Airway basal cells show a dedifferentiated KRT17highPhenotype and promote fibrosis in idiopathic pulmonary fibrosis.

Autor: Jaeger, Benedikt, Schupp, Jonas Christian, Plappert, Linda, Terwolbeck, Oliver, Artysh, Nataliia, Kayser, Gian, Engelhard, Peggy, Adams, Taylor Sterling, Zweigerdt, Robert, Kempf, Henning, Lienenklaus, Stefan, Garrels, Wiebke, Nazarenko, Irina, Jonigk, Danny, Wygrecka, Malgorzata, Klatt, Denise, Schambach, Axel, Kaminski, Naftali, Prasse, Antje
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Zdroj: Nature Communications; 9/26/2022, Vol. 13 Issue 1, p1-17, 17p
Abstrakt: 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 KRT17high PTENlow 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. The functional role of airway basal cells has not been comprehensively studied in idiopathic pulmonary fibrosis (IPF). Here, the authors show that airway basal cells of IPF patients display a distinct phenotype, are profibrotic if transplanted to mice and that fibrosis can be ameliorated by Src iinhibitors. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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