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Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis
Open accessAbstract
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.
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“…), collagen produced by myofibroblasts ( Zhang et al., 1994 ), genes upregulated in myofibroblasts derived from idiopathic pulmonary fibrosis (IPF) patients ( Strunz et al., 2020 ), and effectors and targets of TGF-β signaling in two data modalities: bulk RNA-seq and bulk proteomics ( Figure 8A ).”
Regulation of the alveolar regenerative niche by amphiregulin-producing regulatory T cells
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Metadata
- Authors
- Strunz, M., Simon, L. M., Ansari, M., Kathiriya, J. J., Angelidis, I., Mayr, C. H., Tsidiridis, G., Lange, M., Mattner, L. F., Yee, M., Ogar, P., Sengupta, A., Kukhtevich, I., Schneider, R., Zhao, Z., Voss, C., Stoeger, 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.
- Venue
- Nature Communications
- Published
- 2020-07-16
- Volume
- 11
- Issue
- 1
- Pages
- 3559-3559
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W3043344901
- Cited by
- 728
- References
- 24
- FWCI
- 39.03
- Type
- journal article
- Language
- en
- Open access
- gold
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- Strunz, M., Simon, L. M., Ansari, M., Kathiriya, J. J., Angelidis, I., Mayr, C. H., Tsidiridis, G., Lange, M., Mattner, L. F., Yee, M., Ogar, P., Sengupta, A., Kukhtevich, I., Schneider, R., Zhao, Z., Voss, C., Stoeger, T., Neumann, J. H. L., Hilgendorff, A., . . . Schiller, H. B. (2020). Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nature Communications. https://doi.org/10.1038/s41467-020-17358-3
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