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Senescence of Alveolar Stem Cells Drives Progressive Pulmonary Fibrosis

54 Pages Posted: 16 Aug 2019 Sneak Peek Status: Review Complete

See all articles by Changfu Yao

Changfu Yao

Cedars Sinai Medical Center - Women’s Guild Lung Institute

Xiangrong Guan

Cedars Sinai Medical Center - Women’s Guild Lung Institute

Gianni Carraro

Cedars Sinai Medical Center - Lung and Regenerative Medicine Institutes

Tanyalak Parimon

Cedars Sinai Medical Center - Women’s Guild Lung Institute

Xue Liu

Cedars Sinai Medical Center - Women’s Guild Lung Institute

Harmik J. Soukiasian

Cedars Sinai Medical Center - Division of Thoracic Surgery

Gregory David

New York University (NYU) - Department of Biochemistry and Molecular Pharmacology

Stephen S. Weigt

University of California, Los Angeles (UCLA) - Department of Medicine

John A. Belperio

University of California, Los Angeles (UCLA) - Department of Medicine

Peter Chen

Cedars Sinai Medical Center - Women’s Guild Lung Institute

Dianhua Jiang

Cedars Sinai Medical Center - Women’s Guild Lung Institute

Paul W. Noble

Cedars Sinai Medical Center - Women’s Guild Lung Institute

Barry R. Stripp

Cedars Sinai Medical Center - Lung and Regenerative Medicine Institutes

More...

Abstract

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.

Keywords: Fibrosis, IPF, Alveolar Type 2 cells, Cellular Senescence, Sin3a, p53, TGFβ

Suggested Citation

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). CELL-STEM-CELL-D-19-00545. Available at SSRN: https://ssrn.com/abstract=3438364 or http://dx.doi.org/10.2139/ssrn.3438364
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Changfu Yao

Cedars Sinai Medical Center - Women’s Guild Lung Institute ( email )

United States

Xiangrong Guan

Cedars Sinai Medical Center - Women’s Guild Lung Institute

United States

Gianni Carraro

Cedars Sinai Medical Center - Lung and Regenerative Medicine Institutes

United States

Tanyalak Parimon

Cedars Sinai Medical Center - Women’s Guild Lung Institute

United States

Xue Liu

Cedars Sinai Medical Center - Women’s Guild Lung Institute

United States

Harmik J. Soukiasian

Cedars Sinai Medical Center - Division of Thoracic Surgery

United States

Gregory David

New York University (NYU) - Department of Biochemistry and Molecular Pharmacology

United States

Stephen S. Weigt

University of California, Los Angeles (UCLA) - Department of Medicine

Los Angeles, CA
United States

John A. Belperio

University of California, Los Angeles (UCLA) - Department of Medicine

Los Angeles, CA
United States

Peter Chen

Cedars Sinai Medical Center - Women’s Guild Lung Institute

United States

Dianhua Jiang

Cedars Sinai Medical Center - Women’s Guild Lung Institute ( email )

United States

Paul W. Noble

Cedars Sinai Medical Center - Women’s Guild Lung Institute

United States

Barry R. Stripp (Contact Author)

Cedars Sinai Medical Center - Lung and Regenerative Medicine Institutes ( email )

United States

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