2. Academic Validation
  3. Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis

Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis

  • Cell Death Discov. 2021 Nov 12;7(1):349. doi: 10.1038/s41420-021-00741-4.
Amitava Mukherjee 1,  Michael W Epperly 1,  Donna Shields 1,  Wen Hou 1,  Renee Fisher 1,  Diala Hamade 1,  Hong Wang 2,  M Saiful Huq 1,  Riyue Bao 3,  Tracy Tabib 4,  Daisy Monier 4,  Simon Watkins 5,  Michael Calderon 5,  Joel S Greenberger 6
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
  • 2 Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
  • 3 Department of Hematology/Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
  • 4 Department of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5 Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 6 Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. greenbergerjs@upmc.edu.
PMID: 34772919 DOI: 10.1038/s41420-021-00741-4
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.

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