fetuses with diaphragmatic hernia","volume":"4","author":"Boucherat","year":"2007","journal-title":"PLoS Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"L44","DOI":"10.1152\/ajplung.00342.2004","article-title":"Congenital diaphragmatic hernia, tracheal occlusion, thyroid transcription factor-1, and fetal pulmonary epithelial maturation","volume":"289","author":"Chapin","year":"2005","journal-title":"Am J Physiol Lung Cell Mol Physiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1002\/ppul.20175","article-title":"Surfactant protein expression is increased in the ipsilateral but not contralateral lungs of fetal sheep with left-sided diaphragmatic hernia","volume":"39","author":"Davey","year":"2005","journal-title":"Pediatr Pulmonol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"L311","DOI":"10.1152\/ajplung.00122.2015","article-title":"Increased TGF-beta: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?","volume":"310","author":"Vuckovic","year":"2016","journal-title":"Am J Physiol Lung Cell Mol Physiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1242\/dmm.021626","article-title":"Pulmonary transcriptome analysis in the surgically induced rabbit model of diaphragmatic hernia treated with fetal tracheal occlusion","volume":"9","author":"Engels","year":"2016","journal-title":"DMM."},{"key":"B9","doi-asserted-by":"publisher","first-page":"22","DOI":"10.2119\/molmed.2016.00121","article-title":"Excessive reversal of epidermal growth factor receptor and ephrin signaling following tracheal occlusion in rabbit model of congenital diaphragmatic hernia","author":"Varisco","year":"2016","journal-title":"Mol Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"L1028","DOI":"10.1152\/ajplung.00148.2018","article-title":"Proteomic profiling of tracheal fluid in an ovine model of congenital diaphragmatic hernia and fetal tracheal occlusion","volume":"315","author":"Peiro","year":"2018","journal-title":"Am J Physiol Lung Cell Mol Physiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.jss.2019.12.025","article-title":"Heterogeneous response in rabbit fetal diaphragmatic hernia lungs after tracheal occlusion","volume":"250","author":"Dobrinskikh","year":"2019","journal-title":"J Surg Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.jss.2018.04.028","article-title":"Fetal tracheal occlusion in mice: a novel transuterine method","volume":"229","author":"Aydin","year":"2018","journal-title":"J Surg Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3791\/61772-v","article-title":"Transuterine fetal tracheal occlusion model in mice","author":"Aydin","year":"2021","journal-title":"JoVE."},{"key":"B14","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1093\/jmcb\/mju046","article-title":"Hippo\/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung","volume":"7","author":"Lange","year":"2015","journal-title":"J Mol Cell Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.devcel.2014.06.003","article-title":"The hippo pathway effector Yap controls patterning and differentiation of airway epithelial progenitors","volume":"30","author":"Mahoney","year":"2014","journal-title":"Dev Cell"},{"key":"B16","doi-asserted-by":"publisher","first-page":"dev163105","DOI":"10.1242\/dev.163105","article-title":"Lats inactivation reveals hippo function in alveolar type I cell differentiation during lung transition to air breathing","volume":"145","author":"Nantie","year":"2018","journal-title":"Development."},{"key":"B17","doi-asserted-by":"publisher","first-page":"dev175810","DOI":"10.1242\/dev.175810","article-title":"Yap and its subcellular localization have distinct compartment-specific roles in the developing lung","volume":"146","author":"Soldt","year":"2019","journal-title":"Development."},{"key":"B18","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1096\/fj.15-277350","article-title":"Stretch regulates expression and binding of chymotrypsin-like elastase 1 in the postnatal lung","volume":"30","author":"Joshi","year":"2016","journal-title":"FASEB."},{"key":"B19","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1136.\/thoraxjnl-2015-207035","article-title":"\u201cLungGENS\u201d: a web-based tool for mapping single-cell gene expression in the developing lung","volume":"70","author":"Du","year":"2015","journal-title":"Thorax."},{"key":"B20","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics."