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Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis.

Publication ,  Journal Article
Kobayashi, Y; Tata, A; Konkimalla, A; Katsura, H; Lee, RF; Ou, J; Banovich, NE; Kropski, JA; Tata, PR
Published in: Nat Cell Biol
August 2020

Stem cells undergo dynamic changes in response to injury to regenerate lost cells. However, the identity of transitional states and the mechanisms that drive their trajectories remain understudied. Using lung organoids, multiple in vivo repair models, single-cell transcriptomics and lineage tracing, we find that alveolar type-2 epithelial cells undergoing differentiation into type-1 cells acquire pre-alveolar type-1 transitional cell state (PATS) en route to terminal maturation. Transitional cells undergo extensive stretching during differentiation, making them vulnerable to DNA damage. Cells in the PATS show an enrichment of TP53, TGFβ, DNA-damage-response signalling and cellular senescence. Gain and loss of function as well as genomic binding assays revealed a direct transcriptional control of PATS by TP53 signalling. Notably, accumulation of PATS-like cells in human fibrotic lungs was observed, suggesting persistence of the transitional state in fibrosis. Our study thus implicates a transient state associated with senescence in normal epithelial tissue repair and its abnormal persistence in disease conditions.

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Published In

Nat Cell Biol

DOI

EISSN

1476-4679

Publication Date

August 2020

Volume

22

Issue

8

Start / End Page

934 / 946

Location

England

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Signal Transduction
  • Pulmonary Fibrosis
  • Organoids
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Humans
  • Gene Expression Regulation
  • Gene Expression Profiling
 

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Kobayashi, Y., Tata, A., Konkimalla, A., Katsura, H., Lee, R. F., Ou, J., … Tata, P. R. (2020). Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis. Nat Cell Biol, 22(8), 934–946. https://doi.org/10.1038/s41556-020-0542-8
Kobayashi, Yoshihiko, Aleksandra Tata, Arvind Konkimalla, Hiroaki Katsura, Rebecca F. Lee, Jianhong Ou, Nicholas E. Banovich, Jonathan A. Kropski, and Purushothama Rao Tata. “Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis.Nat Cell Biol 22, no. 8 (August 2020): 934–46. https://doi.org/10.1038/s41556-020-0542-8.
Kobayashi Y, Tata A, Konkimalla A, Katsura H, Lee RF, Ou J, et al. Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis. Nat Cell Biol. 2020 Aug;22(8):934–46.
Kobayashi, Yoshihiko, et al. “Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis.Nat Cell Biol, vol. 22, no. 8, Aug. 2020, pp. 934–46. Pubmed, doi:10.1038/s41556-020-0542-8.
Kobayashi Y, Tata A, Konkimalla A, Katsura H, Lee RF, Ou J, Banovich NE, Kropski JA, Tata PR. Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis. Nat Cell Biol. 2020 Aug;22(8):934–946.

Published In

Nat Cell Biol

DOI

EISSN

1476-4679

Publication Date

August 2020

Volume

22

Issue

8

Start / End Page

934 / 946

Location

England

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Signal Transduction
  • Pulmonary Fibrosis
  • Organoids
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Humans
  • Gene Expression Regulation
  • Gene Expression Profiling