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

2017 ◽  
Vol 2017 ◽  
pp. 1-22 ◽  
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.

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

2021 ◽  
Vol 23 (1) ◽  
pp. 261
Author(s):  
Svetlana V. Kostyuk ◽  
Elena V. Proskurnina ◽  
Marina S. Konkova ◽  
Margarita S. Abramova ◽  
Andrey A. Kalianov ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Ionizing Radiation ◽  
Low Dose ◽  
Human Mesenchymal Stem Cells ◽  
Mitochondrial Respiratory Chain ◽  
Respiratory Chain Complexes ◽  
Cell Free Dna ◽  
X Ray ◽  
Free Dna

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.

scholarly journals Mesenchymal Stem Cells Early Response to Low-Dose Ionizing Radiation

2020 ◽  
Vol 8 ◽  
Author(s):  
Marina Konkova ◽  
Margarita Abramova ◽  
Andrey Kalianov ◽  
Elizaveta Ershova ◽  
Olga Dolgikh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Mesenchymal Stem Cells ◽  
Ionizing Radiation ◽  
Low Dose ◽  
Early Response ◽  
Dna Breaks ◽  
Essential Components

IntroductionMesenchymal stem cells (MSCs) are applied as the therapeutic agents, e.g., in the tumor radiation therapy.Purpose of the StudyTo evaluate the human adipose MSC early response to low-dose ionizing radiation (LDIR).Materials and MethodsWe investigated different LDIR (3, 10, and 50 cGy) effects on reactive oxygen species production, DNA oxidation (marker 8-oxodG), and DNA breaks (marker ɣ H2AX) in the two lines of human adipose MSC. Using reverse transcriptase–polymerase chain reaction, fluorescence-activated cell sorting, and fluorescence microscopy, we determined expression of genes involved in the oxidative stress development (NOX4), antioxidative response (NRF2), antiapoptotic and proapoptotic response (BCL2, BCL2A1, BCL2L1, BIRC2, BIRC3, and BAX1), in the development of the nuclear DNA damage response (DDR) (BRCA1, BRCA2, ATM, and P53). Cell cycle changes were investigated by genes transcription changes (CCND1, CDKN2A, and CDKN1A) and using proliferation markers KI-67 and proliferating cell nuclear antigen (PCNA).ResultsFifteen to 120 min after exposure to LDIR in MSCs, transient oxidative stress and apoptosis of the most damaged cells against the background of the cell cycle arrest were induced. Simultaneously, DDR and an antiapoptotic response were found in other cells of the population. The 10-cGy dose causes the strongest and fastest DDR following cell nuclei DNA damage. The 3-cGy dose induces a less noticeable and prolonged response. The maximal low range dose, 50 cGy, causes a damaging effect on the MSCs.ConclusionTransient oxidative stress and the death of a small fraction of the damaged cells are essential components of the MSC population response to LDIR along with the development of DDR and antiapoptotic response. A scheme describing the early MSC response to LDIR is proposed.

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

2012 ◽  
Vol 58 (6) ◽  
pp. 673-683 ◽  
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.

scholarly journals The Low-dose Ionizing Radiation Stimulates Cell Proliferation via Activation of the MAPK/ERK Pathway in Rat Cultured Mesenchymal Stem Cells

2011 ◽  
Vol 52 (3) ◽  
pp. 380-386 ◽  
Author(s):  
Xinyue LIANG ◽  
You Ho SO ◽  
Jiuwei CUI ◽  
Kewei MA ◽  
Xiaoyi XU ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
Ionizing Radiation ◽  
Low Dose ◽  
Erk Pathway

Development of the Adaptive Response and Bystander Effect Induced by Low-Dose Ionising Radiation in Human Mesenchymal Stem Cells

2010 ◽  
pp. 225-231
Author(s):  
Aleksey V. Ermakov ◽  
Marina S. Konkova ◽  
Svetlana V. Kostyuk ◽  
Tatjana D. Smirnova ◽  
Liudmila V. Efremova ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adaptive Response ◽  
Low Dose ◽  
Bystander Effect ◽  
Human Mesenchymal Stem Cells ◽  
Ionising Radiation

scholarly journals Fork Slowing and Reversal as an Adaptive Response to Chronic ATR Inhibition

2021 ◽  
Author(s):  
Diego Dibitetto ◽  
Andrea Sanchi ◽  
Ethan J. Sanford ◽  
Massimo Lopes ◽  
Marcus B. Smolka
Keyword(s):  
Cell Cycle ◽  
Cell Survival ◽  
Adaptive Response ◽  
Mitotic Catastrophe ◽  
Cancer Therapies ◽  
Low Doses ◽  
Dna Breaks ◽  
Origin Firing ◽  
Anti Cancer ◽  
Molecular Effects

Inhibitors of the replication stress response kinase ATR are currently being explored in anti-cancer therapy. Acute ATR inhibition is known to impair the proper control of origin firing, DNA repair, and cell cycle, resulting in DNA breaks and mitotic catastrophe. Less is understood about the effects of clinically relevant regimes of ATR inhibition, which involve chronic and low doses of ATR inhibitors (cATRi) to cells. Here we report distinctive molecular effects of cATRi on replication dynamics. cATRi strongly reduces fork speed but has minimal effects on the accumulation of DNA breaks or cell survival. cATRi promotes extensive fork reversal and RAD51- and PARP-mediated fork slowing that correlate with the accumulation of DNA-RNA hybrids. Our work shows that fork reversal is a critical adaptive response ensuring cell survival during cATRi and that the manipulation of fork reversal causes hypersensitivity to cATRi, increasing the effectiveness of ATR inhibitors in anti-cancer therapies.

High Glucose Affects the Cytotoxic Potential of Rapamycin, Metformin and Hydrogen Peroxide in Cultured Human Mesenchymal Stem Cells

2019 ◽  
Vol 19 (9) ◽  
pp. 688-698 ◽  
Author(s):  
Azam Roohi ◽  
Mahin Nikougoftar ◽  
Hamed Montazeri ◽  
Shadisadat Navabi ◽  
Fazel Shokri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Hydrogen Peroxide ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Viability ◽  
High Glucose ◽  
Cell Cycle Distribution ◽  
Efficient Treatment ◽  
Chronic Hyperglycemia ◽  
Placental Mesenchymal Stem Cells

Background: Oxidative stress and chronic hyperglycemia are two major side effects of type 2 diabetes affecting all cell types including mesenchymal stem cells (MSCs). As a cell therapy choice, understanding the behavior of MSCs will provide crucial information for efficient treatment. Methods: Placental mesenchymal stem cells were treated with various concentrations of glucose, metformin, rapamycin, and hydrogen peroxide to monitor their viability and cell cycle distribution. Cellular viability was examined via the MTT assay. Cell cycle distribution was studied by propidium iodide staining and apoptosis was determined using Annexin Vpropidium iodide staining and flow cytometry. Involvement of potential signaling pathways was evaluated by Western blotting for activation of Akt, P70S6K, and AMPK. Results: The results indicated that high glucose augmented cell viability and reduced metformin toxic potential. However, the hydrogen peroxide and rapamycin toxicities were exacerbated. Conclusion: Our findings suggest that high glucose concentration has a major effect on placental mesenchymal stem cell viability in the presence of rapamycin, metformin and hydrogen peroxide in culture.

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