An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis

The appearance of senescent cells in age-related diseases has spurred the search for compounds that can target senescent cells in tissues ("senolytics"). However, a major caveat with current senolytic screens is the use of cell lines as targets where senescence is induced in vitro, which d...

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Published in:The Journal of clinical investigation Vol. 134; no. 9; pp. 1 - 16
Main Authors: Lee, Jin Young, Reyes, Nabora S., Ravishankar, Supriya, Zhou, Minqi, Krasilnikov, Maria, Ringler, Christian, Pohan, Grace, Wilson, Chris, Ang, Kenny Kean-Hooi, Wolters, Paul J., Tsukui, Tatsuya, Sheppard, Dean, Arkin, Michelle R., Peng, Tien
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 01.05.2024
Subjects:
Age
Aging
Animal models
Biomarkers
Cell lines
Cells
Fibroblasts
Fibrosis
Gene expression
High-throughput screening
Hsp90 protein
INK4a protein
Lung diseases
Lungs
p16 Protein
Pulmonary fibrosis
Pulmonology
Senescence
Pulmonology
Aging
Cellular senescence
Fibrosis
Drug screens
ISSN:1558-8238, 0021-9738, 1558-8238
Online Access:Get full text
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Summary:The appearance of senescent cells in age-related diseases has spurred the search for compounds that can target senescent cells in tissues ("senolytics"). However, a major caveat with current senolytic screens is the use of cell lines as targets where senescence is induced in vitro, which does not necessarily reflect the identity and function of pathogenic senescent cells in vivo. Here, we developed a new pipeline leveraging a fluorescent murine reporter that allows for isolation and quantification of p16Ink4a+ cells in diseased tissues. By high-throughput screening in vitro, precision cut lung slice (PCLS) screening ex vivo, and phenotypic screening in vivo, we identified a HSP90 inhibitor (XL888) as a potent senolytic in tissue fibrosis. XL888 treatment eliminated pathogenic p16Ink4a+ fibroblasts in a murine model of lung fibrosis and reduced fibrotic burden. Finally, XL888 preferentially targeted p16INK4a-high human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF), and reduced p16INK4a+ fibroblasts from IPF PCLS ex vivo. This study provides proof of concept for a platform where p16INK4a+ cells are directly isolated from diseased tissues to identify compounds with in vivo and ex vivo efficacy in mouse and human respectively and provides a senolytic screening platform for other age-related diseases.
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ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI173371