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

Author

Listed:
  • Benedikt Jaeger

    (Fraunhofer Institute for Toxicology and Experimental Medicine
    German Center for Lung Research, BREATH)

  • Jonas Christian Schupp

    (German Center for Lung Research, BREATH
    Critical Care and Sleep Medicine, Yale School of Medicine
    Hannover Medical School)

  • Linda Plappert

    (Fraunhofer Institute for Toxicology and Experimental Medicine
    German Center for Lung Research, BREATH)

  • Oliver Terwolbeck

    (Fraunhofer Institute for Toxicology and Experimental Medicine
    German Center for Lung Research, BREATH)

  • Nataliia Artysh

    (Fraunhofer Institute for Toxicology and Experimental Medicine
    German Center for Lung Research, BREATH
    Hannover Medical School)

  • 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
    Partner Site Freiburg and German Cancer Research Center (DKFZ))

  • Danny Jonigk

    (German Center for Lung Research, BREATH
    Institute of Pathology, Hannover Medical School)

  • Malgorzata Wygrecka

    (Justus Liebig University)

  • Denise Klatt

    (Hannover Medical School)

  • Axel Schambach

    (Hannover Medical School
    Boston Children’s Hospital, Harvard Medical School)

  • Naftali Kaminski

    (Critical Care and Sleep Medicine, Yale School of Medicine)

  • Antje Prasse

    (Fraunhofer Institute for Toxicology and Experimental Medicine
    German Center for Lung Research, BREATH
    Hannover Medical School)

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.

Suggested Citation

  • Benedikt Jaeger & Jonas Christian Schupp & Linda Plappert & Oliver Terwolbeck & Nataliia Artysh & Gian Kayser & Peggy Engelhard & Taylor Sterling Adams & Robert Zweigerdt & Henning Kempf & Stefan Lien, 2022. "Airway basal cells show a dedifferentiated KRT17highPhenotype and promote fibrosis in idiopathic pulmonary fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33193-0
    DOI: 10.1038/s41467-022-33193-0
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    References listed on IDEAS

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    1. Ludo Waltman & Nees Eck, 2013. "A smart local moving algorithm for large-scale modularity-based community detection," The European Physical Journal B: Condensed Matter and Complex Systems, Springer;EDP Sciences, vol. 86(11), pages 1-14, November.
    2. Andrew E. Vaughan & Alexis N. Brumwell & Ying Xi & Jeffrey E. Gotts & Doug G. Brownfield & Barbara Treutlein & Kevin Tan & Victor Tan & Feng Chun Liu & Mark R. Looney & Michael A. Matthay & Jason R. R, 2015. "Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury," Nature, Nature, vol. 517(7536), pages 621-625, January.
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    Cited by:

    1. Ilianna Barbayianni & Paraskevi Kanellopoulou & Dionysios Fanidis & Dimitris Nastos & Eleftheria-Dimitra Ntouskou & Apostolos Galaris & Vaggelis Harokopos & Pantelis Hatzis & Eliza Tsitoura & Robert H, 2023. "SRC and TKS5 mediated podosome formation in fibroblasts promotes extracellular matrix invasion and pulmonary fibrosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Richard J. Hewitt & Franz Puttur & David C. A. Gaboriau & Frédéric Fercoq & Maryline Fresquet & William J. Traves & Laura L. Yates & Simone A. Walker & Philip L. Molyneaux & Samuel V. Kemp & Andrew G., 2023. "Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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