Airway basal cells show a dedifferentiated KRT17(high)Phenotype and promote fibrosis in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. In this study, we focus on the properties of airway basal cells (ABC) obtained from patients with IPF (IPF-ABC). Single cell RNA sequencing (scRNAseq) of bronchial brushes revealed extensive reprogramming of IPF-ABC towards a KRT17(high) PTEN(low) dedifferentiated cell type. In the 3D organoid model, compared to ABC obtained from healthy volunteers, IPF-ABC give rise to more bronchospheres, de novo bronchial structures resembling lung developmental processes, induce fibroblast proliferation and extracellular matrix deposition in co-culture. Intratracheal application of IPF-ABC into minimally injured lungs of Rag2(-/-) or NRG mice causes severe fibrosis, remodeling of the alveolar compartment, and formation of honeycomb cyst-like structures. Connectivity MAP analysis of scRNAseq of bronchial brushings suggested that gene expression changes in IPF-ABC can be reversed by SRC inhibition. After demonstrating enhanced SRC expression and activity in these cells, and in IPF lungs, we tested the effects of saracatinib, a potent SRC inhibitor previously studied in humans. We demonstrate that saracatinib modified in-vitro and in-vivo the profibrotic changes observed in our 3D culture system and novel mouse xenograft model.

  • Jaeger, B.
  • Schupp, J. C.
  • Plappert, L.
  • Terwolbeck, O.
  • Artysh, N.
  • Kayser, G.
  • Engelhard, P.
  • Adams, T. S.
  • Zweigerdt, R.
  • Kempf, H.
  • Lienenklaus, S.
  • Garrels, W.
  • Nazarenko, I.
  • Jonigk, D.
  • Wygrecka, M.
  • Klatt, D.
  • Schambach, A.
  • Kaminski, N.
  • Prasse, A.

Keywords

  • Animals
  • Disease Models, Animal
  • Fibroblasts/metabolism
  • Fibrosis
  • Humans
  • *Idiopathic Pulmonary Fibrosis/pathology
  • Lung/pathology
  • Mice
  • Phenotype
Publication details
DOI: 10.1038/s41467-022-33193-0
Journal: Nat Commun
Pages: 5637
Number: 1
Work Type: Original
Access number: 36163190
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