Time- and compartment-resolved proteome profiling of the extracellular niche in lung injury and repair

Herbert B Schiller, Isis E Fernandez, Gerald Burgstaller, Christoph Schaab, Richard A Scheltema, Thomas Schwarzmayr, Tim M Strom, Oliver Eickelberg, Matthias Mann

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The extracellular matrix (ECM) is a key regulator of tissue morphogenesis and repair. However, its composition and architecture are not well characterized. Here, we monitor remodeling of the extracellular niche in tissue repair in the bleomycin-induced lung injury mouse model. Mass spectrometry quantified 8,366 proteins from total tissue and bronchoalveolar lavage fluid (BALF) over the course of 8 weeks, surveying tissue composition from the onset of inflammation and fibrosis to its full recovery. Combined analysis of proteome, secretome, and transcriptome highlighted post-transcriptional events during tissue fibrogenesis and defined the composition of airway epithelial lining fluid. To comprehensively characterize the ECM, we developed a quantitative detergent solubility profiling (QDSP) method, which identified Emilin-2 and collagen-XXVIII as novel constituents of the provisional repair matrix. QDSP revealed which secreted proteins interact with the ECM, and showed drastically altered association of morphogens to the insoluble matrix upon injury. Thus, our proteomic systems biology study assigns proteins to tissue compartments and uncovers their dynamic regulation upon lung injury and repair, potentially contributing to the development of anti-fibrotic strategies. Synopsis A proteome-wide view of lung injury and repair was elucidated by mass spectrometry analysis of the dynamic composition of lung tissue compartments. In particular, the extracellular matrix proteome uncovers potential factors in stem cell mobilization and fibrosis resolution. Proteomic analysis discovers signatures of consecutive phases of lung injury, fibrosis, and repair. Combined proteomics and transcriptomics define the prevalence of post-transcriptional events. Compartment proteomics uncovers extracellular matrix and epithelial lining fluid composition. In vivo solubility profiling reveals extracellular matrix interactions with secreted proteins. A proteome-wide view of lung injury and repair was elucidated by mass spectrometry analysis of the dynamic composition of lung tissue compartments. In particular, the extracellular matrix proteome uncovers potential factors in stem cell mobilization and fibrosis resolution.
Original languageEnglish
Article number819
Pages (from-to)1-19
JournalMolecular Systems Biology
Volume11
Issue number7
DOIs
Publication statusPublished - 1 Jul 2015

Keywords

  • extracellular matrix
  • fibrosis
  • proteomics
  • regeneration
  • secretome
  • activated leukocyte cell adhesion molecule
  • collagen
  • collagen type 28
  • collagen type 4
  • emilin 2
  • glutamyl aminopeptidase
  • glycosylphosphatidylinositol phospholipase D
  • laminin alpha1
  • laminin alpha2
  • laminin alpha4
  • microsomal aminopeptidase
  • morphogen
  • multimerin 2
  • netrin 1
  • neuropillin 1
  • proteome
  • tenascin
  • thrombospondin 1
  • transcriptome
  • unclassified drug
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • article
  • basement membrane
  • bleomycin-induced lung injury
  • controlled study
  • epithelial lining fluid
  • female
  • fibrogenesis
  • in vivo study
  • lung fibrosis
  • lung lavage
  • mouse
  • multipotent stem cell
  • next generation sequencing
  • nonhuman
  • pneumonia
  • priority journal
  • protein analysis
  • protein localization
  • protein processing
  • protein protein interaction
  • quadrupole mass spectrometry
  • quantitative analysis
  • quantitative detergent solubility profiling
  • stem cell mobilization
  • systems biology
  • tissue regeneration
  • tissue repair
  • transcription regulation

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