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Characteristics of microRNA expression in osteoblasts exposed to high dose rate of alpha particle radiation

ABSTRACT: Osteoblast is one of the bone marrow cells and not only play a central role in bone turnover, but also play a role as supporting cell for hematopoietic stem/progenitor cells. In the field of radiotherapy, internal radiotherapy using radioactive isotopes that emit alpha particles is performed, and antitumor effect is expected by radioisotopes (such as 223-Ra) when the primary cancer cells metastasize to bone marrow. In general, higher dose rates of ionising radiation can induce cell death through DNA damage. However, the extent of DNA damage and repair (radiosensitivity) varies between tissue cell types. In the bone marrow environment, there are many unknowns regarding the radiosensitivity and the its related gene expression in osteoblast, especially the expression status of micro RNAs (miRNAs). The purpose of this study is to reveal the expression pattern of miRNAs in osteoblasts exposed to alpha particle radiation and to identify miRNAs associated with radiosensitivity. Osteoblastic cell line, MC3T3-E1 cell was exposed to 0.223 Gy/min alpha particles (total dose: 0.5 Gy and 1 Gy) and extracted total RNAs after the incubation of 24 h. A significantly up- or down-regulated 21 miRNAs were observed in comparison to non-irradiated control. Using omicsnet data analysis system, we focused on 5 miRNAs (miR-467f, miR-362-3p, miR-5119, miR-292a-5p, miR-466h-3p) and validated them using RT-qPCR. As a result, A higher expression of miR-362-3p after exposure of alpha particle irradiation was reproducibly observed. These results suggested that osteoblastic cell irradiated to alpha particle radiation has a unique miRNA expression pattern.

ORGANISM(S): Mus musculus

PROVIDER: GSE285946 | GEO | 2025/02/15

REPOSITORIES: GEO

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Project description:Osteoblastic cells in the bone marrow produce the bone matrix, participate in mineralization of bone and regulate the balance of calcium and phosphate ions in the developing bone. In addition, the radiosensitive hematopoietic stem/progenitor cells form a niche with osteoblastic cells to maintain immature state and self-renewal in the bone marrow microenvironment. In the field of radiotherapy, internal radiotherapy using radioactive isotopes that emit alpha particles is performed, and antitumor effect is expected by radioisotopes (such as 223-Ra) when the primary cancer cells metastasize to bone marrow. A major problem in this treatment is that the efficacy and side effects form show a high degree of individual variability, and the response of a patient is very difficult to predict. The mechanisms of the variability are not known, but it is possible that some contributing factors are the alpha radiation-induced modulation of osteoblastic cell activity. However, the characteristics of micro-RNA expressions in alpha-irradiated osteoblastic cells remain unclear. The purpose of this study is to clarify the pattern of miRNA expressions in osteoblast derived from freshly bone marrow cells exposed to alpha particle radiation. Murine bone marrow cells from both femurs were differentiated to osteoblastic cells using cell culture medium and exposed to 0-1 Gy of alpha radiation. The 24 miRNAs were significantly up- or down-regulated: mmu-let-7a-5p, mmu-let-7b-5p, mmu-let-7c-5p, mmu-miR-1224-5p, mmu-miR-125b-5p, mmu-miR-296-5p, mmu-miR-331-3p, mmu-miR-3473b, mmu-miR-3960, mmu-miR-3963, mmu-miR-466i-5p, mmu-miR-494-3p, mmu-miR-5126, mmu-miR-6360, mmu-miR-6366, mmu-miR-6378, mmu-miR-6769b-5p, mmu-miR-6937-5p, mmu-miR-7005-5p, mmu-miR-7042-5p, mmu-miR-7047-5p, mmu-miR-709, mmu-miR-8110, mmu-miR-8117). These results indicate that exposure of osteoblastic cells to alpha particles leads to unique expression of miRNAs and it may give the cell radiosensitive environment.

Project description:Acute radiation syndrome (ARS) is a severe condition that develops after exposure to high doses of ionizing radiation that features immune suppression and organ failure. Currently, there are no diagnostics to identify the occurrence or severity of radiation exposure. There are also no current treatments or preventative strategies to mitigate ARS. Extracellular vesicles (EVs) are mediators of intercellular communication that contribute to immune dysfunction across diseases. We investigated if EV cargo would be able to identify whole body irradiation (WBIR) exposure and if EVs promote ARS immune dysfunction. We hypothesized that beneficial EVs derived from mesenchymal stem cells (MSC-EVs) would blunt ARS immune dysfunction and might serve as prophylactic radioprotectants. Mice received WBIR (2 or 9 Gy) with assessment of EVs at 3 and 7 days after exposure. LC-MS/MS proteomic analysis of WBIR-EVs found dose-related changes as well as candidate proteins that were increased with both doses and timepoints (34 total) such as Thromboxane-A Synthase and lymphocyte cytosolic protein 2. Suprabasin and Sarcalumenin were increased only after 9 Gy suggesting these proteins may indicate high dose/lethal exposure. Analysis of EV miRNAs identified miR-376 and miR-136, which were increased up to 200- and 60-fold respectively by both levels of WBIR and select miRNAs such as miR-1839 and miR-664 that were increased only with 9 Gy. WBIR-EVs (9 Gy) were biologically active and blunted immune responses to LPS in RAW264.7 macrophages, inhibiting canonical signaling pathways associated with wound healing and phagosome formation. Accordingly, WBIR-EVs also blunted RAW macrophage phagocytosis. When given 3 days after exposure, MSC-EVs slightly modified immune gene expression changes in the spleens of mice in response to WBIR and a combined radiation plus burn injury exposure (RCI). MSC-EVs normalized the expression of certain key immune genes such as NFκBia and Cxcr4 (WBIR), Map4k1, Ccr9 and Cxcl12 (RCI) lowered plasma TNFα cytokine levels after RCI, though most gene changes were not influenced. When given prophylactically (24 and 3 hours before exposure), MSC-EVs prolonged survival to the 9 Gy lethal exposure. Thus, EVs are important participants in ARS. EV cargo might be used to diagnose WBIR exposure, and MSC-EVs might serve as radioprotectants to blunt the impact of toxic radiation exposure.

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Characteristics of microRNA expression in osteoblasts exposed to high dose rate of alpha particle radiation

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