PMID- 38451724
OWN - NLM
STAT- MEDLINE
DCOM- 20240501
LR  - 20240503
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 134
IP  - 9
DP  - 2024 Mar 7
TI  - An in vivo screening platform identifies senolytic compounds that target 
      p16INK4a+ fibroblasts in lung fibrosis.
LID - 10.1172/JCI173371 [doi]
LID - e173371
AB  - The appearance of senescent cells in age-related diseases has spurred the search 
      for compounds that can target senescent cells in tissues, termed 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-hi 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 mice and humans, 
      respectively, and provides a senolytic screening platform for other age-related 
      diseases.
FAU - Lee, Jin Young
AU  - Lee JY
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep.
FAU - Reyes, Nabora S
AU  - Reyes NS
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep.
FAU - Ravishankar, Supriya
AU  - Ravishankar S
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep.
FAU - Zhou, Minqi
AU  - Zhou M
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep.
FAU - Krasilnikov, Maria
AU  - Krasilnikov M
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep.
FAU - Ringler, Christian
AU  - Ringler C
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep.
FAU - Pohan, Grace
AU  - Pohan G
AD  - Small Molecule Discovery Center, and.
FAU - Wilson, Chris
AU  - Wilson C
AD  - Small Molecule Discovery Center, and.
FAU - Ang, Kenny Kean-Hooi
AU  - Ang KK
AD  - Small Molecule Discovery Center, and.
FAU - Wolters, Paul J
AU  - Wolters PJ
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep.
FAU - Tsukui, Tatsuya
AU  - Tsukui T
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep.
FAU - Sheppard, Dean
AU  - Sheppard D
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep.
FAU - Arkin, Michelle R
AU  - Arkin MR
AD  - Small Molecule Discovery Center, and.
FAU - Peng, Tien
AU  - Peng T
AD  - Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep.
AD  - Bakar Aging Research Institute, UCSF, San Francisco, California, USA.
LA  - eng
GR  - P30 DK063720/DK/NIDDK NIH HHS/United States
GR  - R00 HL155786/HL/NHLBI NIH HHS/United States
GR  - R01 HL155622/HL/NHLBI NIH HHS/United States
GR  - K99 HL168365/HL/NHLBI NIH HHS/United States
GR  - R01 HL160895/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20240307
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Senotherapeutics)
RN  - 0 (Cdkn2a protein, mouse)
RN  - 0 (CDKN2A protein, human)
RN  - 0 (HSP90 Heat-Shock Proteins)
SB  - IM
CIN - A pipeline for senolytics
MH  - Animals
MH  - *Cyclin-Dependent Kinase Inhibitor p16/metabolism/genetics
MH  - Mice
MH  - Humans
MH  - *Fibroblasts/metabolism/pathology/drug effects
MH  - *Cellular Senescence/drug effects
MH  - *Idiopathic Pulmonary Fibrosis/pathology/metabolism/drug therapy/genetics
MH  - Senotherapeutics/pharmacology
MH  - Male
MH  - Lung/pathology/metabolism
MH  - Female
MH  - HSP90 Heat-Shock Proteins/metabolism/antagonists & inhibitors/genetics
PMC - PMC11060735
OTO - NOTNLM
OT  - Aging
OT  - Cellular senescence
OT  - Drug screens
OT  - Fibrosis
OT  - Pulmonology
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists.
EDAT- 2024/03/07 18:42
MHDA- 2024/05/01 13:31
PMCR- 2024/03/07
CRDT- 2024/03/07 12:04
PHST- 2023/06/27 00:00 [received]
PHST- 2024/03/05 00:00 [accepted]
PHST- 2024/05/01 13:31 [medline]
PHST- 2024/03/07 18:42 [pubmed]
PHST- 2024/03/07 12:04 [entrez]
PHST- 2024/03/07 00:00 [pmc-release]
AID - 173371 [pii]
AID - 10.1172/JCI173371 [doi]
PST - epublish
SO  - J Clin Invest. 2024 Mar 7;134(9):e173371. doi: 10.1172/JCI173371.