Oxidative Stress and Gene Expression Modifications Mediated by Extracellular Vesicles: An In Vivo Study of the Radiation-Induced Bystander Effect

Abstract

Radiation-induced bystander effect is a biological response in nonirradiated cells receiving signals from cells exposed to ionising radiation. The aim of this in vivo study was to analyse whether extracellular vesicles (EVs) originating from irradiated mice could induce modifications in the redox status and expression of radiation-response genes in bystander mice. C57BL/6 mice were whole-body irradiated with 0.1-Gy and 2-Gy X-rays, and EVs originating from mice irradiated with the same doses were injected into naïve, bystander mice. Lipid peroxidation in the spleen and plasma reactive oxygen metabolite (ROM) levels increased 24 h after irradiation with 2 Gy. The expression of antioxidant enzyme genes and inducible nitric oxide synthase 2 (iNOS2) decreased, while cell cycle arrest-, senescence- and apoptosis-related genes were upregulated after irradiation with 2 Gy. In bystander mice, no significant alterations were observed in lipid peroxidation or in the expression of genes connected to cell cycle arrest, senescence and apoptosis. However, there was a systemic increase in the circulating ROM level after an intravenous EV injection, and EVs originating from 2-Gy-irradiated mice caused a reduced expression of antioxidant enzyme genes and iNOS2 in bystander mice. In conclusion, we showed that ionising radiation-induced alterations in the cellular antioxidant system can be transmitted in vivo in a bystander manner through EVs originating from directly irradiated animals.

Roles of extracellular vesicles in the aging microenvironment and age‐related diseases

“…In genotoxic aging models with either irradiated breast cancer cells or irradiated mice, EVs can directly induce telomere attrition and DDR in recipients, causing genomic instability and aging. However, this effect is reduced by RNase treatment or thermal denaturation by boiling, which suggests that protein-and RNA-containing EVs indeed have effects on telomere shortening and DNA damage (Al-Mayah et al, 2017;Hargitai et al, 2021). In addition, EVs can mediate genomic instability through senescenceassociated genome-wide hypomethylation to spread senescence characteristics to neighbouring cells.…”

Extracellular Vesicles as Natural Delivery Carriers Regulate Oxidative Stress Under Pathological Conditions

“…And this radiation-induced bystander effect is also present in the body. EVs originated from mice irradiated with 2-Gy X-rays are intravenously injected into bystander mice, and the circulating reactive oxygen metabolite (ROM) level is increased ( Hargitai et al, 2021 ). Ketamine-injured human uroepithelial cells (SV-HUC-1) cells can secrete EVs containing specific miRNAs.…”

Extracellular Vesicles for the Treatment of Radiation Injuries

“…In an in vivo study, the damaged DNA foci were significantly higher in non-irradiated mouse fibroblast cells when treated with the irradiated mouse's serum-EVs than non-irradiated mouse serum-EVs ( Ariyoshi et al, 2019 ). In another study, downregulation of antioxidant enzyme genes and cellular redox system (iNOS2) genes was observed in non-irradiated mice as a bystander effect when injected with bone marrow-EVs from irradiated mice ( Hargitai et al, 2021 ). In the same token, recent evidence suggests that EVs as SASP, secreted from senescent cells might contribute to tumorigenesis and age-associated pathologies ( Misawa et al, 2020 ).…”