Effect of Low-Dose Ionizing Radiation on the Expression of Mitochondria-Related Genes in Human Mesenchymal Stem Cells

The concept of hormesis describes a phenomenon of adaptive response to low-dose ionizing radiation (LDIR). Similarly, the concept of mitohormesis states that the adaptive program in mitochondria is activated in response to minor stress effects. The mechanisms of hormesis effects are not clear, but it is assumed that they can be mediated by reactive oxygen species. Here, we studied effects of LDIR on mitochondria in mesenchymal stem cells. We have found that X-ray radiation at a dose of 10 cGy as well as oxidized fragments of cell-free DNA (cfDNA) at a concentration of 50 ng/mL resulted in an increased expression of a large number of genes regulating the function of the mitochondrial respiratory chain complexes in human mesenchymal stem cells (MSC). Several genes remained upregulated within hours after the exposure. Both X-ray radiation and oxidized cfDNA resulted in upregulation of FIS1 and MFN1 genes, which regulated fusion and fission of mitochondria, within 3–24 h after the exposure. Three hours after the exposure, the number of copies of mitochondrial DNA in cells had increased. These findings support the hypothesis that assumes oxidized cell-free DNA as a mediator of MSC response to low doses of radiation.

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Low-Dose Ionizing Radiation Affects Mesenchymal Stem Cells via Extracellular Oxidized Cell-Free DNA: A Possible Mediator of Bystander Effect and Adaptive Response

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/9515809 ◽

2017 ◽

Vol 2017 ◽

pp. 1-22 ◽

Cited By ~ 8

Author(s):

V. A. Sergeeva ◽

E. S. Ershova ◽

N. N. Veiko ◽

E. M. Malinovskaya ◽

A. A. Kalyanov ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Ionizing Radiation ◽

Adaptive Response ◽

Low Dose ◽

Low Doses ◽

Dna Breaks ◽

Cell Free Dna ◽

Free Dna

We have hypothesized that the adaptive response to low doses of ionizing radiation (IR) is mediated by oxidized cell-free DNA (cfDNA) fragments. Here, we summarize our experimental evidence for this model. Studies involving measurements of ROS, expression of the NOX (superoxide radical production), induction of apoptosis and DNA double-strand breaks, antiapoptotic gene expression and cell cycle inhibition confirm this hypothesis. We have demonstrated that treatment of mesenchymal stem cells (MSCs) with low doses of IR (10 cGy) leads to cell death of part of cell population and release of oxidized cfDNA. cfDNA has the ability to penetrate into the cytoplasm of other cells. Oxidized cfDNA, like low doses of IR, induces oxidative stress, ROS production, ROS-induced oxidative modifications of nuclear DNA, DNA breaks, arrest of the cell cycle, activation of DNA reparation and antioxidant response, and inhibition of apoptosis. The MSCs pretreated with low dose of irradiation or oxidized cfDNA were equally effective in induction of adaptive response to challenge further dose of radiation. Our studies suggest that oxidized cfDNA is a signaling molecule in the stress signaling that mediates radiation-induced bystander effects and that it is an important component of the development of radioadaptive responses to low doses of IR.

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Cell-free DNA fragments increase transcription in human mesenchymal stem cells, activate tlr-dependent signal pathway and supress apoptosis

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20125806673 ◽

2012 ◽

Vol 58 (6) ◽

pp. 673-683 ◽

Cited By ~ 5

Author(s):

S.V. Kostyuk ◽

E.M. Malinovskaya ◽

A.V. Ermakov ◽

T.D. Smirnova ◽

L.V. Kameneva ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Functional Activity ◽

Human Mesenchymal Stem Cells ◽

Signal Pathway ◽

Signal Pathways ◽

Dna Fragments ◽

Cell Free Dna ◽

Free Dna ◽

Dependent Signal

Human mesenchymal stem cells (MSCs) are now widely adopted in regenerative medicine. However, many questions on the role of different signaling pathways in the regulation of stem cell (SC) functional activity within the organism remain unaswered. In damaged regions the level of cell death increases and DNA fragments from dead cells (cell-free DNA, cfDNA) are accumulated in blood. We showed that in adipose-derived MSCs exposed in vitro to cfDNA fragments the transcription level increased (the total amount of cellular RNA and the rRNA amount rose). GC-rich CfDNA fragments (GC-DNA) activated the TLR9-dependent signal pathway: the expression of TLR9 and of TLR9-signaling pathway adapter - MyD88 - was up-regulated. AT-rich DNA fragments did not increase the TLR9 expression, though, the MyD88 expression level rose. So we suggest that AT-DNA acts via some other receptors that nevertheless activate MyD88-dependent signalling in MSCs. We also showed that cfDNA fragments decreased the activity of caspase, an apoptotic enzyme. So, cfDNA can significantly influence the functional activity of MSC by activating TLR9- and MyD88-dependent signal pathways and lowering the apoptosis level.

