SummaryTissue fibrosis is a common pathological outcome of chronic disease that markedly impairs organ function leading to morbidity and mortality. In the lung, idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Here, we show that alveolar type 2 (AT2) stem cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence with associated loss of SIN3A, a critical determinant of endodermal progenitor cell function in the developing lung. Conditional loss of Sin3a in adult mouse AT2 cells initiated a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of epithelial stem cells serves as a proximal driver of Tgfβ activation and progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation, senescence, or downstream Tgfβ activation, block fibrogenesis.
Yao, Changfu and Guan, Xiangrong and Carraro, Gianni and Parimon, Tanyalak and Liu, Xue and Soukiasian, Harmik J. and David, Gregory and Weigt, Stephen S. and Belperio, John A. and Chen, Peter and Jiang, Dianhua and Noble, Paul W. and Stripp, Barry R., Senescence of Alveolar Stem Cells Drives Progressive Pulmonary Fibrosis (August 16, 2019). Available at SSRN: https://ssrn.com/abstract=3438364 or http://dx.doi.org/10.2139/ssrn.3438364
This version of the paper has not been formally peer reviewed.
Subscribe to this free journal for more curated articles on this topic
FOLLOWERS
20
PAPERS
9,156
Feedback
Feedback to SSRN
If you need immediate assistance, call 877-SSRNHelp (877 777 6435) in the United States, or +1 212 448 2500 outside of the United States, 8:30AM to 6:00PM U.S. Eastern, Monday - Friday.