Mesenchymal Stem Cells Early Response to Low-Dose Ionizing Radiation

Konkova, Marina S.; Abramova, M. S.; Кальянов, А. А.; Ershova, Elizaveta S.; Долгих, О. А.; Umriukhin, Pavel E.; Izhevskaya, Vera L.; Kutsev, Sergey I.; Veiko, Natalia N.; Kostyuk, Svetlana V.

doi:10.3389/fcell.2020.584497

Cited by 11 publications

(9 citation statements)

References 60 publications

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“…To sum, low-dose X-ray radiation, as well as oxidized cfDNA, lead to short-term intracellular oxidative stress. We have previously shown that an increase in intracellular ROS is a consequence of the activation of NADPH oxidases, one of which is NOX4 [ 21 , 22 , 23 ]. Another source of intracellular ROS is a mitochondrial respiratory chain.…”

Section: Resultsmentioning

confidence: 99%

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

Kostyuk

Проскурнина

Konkova

et al. 2021

IJMS

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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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Section: Resultsmentioning

confidence: 99%

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

Kostyuk

Проскурнина

Konkova

et al. 2021

IJMS

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“…It can be speculatively assumed that NOX4 gene over-expression in the lymphocytes of some SZ patients results from the development of an adaptive response improving cell survival under conditions of oxidative stress, which is aggravated during disease exacerbation. We discussed earlier that the response of schizophrenic lymphocytes to endogenous oxidative stress is very similar to the response of healthy donor cells to the low doses of ionizing radiation (LDIR) [ 20 , 49 ]. Indeed, NOX4 gene expression seemed to elevate significantly in both in differentiated and stem human cells within the first hours after LDIR exposure [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

NADPH-oxidase 4 gene over-expression in peripheral blood lymphocytes of the schizophrenia patients

et al. 2022

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Introduction Increased systemic oxidative stress is common in schizophrenia (SZ) patients. NADPH-oxidase 4 (NOX4) is the cell oxidoreductase, catalyzing the hydrogen peroxide formation. Presumably, NOX4 is the main oxidative stress factor in a number of diseases such as cardiovascular diseases and cancer. We hypothesized that NOX4 may be involved in the oxidative stress development caused by the disease in the schizophrenic patients’ peripheral blood lymphocytes (PBL). Materials and methods The SZ group included 100 patients (68 men and 32 women aged 28 ± 11 years). The control group included 60 volunteers (35 men and 25 women aged 25 ± 12 years). Flow cytometry analysis (FCA) was used for DNA damage markers (8-oxodG, ɣH2AX), pro- and antiapoptotic proteins (BAX1 and BCL2) and the master-regulator of anti-oxidant response NRF2 detection in the lymphocytes of the untreated SZ patients (N = 100) and the healthy control (HC, N = 60). FCA and RT-qPCR were used for NOX4 and RNANOX4 detection in the lymphocytes. RT-qPCR was used for mtDNA quantitation in peripheral blood mononuclear cells. Cell-free DNA concentration was determined in blood plasma fluorimetrically. Results 8-oxodG, NOX4, and BCL2 levels in the PBL in the SZ group were higher than those in the HC group (p < 0.001). ɣH2AX protein level was increased in the subgroup with high 8-oxodG (p<0.02) levels and decreased in the subgroup with low 8-oxodG (p <0.0001) levels. A positive correlation was found between 8-oxodG, ɣH2AX and BAX1 levels in the SZ group (p <10−6). NOX4 level in lymphocytes did not depend on the DNA damage markers values and BAX1 and BCL2 proteins levels. In 15% of PBL of the HC group a small cellular subfraction was found (5–12% of the total lymphocyte pool) with high DNA damage level and elevated BAX1 protein level. The number of such cells was maximal in PBL samples with low NOX4 protein levels. Conclusion Significant NOX4 gene expression was found a in SZ patients’ lymphocytes, but the corresponding protein is probably not a cause of the DNA damage.

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“…However, low-dose responses clearly differ in normal and cancer cells [ 484 ]. In fact, in quiescent cancer stem cells, low doses may as act “wake-up” signals [ 485 , 486 ]. C-ions and miRNAs may inhibit them [ 487 ].…”

Section: Discussionmentioning

confidence: 99%

Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts

Averbeck

Rodriguez-Lafrasse

2021

IJMS

115

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Until recently, radiation effects have been considered to be mainly due to nuclear DNA damage and their management by repair mechanisms. However, molecular biology studies reveal that the outcomes of exposures to ionizing radiation (IR) highly depend on activation and regulation through other molecular components of organelles that determine cell survival and proliferation capacities. As typical epigenetic-regulated organelles and central power stations of cells, mitochondria play an important pivotal role in those responses. They direct cellular metabolism, energy supply and homeostasis as well as radiation-induced signaling, cell death, and immunological responses. This review is focused on how energy, dose and quality of IR affect mitochondria-dependent epigenetic and functional control at the cellular and tissue level. Low-dose radiation effects on mitochondria appear to be associated with epigenetic and non-targeted effects involved in genomic instability and adaptive responses, whereas high-dose radiation effects (>1 Gy) concern therapeutic effects of radiation and long-term outcomes involving mitochondria-mediated innate and adaptive immune responses. Both effects depend on radiation quality. For example, the increased efficacy of high linear energy transfer particle radiotherapy, e.g., C-ion radiotherapy, relies on the reduction of anastasis, enhanced mitochondria-mediated apoptosis and immunogenic (antitumor) responses.

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Mesenchymal Stem Cells Early Response to Low-Dose Ionizing Radiation

Cited by 11 publications

References 60 publications

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

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

NADPH-oxidase 4 gene over-expression in peripheral blood lymphocytes of the schizophrenia patients

Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts

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