{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:04:09Z","timestamp":1790791449568,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,13]],"date-time":"2020-09-13T00:00:00Z","timestamp":1599955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["TMLGCBX16TT"],"award-info":[{"award-number":["TMLGCBX16TT"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["GALIET19G0"],"award-info":[{"award-number":["GALIET19G0"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008385","name":"Fondazione per la Ricerca sulla Fibrosi Cistica","doi-asserted-by":"publisher","award":["FFC#6\/2019"],"award-info":[{"award-number":["FFC#6\/2019"]}],"id":[{"id":"10.13039\/501100008385","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The airway epithelium contains ionocytes, a rare cell type with high expression of Forkhead Box I1 (FOXI1) transcription factor and Cystic Fibrosis Transmembrane conductance Regulator (CFTR), a chloride channel that is defective in cystic fibrosis (CF). Our aim was to verify if ionocyte development is altered in CF and to investigate the relationship between ionocytes and CFTR-dependent chloride secretion. We collected nasal cells by brushing to determine ionocyte abundance. Nasal and bronchial cells were also expanded in vitro and reprogrammed to differentiated epithelia for morphological and functional studies. We found a relatively high (~3%) ionocyte abundance in ex vivo nasal samples, with no difference between CF and control individuals. In bronchi, ionocytes instead appeared very rarely as previously reported, thus suggesting a possible proximal\u2013distal gradient in human airways. The difference between nasal and bronchial epithelial cells was maintained in culture, which suggests an epigenetic control of ionocyte development. In the differentiation phase of the culture procedure, we used two media that resulted in a different pattern of CFTR expression: confined to ionocytes or more broadly expressed. CFTR function was similar in both conditions, thus indicating that chloride secretion equally occurs irrespective of CFTR expression pattern.<\/jats:p>","DOI":"10.3390\/cells9092090","type":"journal-article","created":{"date-parts":[[2020,9,13]],"date-time":"2020-09-13T21:11:32Z","timestamp":1600031492000},"page":"2090","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Ionocytes and CFTR Chloride Channel Expression in Normal and Cystic Fibrosis Nasal and Bronchial Epithelial Cells"],"prefix":"10.3390","volume":"9","author":[{"given":"Paolo","family":"Scudieri","sequence":"first","affiliation":[{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, 16147 Genova, Italy"},{"name":"Medical Genetics Unit, Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Musante","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, 16147 Genova, Italy"},{"name":"Medical Genetics Unit, Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4265-1517","authenticated-orcid":false,"given":"Arianna","family":"Venturini","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli (NA), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Guidone","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli (NA), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Genovese","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli (NA), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Cresta","sequence":"additional","affiliation":[{"name":"Centro Fibrosi Cistica, Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5630-2428","authenticated-orcid":false,"given":"Emanuela","family":"Caci","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Istituto Giannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4510-5167","authenticated-orcid":false,"given":"Alessandro","family":"Palleschi","sequence":"additional","affiliation":[{"name":"Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca\u2019 Granda-Ospedale Maggiore Policlinico, 20122 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7515-1394","authenticated-orcid":false,"given":"Marco","family":"Poeta","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Universit\u00e0 di Napoli \u201cFederico II\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Santamaria","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Universit\u00e0 di Napoli \u201cFederico II\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1493-9767","authenticated-orcid":false,"given":"Fabiana","family":"Ciciriello","sequence":"additional","affiliation":[{"name":"Cystic Fibrosis Unit, Bambino Ges\u00f9 Children\u2019s Hospital, 00165 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzina","family":"Lucidi","sequence":"additional","affiliation":[{"name":"Cystic Fibrosis Unit, Bambino Ges\u00f9 Children\u2019s Hospital, 00165 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis J. V.","family":"Galietta","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli (NA), Italy"},{"name":"Department of Translational Medical Sciences, Universit\u00e0 di Napoli \u201cFederico II\u201d, 80131 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1513\/pats.200805-041HR","article-title":"Airway epithelial cells","volume":"5","author":"Crystal","year":"2008","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1165\/rcmb.2009-0151TR","article-title":"Advances in mucous cell metaplasia: A plug for mucus as a therapeutic focus in chronic airway disease","volume":"42","author":"Curran","year":"2010","journal-title":"Am. J. Respir. Cell. Mol. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1172\/JCI29176","article-title":"SPDEF regulates goblet cell hyperplasia in the airway epithelium","volume":"117","author":"Park","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6141","DOI":"10.1113\/jphysiol.2012.240838","article-title":"Association of TMEM16A chloride channel overexpression with airway goblet cell metaplasia","volume":"590","author":"Scudieri","year":"2012","journal-title":"J. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1164\/ajrccm.159.5.9806044","article-title":"Number and Proliferation of Clara Cells in Normal Human Airway Epithelium","volume":"159","author":"Boers","year":"1999","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"26","DOI":"10.5114\/kitp.2016.58961","article-title":"The role and importance of club cells (Clara cells) in the pathogenesis of some respiratory diseases","volume":"13","author":"Rokicki","year":"2016","journal-title":"Pol. J. Cardio-Thorac. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.stem.2014.07.012","article-title":"Repair and regeneration of the respiratory system: Complexity, plasticity, and mechanisms of lung stem cell function","volume":"15","author":"Hogan","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1146\/annurev-cellbio-100109-104040","article-title":"Epithelial Progenitor Cells in Lung Development, Maintenance, Repair, and Disease","volume":"27","author":"Rock","year":"2011","journal-title":"Annu. Rev. Cell Dev. Boil."