RT Journal Article
SR Electronic
T1 Senescence of alveolar stem cells drives progressive pulmonary fibrosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 820175
DO 10.1101/820175
A1 Changfu Yao
A1 Xiangrong Guan
A1 Gianni Carraro
A1 Tanyalak Parimon
A1 Xue Liu
A1 Guanling Huang
A1 Harmik J. Soukiasian
A1 Gregory David
A1 Stephen S. Weigt
A1 John A. Belperio
A1 Peter Chen
A1 Dianhua Jiang
A1 Paul W. Noble
A1 Barry R. Stripp
YR 2019
UL http://biorxiv.org/content/early/2019/11/18/820175.abstract
AB Tissue 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. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate 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.