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

• DOI: 10.1038/s41467-022-33193-0
• Publication Date: 2022-09-26T10:03:16Z
• Authors: Benedikt Jaeger; Jonas Christian S...; Linda Plappert; Oliver Terwolbeck; Nataliia Artysh; Gian Kayser; Peggy Engelhard; Taylor Sterling A...; Robert Zweigerdt; Henning Kempf; Stefan Lienenklaus; Wiebke Garrels; Irina Nazarenko; Danny Jonigk; Malgorzata Wygrecka; Denise Klatt; Axel Schambach; Naftali Kaminski; Antje Prasse
• Keywords: Science; Q; 610; Fibroblasts; Fibrosis; Article; Idiopathic Pulmonary Fibrosis; 3. Good health; Disease Models, Animal; Mice; Phenotype; Animals; Humans; Lung

AbstractIdiopathic 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.