Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis

Mukherjee, Amitava; Epperly, Michael W.; Shields, Donna; Hou, Wen Chi; Fisher, Renee; Hamade, Diala Fatima; Wang, Hong; Huq, M. Saiful; Bao, Riyue; Tabib, Tracy; Monier, Daisy; Watkins, Simon C.; Calderon, Michael; Greenberger, Joel S.

doi:10.1038/s41420-021-00741-4

Cited by 18 publications

(22 citation statements)

References 62 publications

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“…Whether cellular senescence is responsible for RIF remains to be answered. Studies to date indicate that several cell types with biomarkers of senescence have been identified including SA-β-gal positive alveolar epithelial cells, putative alveolar stem cells, and mesenchymal stem cells [31][32][33].…”

Section: Biomarkers-available Evidence and Lack Of Consensusmentioning

confidence: 99%

Radiation-induced senescence: therapeutic opportunities

Kim¹,

Brown²,

Gordon

2023

Radiat Oncol

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The limitation of cancer radiotherapy does not derive from an inability to ablate tumor, but rather to do so without excessively damaging critical tissues and organs and adversely affecting patient’s quality of life. Although cellular senescence is a normal consequence of aging, there is increasing evidence showing that the radiation-induced senescence in both tumor and adjacent normal tissues contributes to tumor recurrence, metastasis, and resistance to therapy, while chronic senescent cells in the normal tissue and organ are a source of many late damaging effects. In this review, we discuss how to identify cellular senescence using various bio-markers and the role of the so-called senescence-associated secretory phenotype characteristics on the pathogenesis of the radiation-induced late effects. We also discuss therapeutic options to eliminate cellular senescence using either senolytics and/or senostatics. Finally, a discussion of cellular reprogramming is presented, another promising avenue to improve the therapeutic gain of radiotherapy.

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Section: Biomarkers-available Evidence and Lack Of Consensusmentioning

confidence: 99%

Radiation-induced senescence: therapeutic opportunities

Kim¹,

Brown²,

Gordon

2023

Radiat Oncol

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“…All of the senescent cells were found in the Non-SP cell population. The esophagi from mice treated with 4-NQO had 40.0±6.5% senescent cells, 25.7±7.2% OSM positive cells, and 20.9±7.5% senescent cells, which were OSM positive (Figure 1B) (51,52).…”

Section: Resultsmentioning

confidence: 99%

“…At the time of detection of senescence by scanning and imaging of p16 +/LUC mice, we sacrificed other tdTOMp16+ mice that had been similarly treated with 4-NQO for the same time duration (52). The esophagus was removed from tdTOMp16+ mice, SP and Non-SP cell populations were separated (44), and each subpopulation was analyzed for the percent of senescent cells (red color) and those simultaneously expressing biomarkers of carcinogenesis using RNAseq.…”

Section: Preparation Of Gfp+ Bone Marrow Chimeric Micementioning

confidence: 99%

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Carcinogen 4-Nitroquinoline Oxide (4-NQO) Induces Oncostatin-M (OSM) in Esophageal Cells

Mukherjee

Epperly

Fisher

et al. 2023

In Vivo

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Background/Aim: The earliest cellular and molecular biologic changes in the esophagus that lead to esophageal cancer were evaluated in a mouse model. We correlated numbers of senescent cells with the levels of expression of potentially carcinogenic genes in sorted side population (SP) cells containing esophageal stem cells and non-stem cells in the non-side population cells in the 4nitroquinolone oxide (NQO)-treated esophagus. Materials and Methods: We compared stem cells with non-stem cells from the esophagus of mice treated with the chemical carcinogen 4-NQO (100 μg/ml) in drinking water. We also compared gene expression in human esophagus samples treated with 4-NQO (100 μg/ml media) to non-treated samples. We separated and quantitated the relative levels of expression of RNA using RNAseq analysis. We identified senescent cells by luciferase imaging of p16 +/LUC mice and senescent cells in excised esophagus from tdTOMp16+ mice. Results: A significant increase in the levels of RNA for oncostatin-M was found in senescent cells of the esophagus from 4-NQO-treated mice and human esophagus in vitro. Conclusion: Induction of OSM in chemically-induced esophageal cancer in mice correlates with the appearance of senescent cells.

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“…Our work has been validated by immunofluorescence staining to confirm the presence of selected markers in specific cell populations, confirming the potential to reveal meaningful biological insights. It is noteworthy that scRNAseq of in vivo models of chronic IR injury has only been performed in liver (Xu et al, 2021), lung (Mukherjee et al, 2021), and skin (Paldor et al, 2022), and data is only publicly available for lung and skin. Thus, our study will also be an essential resource to better understand cell-specific responses to IR in general.…”

Section: Introductionmentioning

confidence: 99%

scRNAseq of healthy and irradiated mouse parotid glands highlights crosstalk between immune and secretory cells during chronic injury

Rheinheimer

Pasquale

Limesand

et al. 2022

Preprint

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Translational frameworks to understand the chronic loss of salivary dysfunction that follows after clinical irradiation, and the development of regenerative therapies remain an unmet clinical need. Understanding the transcriptional landscape long after irradiation treatment that results in chronic salivary hypofunction will help identify injury mechanisms and develop regenerative therapies to address this need. Advances in single cell (sc)RNAseq have made it possible to identify previously uncharacterized cell types within tissues and to uncover gene regulatory networks that mediate cell-cell communication and drive specific cell states. scRNAseq studies have been performed for virtually all major tissues including salivary glands; however, there are currently no scRNAseq studies the long-term chronic effects of irradiation on salivary glands. Here, we present scRNAseq from control and irradiated murine parotid glands collected 10 months post-irradiation. We identify a previously uncharacterized population of epithelial cells in the gland defined by expression of Etv1, which may be an acinar cell precursor. These Etv1+ cells also express Ntrk2 and Erbb3 and thus may respond to myoepithelial cell-derived growth factor ligands. Furthermore, our data suggests that CD8+ T-cells and secretory cells are the most transcriptionally affected during chronic injury with radiation, suggesting active immune involvement during chronic injury post-irradiation. Thus, our study provides a resource to understand the transcriptional landscape in a chronic post-irradiation microenvironment and identifies cell-specific pathways that may be targeted to repair chronic damage.

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Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis

Cited by 18 publications

References 62 publications

Radiation-induced senescence: therapeutic opportunities

Radiation-induced senescence: therapeutic opportunities

Carcinogen 4-Nitroquinoline Oxide (4-NQO) Induces Oncostatin-M (OSM) in Esophageal Cells

scRNAseq of healthy and irradiated mouse parotid glands highlights crosstalk between immune and secretory cells during chronic injury

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