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.