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

Benedikt Jaeger, Jonas Christian Schupp, Linda Plappert, Oliver Terwolbeck, Nataliia Artysh, Gian Kayser, Peggy Engelhard, Taylor Sterling Adams, Robert Zweigerdt, Henning Kempf, Stefan Lienenklaus, Wiebke Garrels, Irina Nazarenko, Danny Jonigk, Malgorzata Wygrecka, Denise Klatt, Axel Schambach, Naftali Kaminski and Antje Prasse ()
Additional contact information
Benedikt Jaeger: Fraunhofer Institute for Toxicology and Experimental Medicine
Jonas Christian Schupp: German Center for Lung Research, BREATH
Linda Plappert: Fraunhofer Institute for Toxicology and Experimental Medicine
Oliver Terwolbeck: Fraunhofer Institute for Toxicology and Experimental Medicine
Nataliia Artysh: Fraunhofer Institute for Toxicology and Experimental Medicine
Gian Kayser: University Medical Center
Peggy Engelhard: University Medical Center
Taylor Sterling Adams: Critical Care and Sleep Medicine, Yale School of Medicine
Robert Zweigerdt: Leibniz Research Laboratories for Biotechnology and Artificial Organs, Hannover Medical School
Henning Kempf: Leibniz Research Laboratories for Biotechnology and Artificial Organs, Hannover Medical School
Stefan Lienenklaus: Hannover Medical School
Wiebke Garrels: Hannover Medical School
Irina Nazarenko: Medical Center - University of Freiburg
Danny Jonigk: German Center for Lung Research, BREATH
Malgorzata Wygrecka: Justus Liebig University
Denise Klatt: Hannover Medical School
Axel Schambach: Hannover Medical School
Naftali Kaminski: Critical Care and Sleep Medicine, Yale School of Medicine
Antje Prasse: Fraunhofer Institute for Toxicology and Experimental Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33193-0

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