Journal Article Preprint Epublish 8 citations
PubMed: 40667263 DOI: 10.1101/2025.06.10.658504
Alveolar epithelial cell plasticity and injury memory in human pulmonary fibrosis.
bioRxiv
Authors: Taylor S Adams, Jonas C Schupp, Agshin Balayev, Johad Khoury, Aurélien Justet, Fadi Nikola, Laurens J De Sadeleer, Juan Cala-Garcia, Marta Zapata-Ortega, Panayiotis V Benos, John E McDonough, Farida Ahangari, Melanie Königshoff, Jun Ding, Robert J Homer, Ivan Rosas, Xiting Yan, Bart M Vanaudenaerde, Wim A Wuyts, Naftali Kaminski
Affiliations
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA.
- Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany.
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany.
- Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany.
- Department of Respiratory Medicine, University Hospital of Caen, France; Unicaen, CEA, CNRS, UMR 6030, ISTCT Group, GIP Cyceron, Université de Normandie, Caen, France.
- Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
- Unit for Interstitial Lung Diseases, Department of Pneumology, University Hospitals Leuven, Leuven, Belgium.
- Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine.
- Department of Epidemiology, University of Florida, Florida, USA.
- Department of Medicine McMaster University Hamilton, Ontario, Canada.
- Firestone Institute for Respiratory Health St. Joseph's Healthcare Hamilton Hamilton, Ontario, Canada.
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
- Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada.
- Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
- School of Computer Science, McGill University, Montreal, Quebec, Canada.
- Mila - Quebec AI Institute, Montreal, Quebec, Canada.
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
- Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
Abstract
Acute and repetitive lung epithelial injury can lead to irreversible and even progressive pulmonary fibrosis; Idiopathic pulmonary fibrosis (IPF) is a fatal disease and quintessential example of this phenomenon. The composition of epithelial cells in human pulmonary fibrosis - irrespective of disease etiology - is marked by the presence of Aberrant Basaloid cells: an abnormal cell phenotype with pro-fibrotic and senescent features, localized to the surface of fibrotic lesions. Despite their relevance to human pulmonary fibrosis, the exotic molecular profile of Aberrant Basaloid cells has obscured their etiology, preventing insights into how or why these cells emerge with fibrosis. Here we identify cellular intermediaries between Aberrant Basaloid and normal alveolar epithelial cells in human IPF tissue. We track the emergence of Aberrant Basaloid cells from alveolar epithelial cells ex vivo and uncover a role for similar cells in epithelial regeneration under normal conditions. Lastly, we characterize the epigenetic changes that distinguish Aberrant Basaloid cells from their progenitors and identify hallmarks of AP-1 injury memory retention. This study elucidates the phenomenon of maladaptive epithelial plasticity and regeneration in pulmonary fibrosis and re-contextualizes therapeutic strategies for epithelial dysfunction.
MeSH
Cells, Idiopathic Pulmonary Fibrosis, Cell Plasticity, Alveolar Epithelial Cells, Fibrosis, Epithelial Cells, Pulmonary Fibrosis, Memory