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

Abstract: 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

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Nature communications. - 13 (2022) , 5637, ISSN: 2041-1723

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2022
• Creator: Jäger, 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 David ; Wygrecka, Małgorzata ; Klatt, Denise ; Schambach, Axel ; Kaminski, Naftali ; Prasse, Antje

Further information

• DOI: 10.1038/s41467-022-33193-0
• URN: urn:nbn:de:bsz:25-freidok-2307282
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:44 PM CET