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| Status |
Public on Jun 30, 2020 |
| Title |
Senescence rather than apoptosis of alveolar progenitor cells drives pulmonary fibrosis (human) |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Idiopathic pulmonary fibrosis (IPF) is a fatal form of interstitial lung disease associated with progressive scarring of lung tissue and declining pulmonary function in aging individuals. Here we employ data mining and single cell RNA sequencing (scRNAseq) to define candidate drivers of AT2 senescence in IPF lung tissue. We show that AT2 cells isolated from IPF lung tissue exhibit characteristic features of cellular senescence and reduced abundance of Sin3a, critical determinant of endodermal progenitor cell maintenance in the developing lung. Conditional loss of Sin3a within AT2 cells of the adult mouse lung activated a program of p53-dependent cellular senescence and AT2 cell depletion, leading to progressive pulmonary fibrosis. In contrast, ablation of AT2 cells through conditional activation of a DTA toxin gene led to transient fibrosis that resolved over time, suggesting that senescence of AT2 cells was a critical driver of progressive fibrosis. Activation of b6 integrin was observed within a subset of AT2 cells with Sin3a loss-of-function that localized to the advancing margin of advancing fibroproliferative lesions. Systemic inhibition of TGF signaling or delivery of senolytic drugs prevented lung fibrosis in Sin3a loss-of-function mice. Our findings establish a novel mouse model that recapitulates key pathological features of human IPA and show that p53-dependent senescence is a proximal regulator of TGF induction and progressive pulmonary fibrosis.
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| Overall design |
Single cell RNA-seq using 10x chromium system on enriched epithelial cells from 3 IPF patient samples ( Fibrotic region) and 3 donor control samples
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| Contributor(s) |
Yao C, Stripp BR |
| Citation(s) |
32991815 |
| Submission date |
Jun 18, 2019 |
| Last update date |
Oct 01, 2020 |
| Contact name |
Changfu Yao |
| E-mail(s) |
changfu.yao@cshs.org
|
| Phone |
424-315-4333
|
| Organization name |
cedars-sinai medical center
|
| Department |
Lung and Regenerative Medicine Institutes
|
| Lab |
Stripp Lab
|
| Street address |
8700 Beverly Blvd. AHSP Room A9401
|
| City |
los angeles |
| State/province |
Ca |
| ZIP/Postal code |
90048 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
|
| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE132915 |
Senescence rather than apoptosis of alveolar progenitor cells drives pulmonary fibrosis |
|
| Relations |
| BioProject |
PRJNA549454 |
| SRA |
SRP201755 |
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