IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33193-0.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33193-0
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-33193-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Lutz Bornmann & Robin Haunschild & Sven E. Hug, 2018. "Visualizing the context of citations referencing papers published by Eugene Garfield: a new type of keyword co-occurrence analysis," Scientometrics, Springer;Akadémiai Kiadó, vol. 114(2), pages 427-437, February.
    2. Nina Sakinah Ahmad Rofaie & Seuk Wai Phoong & Muzalwana Abdul Talib & Ainin Sulaiman, 2023. "Light-emitting diode (LED) research: A bibliometric analysis during 2003–2018," Quality & Quantity: International Journal of Methodology, Springer, vol. 57(1), pages 173-191, February.
    3. Giovanni Matteo & Pierfrancesco Nardi & Stefano Grego & Caterina Guidi, 2018. "Bibliometric analysis of Climate Change Vulnerability Assessment research," Environment Systems and Decisions, Springer, vol. 38(4), pages 508-516, December.
    4. Loredana Canfora & Corrado Costa & Federico Pallottino & Stefano Mocali, 2021. "Trends in Soil Microbial Inoculants Research: A Science Mapping Approach to Unravel Strengths and Weaknesses of Their Application," Agriculture, MDPI, vol. 11(2), pages 1-21, February.
    5. Evi Sachini & Nikolaos Karampekios & Pierpaolo Brutti & Konstantinos Sioumalas-Christodoulou, 2020. "Should I stay or should I go? Using bibliometrics to identify the international mobility of highly educated Greek manpower," Scientometrics, Springer;Akadémiai Kiadó, vol. 125(1), pages 641-663, October.
    6. Tzuhua D. Lin & Nimrod D. Rubinstein & Nicole L. Fong & Megan Smith & Wendy Craft & Baby Martin-McNulty & Rebecca Perry & Martha A. Delaney & Margaret A. Roy & Rochelle Buffenstein, 2024. "Evolution of T cells in the cancer-resistant naked mole-rat," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    7. Chuyou Fu & Jun Wang & Ziyi Qu & Martin Skitmore & Jiaxin Yi & Zhengjie Sun & Jianli Chen, 2024. "Structural Equation Modeling in Technology Adoption and Use in the Construction Industry: A Scientometric Analysis and Qualitative Review," Sustainability, MDPI, vol. 16(9), pages 1-23, May.
    8. Collins C. Okolie & Gideon Danso-Abbeam & Okechukwu Groupson-Paul & Abiodun A. Ogundeji, 2022. "Climate-Smart Agriculture Amidst Climate Change to Enhance Agricultural Production: A Bibliometric Analysis," Land, MDPI, vol. 12(1), pages 1-23, December.
    9. Oleg E. Karpov & Elena N. Pitsik & Semen A. Kurkin & Vladimir A. Maksimenko & Alexander V. Gusev & Natali N. Shusharina & Alexander E. Hramov, 2023. "Analysis of Publication Activity and Research Trends in the Field of AI Medical Applications: Network Approach," IJERPH, MDPI, vol. 20(7), pages 1-17, March.
    10. Zhong, Sheng & Verspagen, Bart, 2016. "The role of technological trajectories in catching-up-based development: An application to energy efficiency technologies," MERIT Working Papers 2016-013, United Nations University - Maastricht Economic and Social Research Institute on Innovation and Technology (MERIT).
    11. Gregor Werba & Daniel Weissinger & Emily A. Kawaler & Ende Zhao & Despoina Kalfakakou & Surajit Dhara & Lidong Wang & Heather B. Lim & Grace Oh & Xiaohong Jing & Nina Beri & Lauren Khanna & Tamas Gond, 2023. "Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    12. Theresa Velden & Kevin W. Boyack & Jochen Gläser & Rob Koopman & Andrea Scharnhorst & Shenghui Wang, 2017. "Comparison of topic extraction approaches and their results," Scientometrics, Springer;Akadémiai Kiadó, vol. 111(2), pages 1169-1221, May.
    13. R. Fileto Maciel & P. Saskia Bayerl & Marta Macedo Kerr Pinheiro, 2019. "Technical research innovations of the US national security system," Scientometrics, Springer;Akadémiai Kiadó, vol. 120(2), pages 539-565, August.
    14. Itsuki Kageyama & Karin Kurata & Shuto Miyashita & Yeongjoo Lim & Shintaro Sengoku & Kota Kodama, 2022. "A Bibliometric Analysis of Wearable Device Research Trends 2001–2022—A Study on the Reversal of Number of Publications and Research Trends in China and the USA," IJERPH, MDPI, vol. 19(24), pages 1-19, December.
    15. Borazon, Elaine Quintana & Chuang, Hsueh-Hua, 2023. "Resilience in educational system: A systematic review and directions for future research," International Journal of Educational Development, Elsevier, vol. 99(C).
    16. Daraio, Cinzia & Diana, Marco & Di Costa, Flavia & Leporelli, Claudio & Matteucci, Giorgio & Nastasi, Alberto, 2016. "Efficiency and effectiveness in the urban public transport sector: A critical review with directions for future research," European Journal of Operational Research, Elsevier, vol. 248(1), pages 1-20.
    17. Ana Lagos & Joaquín E. Caicedo & Gustavo Coria & Andrés Romero Quete & Maximiliano Martínez & Gastón Suvire & Jesús Riquelme, 2022. "State-of-the-Art Using Bibliometric Analysis of Wind-Speed and -Power Forecasting Methods Applied in Power Systems," Energies, MDPI, vol. 15(18), pages 1-40, September.
    18. Lima, Pedro G. & Teixeira, Pedro N. & Silva, Sandra T., 2021. "Major Streams in the Economics of Inequality: A Qualitative and Quantitative Analysis of the Literature since 1950s," IZA Discussion Papers 14777, Institute of Labor Economics (IZA).
    19. 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.
    20. Ruiz-Castillo, Javier & Waltman, Ludo, 2015. "Field-normalized citation impact indicators using algorithmically constructed classification systems of science," Journal of Informetrics, Elsevier, vol. 9(1), pages 102-117.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33193-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.