Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis
Strunz M, Simon LM, Ansari M, Kathiriya JJ, Angelidis I, Mayr CH, Tsidiridis G, Lange M, Mattner LF, Yee M, Ogar P, Sengupta A, Kukhtevich I, Schneider R, Zhao Z, Voss C, Stoeger T, Neumann JHL, Hilgendorff A, Behr J, O'Reilly M, Lehmann M, Burgstaller G, Koenigshoff M, Chapman HA, Theis FJ, Schiller HB (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 11
Article Number: 3559
Journal Issue: 1
DOI: 10.1038/s41467-020-17358-3
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.
Involved external institutions
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
University of California San Francisco (UCSF)
United States (USA) (US)
University of Rochester (UR)
United States (USA) (US)
University of Texas Health Science Center at Houston (UTHealth)
United States (USA) (US)
Klinikum der Universität München (Großhadern und Innenstadt)
Germany (DE)
Germany (DE)
University of California San Francisco (UCSF)
United States (USA) (US)
University of Rochester (UR)
United States (USA) (US)
University of Texas Health Science Center at Houston (UTHealth)
United States (USA) (US)
Klinikum der Universität München (Großhadern und Innenstadt)
Germany (DE)
How to cite
APA:
Strunz, M., Simon, L.M., Ansari, M., Kathiriya, J.J., Angelidis, I., Mayr, C.H.,... Schiller, H.B. (2020). Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-17358-3
MLA:
Strunz, Maximilian, et al. "Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis." Nature Communications 11.1 (2020).
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