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12771","DOI":"10.1073\/pnas.0906850106","article-title":"Basal cells as stem cells of the mouse trachea and human airway epithelium","volume":"106","author":"Rock","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1242\/dmm.006031","article-title":"Airway basal stem cells: A perspective on their roles in epithelial homeostasis and remodeling","volume":"3","author":"Rock","year":"2010","journal-title":"Dis. Model. Mech."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1242\/dev.098186","article-title":"Lung development: Orchestrating the generation and regeneration of a complex organ","volume":"141","author":"Herriges","year":"2014","journal-title":"Development"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1172\/JCI0215217","article-title":"Mucus clearance as a primary innate defense mechanism for mammalian airways","volume":"109","author":"Knowles","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_13","first-page":"1134","article-title":"Physiology of airway mucus secretion and pathophysiology of hypersecretion","volume":"52","author":"Rogers","year":"2007","journal-title":"Respir. Care"},{"key":"ref_14","first-page":"a028241","article-title":"Cilia and Mucociliary Clearance","volume":"9","author":"Ostrowski","year":"2016","journal-title":"Cold Spring Harb. Perspect. Boil."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2011\/174306","article-title":"Ion Transport by Pulmonary Epithelia","volume":"2011","author":"Hollenhorst","year":"2011","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1172\/JCI38662","article-title":"Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion","volume":"119","author":"Garcia","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1084\/jem.20120562","article-title":"Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype","volume":"209","author":"Gustafsson","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1126\/science.1255825","article-title":"Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis","volume":"345","author":"Hoegger","year":"2014","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1146\/annurev.biochem.75.103004.142532","article-title":"CFTR Function and Prospects for Therapy","volume":"77","author":"Riordan","year":"2008","journal-title":"Annu. Rev. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1146\/annurev.med.58.071905.105316","article-title":"Airway Surface Dehydration in Cystic Fibrosis: Pathogenesis and Therapy","volume":"58","author":"Boucher","year":"2007","journal-title":"Annu. Rev. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1016\/S0140-6736(16)00576-6","article-title":"Cystic fibrosis","volume":"388","author":"Elborn","year":"2016","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nature11130","article-title":"Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung","volume":"487","author":"Pezzulo","year":"2012","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/s41586-018-0393-7","article-title":"A revised airway epithelial hierarchy includes CFTR-expressing ionocytes","volume":"560","author":"Montoro","year":"2018","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s41586-018-0394-6","article-title":"A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte","volume":"560","author":"Plasschaert","year":"2018","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1038\/s41591-019-0468-5","article-title":"A cellular census of human lungs identifies novel cell states in health and in asthma","volume":"25","author":"Braga","year":"2019","journal-title":"Nat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1091\/mbc.e04-11-1010","article-title":"Characterization of wild-type and deltaF508 cystic fibrosis transmembrane regulator in human respiratory epithelia","volume":"16","author":"Kreda","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/labinvest.3780090","article-title":"Cystic Fibrosis F508del Patients Have Apically Localized CFTR in a Reduced Number of Airway Cells","volume":"80","author":"Penque","year":"2000","journal-title":"Lab. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"36016","DOI":"10.1038\/srep36016","article-title":"Goblet Cell Hyperplasia Requires High Bicarbonate Transport to Support Mucin Release","volume":"6","author":"Gorrieri","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"123616","DOI":"10.1172\/jci.insight.123616","article-title":"Increased expression of ATP12A proton pump in cystic fibrosis airways","volume":"3","author":"Scudieri","year":"2018","journal-title":"Jci Insight"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.stem.2016.05.012","article-title":"Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells","volume":"19","author":"Mou","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1113\/EP087590","article-title":"Peripheral localization of the epithelial sodium channel in the apical membrane of bronchial epithelial cells","volume":"104","author":"Musante","year":"2019","journal-title":"Exp. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1038\/ng.2745","article-title":"Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene","volume":"45","author":"Sosnay","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"eS8","DOI":"10.1016\/S0929-693X(20)30044-0","article-title":"CFTR gene variants, epidemiology and molecular pathology","volume":"27","author":"Bareil","year":"2020","journal-title":"Arch. De P\u00e9diatrie"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"18843","DOI":"10.1073\/pnas.1105787108","article-title":"Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809","volume":"108","author":"Hadida","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1056\/NEJMoa1807120","article-title":"VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles","volume":"379","author":"Keating","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.ejmech.2019.07.037","article-title":"An overview on chemical structures as \u0394F508-CFTR correctors","volume":"180","author":"Montalbano","year":"2019","journal-title":"Eur. J. Med. Chem."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/9\/2090\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:09:31Z","timestamp":1760177371000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/9\/2090"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,13]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["cells9092090"],"URL":"https:\/\/doi.org\/10.3390\/cells9092090","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,13]]}}}