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Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis

Author

Listed:
  • Maximilian Strunz

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL))

  • Lukas M. Simon

    (Helmholtz Zentrum München
    University of Texas Health Science Center)

  • Meshal Ansari

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL)
    Helmholtz Zentrum München)

  • Jaymin J. Kathiriya

    (University of California San Francisco)

  • Ilias Angelidis

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL))

  • Christoph H. Mayr

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL))

  • George Tsidiridis

    (Helmholtz Zentrum München)

  • Marius Lange

    (Helmholtz Zentrum München
    Technische Universität München)

  • Laura F. Mattner

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL))

  • Min Yee

    (University of Rochester)

  • Paulina Ogar

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL))

  • Arunima Sengupta

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL))

  • Igor Kukhtevich

    (Institute of Functional Epigenetics, Helmholtz Zentrum München)

  • Robert Schneider

    (Institute of Functional Epigenetics, Helmholtz Zentrum München)

  • Zhongming Zhao

    (University of Texas Health Science Center)

  • Carola Voss

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL))

  • Tobias Stoeger

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL))

  • Jens H. L. Neumann

    (Institute of Pathology, Ludwig Maximilians University Hospital Munich)

  • Anne Hilgendorff

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL)
    Hospital of the Ludwig-Maximilians University (LMU))

  • Jürgen Behr

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL)
    Ludwig Maximilians University Hospital (LMU) Munich
    Asklepios Fachkliniken in Munich-Gauting)

  • Michael O’Reilly

    (University of Rochester)

  • Mareike Lehmann

    (Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL))

  • Gerald Burgstaller

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL))

  • Melanie Königshoff

    (Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL)
    University of Colorado, Department of Pulmonary Sciences and Critical Care Medicine)

  • Harold A. Chapman

    (University of California San Francisco)

  • Fabian J. Theis

    (Helmholtz Zentrum München
    Technische Universität München)

  • Herbert B. Schiller

    (Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL))

Abstract

The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8 + transitional stem cell state during alveolar regeneration. These cells have squamous morphology, feature p53 and NFkB activation and display transcriptional features of cellular senescence. The Krt8+ state appears in several independent models of lung injury and persists in human lung fibrosis, creating a distinct cell–cell communication network with mesenchyme and macrophages during repair. We generated a model of gene regulatory programs leading to Krt8+ transitional cells and their terminal differentiation to alveolar type-1 cells. We propose that in lung fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states.

Suggested Citation

  • Maximilian Strunz & Lukas M. Simon & Meshal Ansari & Jaymin J. Kathiriya & Ilias Angelidis & Christoph H. Mayr & George Tsidiridis & Marius Lange & Laura F. Mattner & Min Yee & Paulina Ogar & Arunima , 2020. "Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17358-3
    DOI: 10.1038/s41467-020-17358-3
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    Cited by:

    1. Yuanyuan Chen & Reka Toth & Sara Chocarro & Dieter Weichenhan & Joschka Hey & Pavlo Lutsik & Stefan Sawall & Georgios T. Stathopoulos & Christoph Plass & Rocio Sotillo, 2022. "Club cells employ regeneration mechanisms during lung tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Yasunori Enomoto & Hiroaki Katsura & Takashi Fujimura & Akira Ogata & Saori Baba & Akira Yamaoka & Miho Kihara & Takaya Abe & Osamu Nishimura & Mitsutaka Kadota & Daisuke Hazama & Yugo Tanaka & Yoshim, 2023. "Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Minzhe Guo & Michael P. Morley & Cheng Jiang & Yixin Wu & Guangyuan Li & Yina Du & Shuyang Zhao & Andrew Wagner & Adnan Cihan Cakar & Michal Kouril & Kang Jin & Nathan Gaddis & Joseph A. Kitzmiller & , 2023. "Guided construction of single cell reference for human and mouse lung," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Leila R. Martins & Lina Sieverling & Michelle Michelhans & Chiara Schiller & Cihan Erkut & Thomas G. P. Grünewald & Sergio Triana & Stefan Fröhling & Lars Velten & Hanno Glimm & Claudia Scholl, 2024. "Single-cell division tracing and transcriptomics reveal cell types and differentiation paths in the regenerating lung," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    5. Sandra Curras-Alonso & Juliette Soulier & Thomas Defard & Christian Weber & Sophie Heinrich & Hugo Laporte & Sophie Leboucher & Sonia Lameiras & Marie Dutreix & Vincent Favaudon & Florian Massip & Tho, 2023. "An interactive murine single-cell atlas of the lung responses to radiation injury," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Christina Beck & Deepak Ramanujam & Paula Vaccarello & Florenc Widenmeyer & Martin Feuerherd & Cho-Chin Cheng & Anton Bomhard & Tatiana Abikeeva & Julia Schädler & Jan-Peter Sperhake & Matthias Graw &, 2023. "Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Laura Heydemann & Małgorzata Ciurkiewicz & Georg Beythien & Kathrin Becker & Klaus Schughart & Stephanie Stanelle-Bertram & Berfin Schaumburg & Nancy Mounogou-Kouassi & Sebastian Beck & Martin Zickler, 2023. "Hamster model for post-COVID-19 alveolar regeneration offers an opportunity to understand post-acute sequelae of SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    8. Dalia Hassan & Jichao Chen, 2024. "CEBPA restricts alveolar type 2 cell plasticity during development and injury-repair," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    9. Lucy Xia & Christy Lee & Jingyi Jessica Li, 2024. "Statistical method scDEED for detecting dubious 2D single-cell embeddings and optimizing t-SNE and UMAP hyperparameters," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    10. Andrea Toth & Paranthaman Kannan & John Snowball & Matthew Kofron & Joseph A. Wayman & James P. Bridges & Emily R. Miraldi & Daniel Swarr & William J. Zacharias, 2023. "Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    11. Christopher W. Murray & Jennifer J. Brady & Mingqi Han & Hongchen Cai & Min K. Tsai & Sarah E. Pierce & Ran Cheng & Janos Demeter & David M. Feldser & Peter K. Jackson & David B. Shackelford & Monte M, 2022. "LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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