Aberrant and ectopic cell populations in restrictive allograft syndrome after lung transplantation
European Respiratory Journal, vol. 68, pp. 2500537
Abstract
Rationale Restrictive allograft syndrome (RAS) is a major cause of mortality following lung transplantation due to progressive fibrosis of the lung allograft, with no therapeutic options. Knowledge of the cellular and molecular mechanisms driving fibrosis in RAS remains limited. Objective To characterise the cellular and molecular changes in human RAS lungs through single-nucleus transcriptomic profiling. Methods Single-nucleus RNA-sequencing (snRNA-seq) was performed in peripheral lung tissues from 15 RAS patients undergoing lung re-transplantation, and from nine healthy control lungs. Findings were validated and extended using histological techniques including immunofluorescence, RNA in situ hybridisation, Elastica van Gieson immunohistochemistry, quantitative histological analyses, and micro-computed tomography (CT) scans. Measurements and main results snRNA-seq analysis of RAS lungs revealed previously undescribed aberrant basaloid cells, ectopic COL15A1 + peribronchial vascular endothelial cells (pVECs), and CTHRC1 + fibrotic fibroblasts. Histological stains disclosed distinctive distribution patterns: aberrant basaloid cells, primarily localised at the fibrotic edge, together with juxtaposed CTHRC1 + fibrotic fibroblasts and ectopic COL15A1 + pVECs form the fibrotic niche of alveolar fibroelastosis (AFE). PRX + alveolar microvasculature is partially lost in AFE areas. Micro-CT scans revealed changes from pulmonary to systemic perfusion, facilitated by COL15A1 + pVECs. Lastly, our data reveal potential therapeutic targets in RAS, including integrin αvβ6, activator of transforming growth factor-β. Conclusion Considering the multifaceted differences of RAS and idiopathic pulmonary fibrosis, we revealed a surprising general principle of an entity-spanning composition of the fibrotic niche by aberrant basaloid cells localised at the fibrotic edge, ectopic COL15A1 + pVECs and CTHRC1 + fibrotic fibroblasts. This suggests a flexible, but cellular pathogenesis-guided, transferability of potential therapeutic approaches between progressive fibrotic lung diseases.
Authors 31
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Institute of Pathology, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Institute of Pathology, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany
Institute of Pathology, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Institute of Human Genetics, Hannover Medical School, Hannover, Germany
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RWTH Aachen University · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Institute of Pathology, RWTH Aachen, Aachen, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Institute of Pathology, Hannover Medical School, Hannover, Germany
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Centre National de la Recherche Scientifique · Centre Hospitalier Universitaire de Caen Normandie · Université de Caen Normandie · Imagerie et Stratégies Thérapeutiques pour les Cancers et Tissus cérébraux
Affiliation as printed
Service de Pneumologie, CHU de Caen, Centre de compétence des maladies pulmonaires rares, ISTCT, UMR6030-CNRS-CEA-Université de Caen, Caen, France
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Medizinische Hochschule Hannover
Affiliation as printed
Institute of Human Genetics, Hannover Medical School, Hannover, Germany
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Affiliation as printed
Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
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Medizinische Hochschule Hannover
Affiliation as printed
Central Research Facility Cell Sorting, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Clinic for Cardiac, Thoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
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Affiliation as printed
Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
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Medizinische Hochschule Hannover
Affiliation as printed
Institute for Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Clinic for Cardiac, Thoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
Leibniz Research Laboratories for Biotechnology and Artificial Organs, Lower Saxony Center for Biomedical Engineering, Implant Research and Development, Hannover, Germany
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Affiliation as printed
Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
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Affiliation as printed
Institute of Lung Health and Immunity (LHI), Helmholtz Zentrum Muenchen, Institute of Lung Biology and Disease, Munich, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research · Fraunhofer Institute for Toxicology and Experimental Medicine
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Clinic for Cardiac, Thoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
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Affiliation as printed
Institute of Pathology, RWTH Aachen, Aachen, Germany
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany
Died 10 March 2024
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
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Affiliation as printed
Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA
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RWTH Aachen University · Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Institute of Pathology, Hannover Medical School, Hannover, Germany
Institute of Pathology, RWTH Aachen, Aachen, Germany
These authors contributed equally to this work
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Medizinische Hochschule Hannover · German Center for Lung Research
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany
These authors contributed equally to this work
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Yale University · Medizinische Hochschule Hannover · German Center for Lung Research · Fraunhofer Institute for Toxicology and Experimental Medicine
Affiliation as printed
Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany
Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany schupp.jonas@mh-hannover.de
Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA
These authors contributed equally to this work
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