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

Research output: Contribution to journalJournal articleResearchpeer-review

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

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.

Original languageEnglish
Article numbere12871
JournalEMBO Molecular Medicine
ISSN1757-4676
DOIs
Publication statusPublished - 2021
Externally publishedYes

ID: 259053182