{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T13:03:09Z","timestamp":1780491789750,"version":"3.54.1"},"posted":{"date-parts":[[2026,5,30]]},"group-title":"Genomics","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:00:00Z","timestamp":1780099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which the earliest cellular events driving fibrosis remain poorly defined. Here, we analyzed lung samples from three independent and unique cohorts of patients with early disease and preserved lung function (Florence, NIH, Forli), applying an integrated multi-modal approach combining single-nucleus RNA sequencing, bulk transcriptomics, immunostaining, and spatial transcriptomics.<\/jats:p>\n                <jats:p>Single nuclear RNA sequencing of samples obtained by diagnostic bronchoscopic cryobiopsy (Florence, n= 22) revealed that early IPF is characterized by a marked shift in alveolar epithelial composition, with loss of AT1 and AT2 cells and the emergence of aberrant basaloid cells and alveolar epithelial intermediate cells. These populations exhibited transcriptional programs associated with epithelial plasticity and profibrotic signaling and closely resembled those observed in end-stage IPF. Higher proportions of aberrant basaloid and alveolar epithelial intermediate cells were associated with subsequent disease progression, whereas AT2 cell abundance correlated with preserved lung function. Fibrotic CTHRC1+ fibroblasts are largely restricted to advanced disease, while endothelial remodeling and inflammatory fibroblast states are already evident in early IPF. Spatial transcriptomic analyses confirmed early disruption of the alveolar niche, with replacement of normal epithelial\u2013capillary interactions by aberrant epithelial and venous endothelial cells (Forli, n= 24); the findings were replicated through single cell RNA sequencing of samples obtained by video assisted thoracoscopy two decades earlier (NIH n=9).<\/jats:p>\n                <jats:p>Together, these findings identify that alveolar niche remodeling with loss of its normal components, and emergence of aberrant basaloid cells are features of early IPF, highlighting epithelial dysfunction as a key potential target for therapeutic interventions in early disease.<\/jats:p>","DOI":"10.64898\/2026.05.27.727792","type":"posted-content","created":{"date-parts":[[2026,5,31]],"date-time":"2026-05-31T01:10:13Z","timestamp":1780189813000},"source":"Crossref","is-referenced-by-count":0,"title":["Alveolar niche disruption and aberrant epithelial reprogramming are early hallmarks of idiopathic pulmonary fibrosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8639-8667","authenticated-orcid":false,"given":"Aurelien","family":"Justet","sequence":"first","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"},{"name":"Universit\u00e9 de Caen Normandie, CNRS, Normandie Univ, ISTCT UMR6030, CYCERON, F-14000 CAEN, France"},{"name":"Department of Pulmonary Medicine, University Hospital of Caen"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venerino","family":"Poletti","sequence":"additional","affiliation":[{"name":"Department of Medical Specialties, GB Morgagni Hospital, Forl\u00ed, Italy"},{"name":"DIMES, University of Bologna, Bolagna, Italy"},{"name":"Department of respiratory diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Coarfa","sequence":"additional","affiliation":[{"name":"Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nebal","family":"Abu Hussein","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Adams","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Waich","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agshin","family":"Balayev","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8688-9004","authenticated-orcid":false,"given":"Xiting","family":"Yan","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"},{"name":"Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyu","family":"Cai","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"},{"name":"Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah","family":"Moussa","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Caen Normandie, CNRS, Normandie Univ, ISTCT UMR6030, CYCERON, F-14000 CAEN, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5468-0281","authenticated-orcid":false,"given":"Ruben","family":"De Man","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johad","family":"Khoury","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7714-8076","authenticated-orcid":false,"given":"Jonas C","family":"Schupp","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"},{"name":"Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany"},{"name":"Clinic for Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany"},{"name":"Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan D","family":"Zuluaga","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Zhao","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Villalba","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farida","family":"Ahangari","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A","family":"Ochsner","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Manning","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy J","family":"Introne","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Homer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadette R","family":"Gochuico","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA"},{"name":"Early Clinical Development, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurens","family":"De Sadeleer","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Carducci","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Interventional Pulmonology Unit, Careggi University Hospital, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E Ruiz","family":"Echartea","sequence":"additional","affiliation":[{"name":"Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"He","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart M","family":"Vanaudenaerde","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim","family":"Wuyts","sequence":"additional","affiliation":[{"name":"Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Ravaglia","sequence":"additional","affiliation":[{"name":"Department of Medical Specialties, GB Morgagni Hospital, Forl\u00ed, Italy"},{"name":"DIMES, University of Bologna, Bolagna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Rosas","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Tomassetti","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Interventional Pulmonology Unit, Careggi University Hospital, Florence, Italy"},{"name":"Pulmonology Unit, Rimini and Riccione Hospitals, Department of Specialist Medicine, AUSL della Romagna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5917-4601","authenticated-orcid":false,"given":"Naftali","family":"Kaminski","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060305050469000_2026.05.27.727792v1.1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202202-0399ST"},{"key":"2026060305050469000_2026.05.27.727792v1.2","unstructured":"Flaherty, K. R. et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases."