Single-cell and spatial transcriptomics resolve airway obliteration in bronchiolitis obliterans syndrome
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Background Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation, and its most frequent phenotype is bronchiolitis obliterans syndrome (BOS), a fibrotic small-airway disease. Mechanistic work has focused on the immune compartment, yet intensified immunosuppression does not alter established disease. Aim To resolve which structural cell states populate the BOS graft and how they are spatially organized during airway obliteration. Methods We profiled explanted lungs from 33 BOS patients undergoing re-transplantation and 33 controls, combining single-nucleus RNA sequencing (14 BOS, 13 controls) with targeted spatial transcriptomics of 108 regions (27 BOS, 24 controls) and multiplex immunofluorescence validation. Single-nucleus data were integrated with a published restrictive allograft syndrome (RAS) atlas. Results Across 175,128 nuclei and 1.67 million spatially resolved cells, BOS lungs harbored a profibrotic circuit of Aberrant Basaloid cells and CTHRC1 + fibrotic fibroblasts previously described in fibrotic lung diseases, including RAS. Spatial mapping identified a CXCL14 + TNC + injury-associated basal cell state arising early in the obliterative cascade, identifying basal cells as their major reservoir. CTHRC1 + fibroblasts expanded subepithelially replacing resident peribronchial fibroblasts, alongside a peribronchial vascular shift toward systemic venous endothelium. The circuit extended beyond the airway wall to the alveolar interface, defining two convergent remodeling fronts. Conclusion BOS engages structural-cell circuits largely shared with RAS and fibrotic lung diseases, but along an airway-centered rather than parenchyma-centered axis. CLAD thus emerges as a spatial rather than cellular spectrum, defined by anatomical distribution more than cell identity. Shared structural programs may therefore be targetable across CLAD phenotypes.
Authors 35
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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
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
Institute of Transplant Immunology, 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 Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 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 Transplant Immunology, 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
Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
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Medizinische Hochschule Hannover
Affiliation as printed
Institute of Pathology, Hannover Medical School, Hannover, Germany
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University of Antwerp · Antwerp University Hospital
Affiliation as printed
Department of Thoracic and Vascular Surgery & Pneumology, Antwerp University Hospital, Edegem, Belgium; Antwerp Surgical Training Anatomy and Research Centre (ASTARC), University of Antwerp, Antwerpen, 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 · 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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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 Cardiothoracic, Transplantation and Vascular Surgery, 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 Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
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Helmholtz Munich · German Center for Lung Research
Affiliation as printed
Comprehensive Pneumology Center (CPC), Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Neuherberg, Germany
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University of Bern · University Hospital of Bern
Affiliation as printed
Department of Rheumatology and Immunology, Department of Pulmonary Medicine, Allergology and Clinical Immunology, Inselspital, Bern University Hospital and Lung Precision Medicine, Department for BioMedical Research, University of Bern, Bern, Switzerland
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Medizinische Hochschule Hannover · Fraunhofer Institute for Toxicology and Experimental Medicine · 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 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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Affiliation as printed
Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery, KU Leuven, Leuven, Belgium
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Medizinische Hochschule Hannover · German Center for Lung Research · RWTH Aachen University
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
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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 Diagnostic and Interventional Radiology, 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 Cardiothoracic, Transplantation and Vascular Surgery, 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 Pediatric Pneumology, Allergology and Neonatology, 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, United States
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Radboud University Nijmegen · Radboud University Medical Center · Medizinische Hochschule Hannover · Centre for Individualised Infection Medicine · Center for Experimental and Clinical Infection Research · CAIMed - Niedersächsisches Zentrum für KI und Kausale Methoden in der Medizin
Affiliation as printed
Cluster of Excellence Resolving Infection Susceptibility (RESIST), Hannover, Germany
Computational Biology for Individualised Medicine, TWINCORE, Center for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Center for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
Department of Computational Biology for Individualised Medicine, Center for Individualised Infection Medicine (CiiM), a Joint Venture between the Helmholtz Center for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
Lower Saxony Center for Artificial Intelligence and Causal Methods in Medicine (CAIMed), Hannover, Germany
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University of Antwerp · Antwerp University Hospital
Affiliation as printed
Department of Thoracic and Vascular Surgery & Pneumology, Antwerp University Hospital, Edegem, Belgium; Antwerp Surgical Training Anatomy and Research Centre (ASTARC), University of Antwerp, Antwerpen, Belgium
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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 Transplant Immunology, 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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Jonas C. Schupp corresponding
Yale University · Medizinische Hochschule Hannover · Fraunhofer Institute for Toxicology and Experimental Medicine · 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 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
Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, United States
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