},{"key":"B21","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"W305","DOI":"10.1093\/nar\/gkp427","article-title":"ToppGene Suite for gene list enrichment analysis and candidate gene prioritization","volume":"37","author":"Chen","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Kr\u00e4mer","year":"2014","journal-title":"Bioinformatics."},{"key":"B24","volume-title":"R: A Language and Environment for Statistical Computing","year":"2019"},{"key":"B25","unstructured":"ggpubr: Publication Ready Plots-Articles-STHDA\n            KassambaraA\n          2020"},{"key":"B26","volume-title":"rstatix: Pipe-Friendly Framework for Basic Statistical","author":"Kassambara","year":"2020"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1101\/gad.274027.115","article-title":"Mechanisms of Hippo pathway regulation","volume":"30","author":"Meng","year":"2016","journal-title":"Genes Dev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1016\/j.devcel.2018.03.001","article-title":"Spatial-temporal lineage restrictions of embryonic p63(+) progenitors establish distinct stem cell pools in adult airways","volume":"44","author":"Yang","year":"2018","journal-title":"Dev Cell."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1016\/j.stem.2021.04.026","article-title":"Age-dependent alveolar epithelial plasticity orchestrates lung homeostasis and regeneration","volume":"28","author":"Penkala","year":"2021","journal-title":"Cell Stem Cell."},{"key":"B30","doi-asserted-by":"publisher","first-page":"L814","DOI":"10.1152\/ajplung.00484.2020","article-title":"Stretch increases alveolar type 1 cell number in fetal lungs through ROCK-Yap\/Taz pathway","volume":"321","author":"Nguyen","year":"2021","journal-title":"Am J Physiol Lung Cell Mol Physiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1038\/nature14112","article-title":"Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury","volume":"517","author":"Vaughan","year":"2015","journal-title":"Nature."},{"key":"B32","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1186\/s12931-020-01442-9","article-title":"Cell-specific expression of lung disease risk-related genes in the human small airway epithelium","volume":"21","author":"Zuo","year":"2020","journal-title":"Respir Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.jss.2020.11.080","article-title":"Reversible fetal tracheal occlusion in mice: a novel minimal invasive technique","volume":"260","author":"Aydin","year":"2021","journal-title":"J Surg Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1242\/dev.129122","article-title":"Developmental origin of lung macrophage diversity","volume":"143","author":"Tan","year":"2016","journal-title":"Development."},{"key":"B35","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.ydbio.2017.03.020","article-title":"Temporal, spatial, and phenotypical changes of PDGFRalpha expressing fibroblasts during late lung development","volume":"425","author":"Endale","year":"2017","journal-title":"Dev Biol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.matbio.2020.05.002","article-title":"The elephant in the lung: Integrating lineage-tracing, molecular markers, and single cell sequencing data to identify distinct fibroblast populations during lung development and regeneration","author":"Riccetti","year":"2020","journal-title":"Matrix Biol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1159\/000254485","article-title":"Lung tissue blood perfusion changes induced by in utero tracheal occlusion in a rabbit model of congenital diaphragmatic hernia","volume":"26","author":"Cruz-Martinez","year":"2009","journal-title":"Fetal Diagn Ther."},{"key":"B38","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/pr.2013.244","article-title":"Airway and vascular maturation stimulated by tracheal occlusion do not correlate in the rabbit model of diaphragmatic hernia","volume":"75","author":"Prat Ortells","year":"2014","journal-title":"Pediatr Res."}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2021.780166\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T10:56:13Z","timestamp":1645527373000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2021.780166\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,22]]},"references-count":38,"alternative-id":["10.3389\/fped.2021.780166"],"URL":"https:\/\/doi.org\/10.3389\/fped.2021.780166","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.09.17.21263741","asserted-by":"object"}]},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,22]]},"article-number":"780166"}}