Integrative analysis of cell state changes in lung fibrosis with peripheral protein biomarkers.

Edith Silbernagel, Herbert B Schiller, Fabian J Theis, Oliver Eickelberg, Matthias Mann, Jürgen Behr, Antje Prasse, Anne Hilgendorff, Britta Maurer, Michael Lindner, Heiko Adler, Stephan Böhm, Christoph H Mayr, Frank Reichenberger, Nikolaus Kneidinger, Pawandeep Singh, Maximilian Strunz, Ilias Angelidis, Philipp E Geyer, Janine Schniering, Meshal Ansari, Gabriela Leuschner, Lukas M Simon

Journal: EMBO molecular medicine 2021;13(4):e12871

PMID: 33650774

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Abstract

The correspondence of cell state changes in diseased organs to peripheral protein signatures is currently unknown. Here, we generated and integrated single-cell transcriptomic and proteomic data from multiple large pulmonary fibrosis patient cohorts. Integration of 233,638 single-cell transcriptomes (n = 61) across three independent cohorts enabled us to derive shifts in cell type proportions and a robust core set of genes altered in lung fibrosis for 45 cell types. Mass spectrometry analysis of lung lavage fluid (n = 124) and plasma (n = 141) proteomes identified distinct protein signatures correlated with diagnosis, lung function, and injury status. A novel SSTR2+ pericyte state correlated with disease severity and was reflected in lavage fluid by increased levels of the complement regulatory factor CFHR1. We further discovered CRTAC1 as a biomarker of alveolar type-2 epithelial cell health status in lavage fluid and plasma. Using cross-modal analysis and machine learning, we identified the cellular source of biomarkers and demonstrated that information transfer between modalities correctly predicts disease status, suggesting feasibility of clinical cell state monitoring through longitudinal sampling of body fluid proteomes.

Address: Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.; Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany.; Department of Internal Medicine V, Ludwig-Maximilians University (LMU) Munich, Member of the German Center for Lung Research (DZL), CPC-M bioArchive, Munich, Germany.; Department of Rheumatology, Center of Experimental Rheumatology, University & University Hospital Zurich, Zurich, Switzerland.; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.; Asklepios Fachkliniken Munich-Gauting, CPC-M bioArchive, Member of the German Center for Lung Research (DZL), Munich, Germany.; Faculty of Medicine, Max von Pettenkofer-Institute, Virology, National Reference Center for Retroviruses, LMU München, Munich, Germany.; Helmholtz Zentrum München, Research Unit Lung Repair and Regeneration, Member of the German Center for Lung Research (DZL), Munich, Germany.; University Department of Visceral and Thoracic Surgery Salzburg, Paracelsus Medical University, Salzburg, Austria.; Center for Comprehensive Developmental Care (CDeCLMU), Member of the German Center for Lung Research (DZL), Hospital of the Ludwig-Maximilians University (LMU), CPC-M bioArchive, Munich, Germany.; Department of Pneumology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany.; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

DOI: 10.15252/emmm.202012871