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Strunz, M. ; Simon, L. ; Ansari, M. ; Kathiriya, J.J.* ; Angelidis, I. ; Mayr, C. ; Tsidiridis, G. ; Lange, M. ; Mattner, L. ; Yee, M.* ; Ogar, P. ; Sengupta, A. ; Kukhtevich, I. ; Schneider, R. ; Zhao, Z.* ; Voss, C. ; Stöger, T. ; Neumann, J.H.L.* ; Hilgendorff, A. ; Behr, J. ; O'Reilly, M.* ; Lehmann, M. ; Burgstaller, G. ; Königshoff, M. ; Chapman, H.A.* ; Theis, F.J. ; Schiller, H. B.

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

Nat. Commun. 11:3559 (2020)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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. Injury repair is characterized by the generation of transient cell states important for tissue recovery. Here, the authors present a single cell RNA-seq map of recovery from bleomycin lung injury in mice and uncover a Krt8+ transitional stem cell state that precedes the regeneration of AT1 cells and persists in human lung fibrosis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mesenchymal Transition; Pulmonary-fibrosis; C/ebp-alpha; Differentiation; Expression; Repair; Reconstruction; Plasticity; Epithelium; Mobilize
Sprache englisch
Veröffentlichungsjahr 2020
HGF-Berichtsjahr 2020
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 11, Heft: 1, Seiten: , Artikelnummer: 3559 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) German Center for Lung Research (DZL)
Institute of Computational Biology (ICB)
Institute of Functional Epigenetics (IFE)
Institute of Lung Health and Immunity (LHI)
POF Topic(s) 80000 - German Center for Lung Research
30205 - Bioengineering and Digital Health
30203 - Molecular Targets and Therapies
30202 - Environmental Health
Forschungsfeld(er) Lung Research
Enabling and Novel Technologies
Helmholtz Diabetes Center
PSP-Element(e) G-501800-810
G-503800-001
G-502800-001
G-505000-001
G-552100-001
G-501600-002
G-501800-311
G-501600-014
G-503100-001
DOI 10.1038/s41467-020-17358-3
WOS ID WOS:000552415100007
Scopus ID 85088139246
PubMed ID 32678092
Erfassungsdatum 2020-09-29
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