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Fragments of cell-free DNA increase transcription in human mesenchymal stem cells, activate TLR-dependent signal pathway, and suppress apoptosis

Biochemistry (Moscow) Supplement Series B Biomedical Chemistry ◽

10.1134/s1990750812010052 ◽

2012 ◽

Vol 6 (1) ◽

pp. 68-74 ◽

Cited By ~ 3

Author(s):

S. V. Kostyuk ◽

E. M. Malinovskaya ◽

A. V. Ermakov ◽

T. D. Smirnova ◽

L. V. Kameneva ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Human Mesenchymal Stem Cells ◽

Signal Pathway ◽

Cell Free Dna ◽

Free Dna ◽

Dependent Signal

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Fragments of Cell-Free DNA (cfDNA) Enhance Transcription Activity in Human Mesenchymal Stem Cells (hMSCs) and Inhibit Their In Vitro Differentiation

Circulating Nucleic Acids in Plasma and Serum ◽

10.1007/978-90-481-9382-0_27 ◽

2010 ◽

pp. 199-205 ◽

Cited By ~ 1

Author(s):

Elena M. Malinovskaya ◽

Svetlana V. Kostyuk ◽

Aleksey V. Ermakov ◽

Marina S. Konkova ◽

Tatjana D. Smirnova ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Human Mesenchymal Stem Cells ◽

In Vitro Differentiation ◽

Cell Free Dna ◽

Transcription Activity ◽

Free Dna

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The sensitivity of human mesenchymal stem cells to ionizing radiation

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2006.03.062 ◽

2006 ◽

Vol 66 (1) ◽

pp. 244-253 ◽

Cited By ~ 125

Author(s):

Miao-Fen Chen ◽

Ching-Tai Lin ◽

Wen-Cheng Chen ◽

Cheng-Ta Yang ◽

Chih-Cheng Chen ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Ionizing Radiation ◽

Human Mesenchymal Stem Cells

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Photo biostimulatory effect of low dose photodynamic therapy on human mesenchymal stem cells

Photodiagnosis and Photodynamic Therapy ◽

10.1016/j.pdpdt.2020.101886 ◽

2020 ◽

Vol 31 ◽

pp. 101886

Author(s):

Reza Fekrazad ◽

Sohrab Asefi ◽

Khatereh Khorsandi ◽

Marzieh Nejatifard

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Photodynamic Therapy ◽

Low Dose ◽

Human Mesenchymal Stem Cells

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Analysis of the Effects of Low-Dose Radiation on Human Mesenchymal Stem Cells

Medical Radiology and radiation safety ◽

10.12737/1024-6177-2020-65-6-5-10 ◽

2021 ◽

Vol 65 (6) ◽

pp. 5-10

Author(s):

D. Usupzhanova ◽

T. Astrelina ◽

I. Kobzeva ◽

V. Nikitina ◽

Yu. Suchkova ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Conditioned Medium ◽

Adaptive Response ◽

Proliferative Activity ◽

Human Mesenchymal Stem Cells ◽

Conditioned Media ◽

X Ray ◽

Cultivation In Vitro

Purpose: The aim of the study was to study the effect of low X-ray doses on human mesenchymal stem cells (MSCs) in long-term cultivation in vitro. Material and methods: MSCs of the mucosal gum tissue of human were used. Cells were irradiated using an RUST-M1 X-ray unit (Russia) at doses of 50, 80, 100, 250 and 1000 mGy (dose rate40 mGy/min) and then cultivated according to standard methods. Immunological characteristics and viability of MSCs were evaluated on a FACSCanto II flow cytometer (Becton Dickinson CA, USA) for early and late passengers. Proliferative activity (PA) was evaluated using an xCelligence real-time cell analyzer (ACEA Biosciencs, Inc.). Results: It was shown that the proliferative activity (PA) of MSCs of the mucosal gum tissue which were irradiated at dose 50 mGy is comparable with the control group in long-term cultivation while doses of 100 and 250 mGy showed a decrease of PA. Also non-irradiated MSCs showed a significant decrease of the PA during cultivation in a conditioned medium from cells that received dose of 1000 mGy and an increase of PA during cultivation in a conditioned medium of cells that received doses of 50, 100 and 250 mGy. The cells were previously irradiated at dose 250 mGy showed adaptive response during cultivation in conditioned medium from cells that received dose of 1000 mGy. Сonclusion: The assessment of the effects of low radiation doses was focused on the bystander effect in the presented study. It was noted after adding conditioned media from irradiated cells to previously irradiated and non-irradiated MSCs. The bystander effects for low and high doses are different and their biological meaning requires further study. The phenomenon of adaptive response was shown after addition conditioned media from cells irradiated at dose 1000 mGy to pre-irradiated MSCs received a dose of 250 mGy. The obtained result leads to the conclusion that the effects of low doses can be positive. Thus, the results of study mainly correspond to the threshold nonlinear concept, according to which the effect is not proportional to the received radiation dose.

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