Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis

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...

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Autores principales:	Amitava Mukherjee, Michael W. Epperly, Donna Shields, Wen Hou, Renee Fisher, Diala Hamade, Hong Wang, M. Saiful Huq, Riyue Bao, Tracy Tabib, Daisy Monier, Simon Watkins, Michael Calderon, Joel S. Greenberger
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/0d506b65bfd24c52a6be862101f64fb6
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spelling	oai:doaj.org-article:0d506b65bfd24c52a6be862101f64fb62021-11-14T12:12:33ZIonizing irradiation-induced Fgr in senescent cells mediates fibrosis10.1038/s41420-021-00741-42058-7716https://doaj.org/article/0d506b65bfd24c52a6be862101f64fb62021-11-01T00:00:00Zhttps://doi.org/10.1038/s41420-021-00741-4https://doaj.org/toc/2058-7716Abstract 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.Amitava MukherjeeMichael W. EpperlyDonna ShieldsWen HouRenee FisherDiala HamadeHong WangM. Saiful HuqRiyue BaoTracy TabibDaisy MonierSimon WatkinsMichael CalderonJoel S. GreenbergerNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282CytologyQH573-671ENCell Death Discovery, Vol 7, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671 Amitava Mukherjee Michael W. Epperly Donna Shields Wen Hou Renee Fisher Diala Hamade Hong Wang M. Saiful Huq Riyue Bao Tracy Tabib Daisy Monier Simon Watkins Michael Calderon Joel S. Greenberger Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis
description	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.
format	article
author	Amitava Mukherjee Michael W. Epperly Donna Shields Wen Hou Renee Fisher Diala Hamade Hong Wang M. Saiful Huq Riyue Bao Tracy Tabib Daisy Monier Simon Watkins Michael Calderon Joel S. Greenberger
author_facet	Amitava Mukherjee Michael W. Epperly Donna Shields Wen Hou Renee Fisher Diala Hamade Hong Wang M. Saiful Huq Riyue Bao Tracy Tabib Daisy Monier Simon Watkins Michael Calderon Joel S. Greenberger
author_sort	Amitava Mukherjee
title	Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis
title_short	Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis
title_full	Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis
title_fullStr	Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis
title_full_unstemmed	Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis
title_sort	ionizing irradiation-induced fgr in senescent cells mediates fibrosis
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/0d506b65bfd24c52a6be862101f64fb6
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_version_	1718429330018664448

Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis

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