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Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis
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 expressi...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585734/ https://www.ncbi.nlm.nih.gov/pubmed/34772919 http://dx.doi.org/10.1038/s41420-021-00741-4 |
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author | 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. |
author_facet | 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. |
author_sort | Mukherjee, Amitava |
collection | PubMed |
description | 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 | Online Article Text |
id | pubmed-8585734 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85857342021-11-12 Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis 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. Cell Death Discov Article 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. Nature Publishing Group UK 2021-11-12 /pmc/articles/PMC8585734/ /pubmed/34772919 http://dx.doi.org/10.1038/s41420-021-00741-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article 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. Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis |
title | 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_short | Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis |
title_sort | ionizing irradiation-induced fgr in senescent cells mediates fibrosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585734/ https://www.ncbi.nlm.nih.gov/pubmed/34772919 http://dx.doi.org/10.1038/s41420-021-00741-4 |
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