한빛사
>
한빛사논문
한빛사논문
- 조회275
J. Clin. Invest., Mar 07 2024, e173371 | https://doi.org/10.1172/JCI173371
An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis
Jin Young Lee1, Nabora S. Reyes1, Supriya Ravishankar1, Minqi Zhou1, Maria Krasilnikov1, Christian Ringler1, Grace Pohan2, Chris Wilson2, Kenny Kean-Hooi Ang2, Paul J. Wolters1, Tatsuya Tsukui1, Dean Sheppard1, Michelle R. Arkin2 and Tien Peng1,3*
1Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep
2Small Molecule Discovery Center
3Bakar Aging Research Institute University of California San Francisco San Francisco, CA, USA
*Address correspondence to: Tien Peng, M.D.
Abstract
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.
논문정보
- Research article
- 2024년 03월 (BRIC 등록일 2024-03-12)
- 국외 연구진
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
연구자 ID
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