},{"key":"2026060305050469000_2026.05.27.727792v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2503643"},{"key":"2026060305050469000_2026.05.27.727792v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402582"},{"key":"2026060305050469000_2026.05.27.727792v1.5","doi-asserted-by":"publisher","DOI":"10.1513\/pats.200601-003TK"},{"key":"2026060305050469000_2026.05.27.727792v1.6","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2023-0363OC"},{"key":"2026060305050469000_2026.05.27.727792v1.7","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202401-0238SO"},{"key":"2026060305050469000_2026.05.27.727792v1.8","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00788-2025"},{"key":"2026060305050469000_2026.05.27.727792v1.9","doi-asserted-by":"publisher","DOI":"10.1172\/JCI191826"},{"key":"2026060305050469000_2026.05.27.727792v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07660-1"},{"key":"2026060305050469000_2026.05.27.727792v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.06.020"},{"key":"2026060305050469000_2026.05.27.727792v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08542-2"},{"key":"2026060305050469000_2026.05.27.727792v1.13","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aba1983"},{"key":"2026060305050469000_2026.05.27.727792v1.14","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abe4282"},{"key":"2026060305050469000_2026.05.27.727792v1.15","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aba1972"},{"key":"2026060305050469000_2026.05.27.727792v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-021-00809-4"},{"key":"2026060305050469000_2026.05.27.727792v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-020-0542-8"},{"key":"2026060305050469000_2026.05.27.727792v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03569-1"},{"key":"2026060305050469000_2026.05.27.727792v1.19","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00254.2021"},{"key":"2026060305050469000_2026.05.27.727792v1.20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.595811"},{"key":"2026060305050469000_2026.05.27.727792v1.21","doi-asserted-by":"publisher","DOI":"10.1172\/JCI188734"},{"key":"2026060305050469000_2026.05.27.727792v1.22","doi-asserted-by":"publisher","DOI":"10.1172\/JCI191826"},{"key":"2026060305050469000_2026.05.27.727792v1.23","unstructured":"Stromal heterogeneity in the adult lung delineated by single-cell genomics"},{"key":"2026060305050469000_2026.05.27.727792v1.24","unstructured":"Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis."},{"key":"2026060305050469000_2026.05.27.727792v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2025.101066"},{"key":"2026060305050469000_2026.05.27.727792v1.26","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adl5473"},{"key":"2026060305050469000_2026.05.27.727792v1.27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.092134099"},{"key":"2026060305050469000_2026.05.27.727792v1.28","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2018.00087"},{"key":"2026060305050469000_2026.05.27.727792v1.29","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202505-1054ST"},{"key":"2026060305050469000_2026.05.27.727792v1.30","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200702-254OC"},{"key":"2026060305050469000_2026.05.27.727792v1.31","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202206-1075OC"},{"key":"2026060305050469000_2026.05.27.727792v1.32","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201909-1834OC"},{"key":"2026060305050469000_2026.05.27.727792v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02327-2"},{"key":"2026060305050469000_2026.05.27.727792v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2922-4"},{"key":"2026060305050469000_2026.05.27.727792v1.35","doi-asserted-by":"publisher","DOI":"10.1101\/2025.06.10.658504"},{"key":"2026060305050469000_2026.05.27.727792v1.36","doi-asserted-by":"publisher","DOI":"10.1101\/2025.07.06.663336"},{"key":"2026060305050469000_2026.05.27.727792v1.37","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2512911"},{"key":"2026060305050469000_2026.05.27.727792v1.38","unstructured":"Li, R. M. et al. Pre-Treatment MMP7 Predicts Progressive Idiopathic Pulmonary Fibrosis in Antifibrotic Treated Patients."},{"key":"2026060305050469000_2026.05.27.727792v1.39","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201406-1162OC"},{"key":"2026060305050469000_2026.05.27.727792v1.40","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.052318"},{"key":"2026060305050469000_2026.05.27.727792v1.41","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202303-0544LE"},{"key":"2026060305050469000_2026.05.27.727792v1.42","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201512-2523OC"},{"key":"2026060305050469000_2026.05.27.727792v1.43","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01383-2022"},{"key":"2026060305050469000_2026.05.27.727792v1.44","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0"},{"key":"2026060305050469000_2026.05.27.727792v1.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0229-2"},{"key":"2026060305050469000_2026.05.27.727792v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2021.11.007"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.27.727792","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T12:05:18Z","timestamp":1780488318000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.27.727792"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,30]]},"references-count":46,"URL":"https:\/\/doi.org\/10.64898\/2026.05.27.727792","relation":{},"subject":[],"published":{"date-parts":[[2026,5,30]]},"subtype":"preprint"}}