Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis
Open accessAbstract
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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CDKN1A, p53 and γH2AX are upregulated in mouse and human lungs upon senescence.
“Additionally, CDKN1A, p53 and γH2AX are also upregulated in mouse and human lungs upon senescence168,169.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [169]
The Results sections on mouse alveolar regeneration and human fibrotic lungs report increased CDKN1A and γH2AX in specific transitional epithelial cells associated with senescence and DNA damage. The human-lung Results also report enriched p53 signalling, but not an increase in p53 itself. The evidence concerns injured mouse lungs and human lungs with pulmonary fibrosis, rather than mouse and human lungs generally upon senescence; page numbers are unavailable in our copy. (LLM, conf=0.86)
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- Authors
- Kobayashi, Y., Tata, A., Konkimalla, A., Katsura, H., Lee, R. F., Ou, J., Banovich, N. E., Kropski, J. A., & Tata, P. R.
- Affiliations
- Duke University (US)
- Translational Genomics Research Institute (US)
- Vanderbilt University (US)
- Corresponding author
- Tata, Purushothama Rao
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2020-07-13
- Volume
- 22
- Issue
- 8
- Pages
- 934-946
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC7461628
- OpenAlex
- W3040811143
- Cited by
- 559
- References
- 72
- Citations by year
- 2026: 99 · 2025: 103 · 2024: 92 · 2023: 92 · 2022: 98 · 2021: 54 · 2020: 21
- FWCI
- 37.40
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- MEXT | Japan Society for the Promotion of Science (201960752)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (F30HL143911, R01HL145372, K08HL130595, R00HL127181, R01HL146557)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (P30CA014236)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Neonatal Respiratory Health Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- pulmonary fibrosis, alveolar type II cells, alveolar type I cells, epithelial differentiation, cellular senescence, DNA damage response, lung regeneration, lung organoids, lineage tracing, TGF-beta, transcriptional regulation
- MeSH terms
- Animals, Cell Differentiation, DNA Damage, Female, Gene Expression Regulation, Humans, Male, Mice, Inbred C57BL, Organoids, Pulmonary Fibrosis, Signal Transduction, Tumor Suppressor Protein p53, Cellular Senescence, Cell Lineage, Gene Expression Profiling, Cell Shape, Mice, Adult Stem Cells, Alveolar Epithelial Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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