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

• Published in: Nature communications Vol. 13; no. 1; pp. 1 - 17
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 38; 49; 49/91; 631/80/79/750; 631/80/86/2371; 692/4017; 692/699/1785; Alveoli; Basal cells; Cell culture; Extracellular matrix; Fibrosis; Gene expression; Gene sequencing; Humanities and Social Sciences; Lung diseases; Lungs; multidisciplinary; Organoids; Patients; Phenotypes; Pulmonary fibrosis; RAG2 protein; Respiratory tract; Science; Science (multidisciplinary); Three dimensional models; Trachea; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33193-0

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. 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.