Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis.
Amitava MukherjeeMichael W EpperlyDonna ShieldsWen HouRenee FisherDiala HamadeHong WangM Saiful HuqRiyue BaoTracy TabibDaisy MonierSimon WatkinsMichael J CalderonJoel S GreenbergerPublished in: Cell death discovery (2021)
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.
Keyphrases
- radiation induced
- single cell
- rna seq
- radiation therapy
- induced apoptosis
- tyrosine kinase
- cell cycle arrest
- small molecule
- mesenchymal stem cells
- poor prognosis
- endoplasmic reticulum stress
- dna damage
- signaling pathway
- cell therapy
- cell proliferation
- oxidative stress
- epidermal growth factor receptor
- gene expression
- long non coding rna
- climate change
- spinal cord
- transcription factor
- bone marrow
- quantum dots
- pi k akt
- genome wide identification