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- Title
Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis.
- Authors
Mukherjee, Amitava; Epperly, Michael W.; Shields, Donna; Hou, Wen; Fisher, Renee; Hamade, Diala; Wang, Hong; Saiful Huq, M.; Bao, Riyue; Tabib, Tracy; Monier, Daisy; Watkins, Simon; Calderon, Michael; Greenberger, Joel S.
- Abstract
The role of cellular senescence in radiation-induced pulmonary fibrosis (RIPF) and the underlying mechanisms are unknown. We isolated radiation-induced senescent tdTOMp16 positive mesenchymal stem cells, established their absence of cell division, then measured levels of irradiation-induced expression of biomarkers of senescence by RNA-seq analysis. We identified a Log2 6.17-fold upregulation of tyrosine kinase Fgr, which was a potent inducer of biomarkers of fibrosis in target cells in non-contact co-cultures. Inhibition of Fgr by shRNA knockdown did not block radiation-induced senescence in vitro; however, both shRNA knockdown, or addition of a specific small-molecule inhibitor of Fgr, TL02-59, abrogated senescent cell induction of profibrotic genes in transwell-separated target cells. Single-cell RNA-seq (scRNAseq) analysis of mouse lungs at day 150 after 20 Gy thoracic irradiation revealed upregulation of Fgr in senescent neutrophils, and macrophages before detection of lung fibrosis. Thus, upregulated Fgr in radiation-induced senescent cells mediates RIPF and is a potential therapeutic target for the prevention of this radiation late effect.
- Subjects
PULMONARY fibrosis; RNA sequencing; MACROPHAGES; SMALL molecules; CELL division
- Publication
Cell Death Discovery, 2021, Vol 7, Issue 1, p1
- ISSN
2058-7716
- Publication type
Article
- DOI
10.1038/s41420-021-00741-4