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Hattori, Yuya; Yokoya, Akinari; Watanabe, Ritsuko
BMC Systems Biology (Internet), 9, p.90_1 - 90_22, 2015/12
Times Cited Count：17 Percentile：66.16(Mathematical & Computational Biology)The radiation-induced bystander effect is a biological response observed in non-irradiated cells surrounding an irradiated cell, which is known to be caused by two intercellular signaling pathways. However, the behavior of the signals is largely unknown. To investigate the role of these signaling pathways, we developed a mathematical model to describe the cellular response to direct irradiation and the bystander effect, with a particular focus on cell-cycle modification. The analysis of model dynamics revealed that bystander effect on cell cycle modification was different between low-dose irradiation and high-dose irradiation. We demonstrated that signaling through both pathways induced cell cycle modification via the bystander effect. By simulating various special and temporal conditions of irradiation and cell characteristics, our model will be a powerful tool for the analysis of the bystander effect.
Hattori, Yuya; Yokoya, Akinari; Watanabe, Ritsuko
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Kaminaga, Kiichi; Kanari, Yukiko; Sakamoto, Yuka; Narita, Ayumi; Usami, Noriko*; Kobayashi, Katsumi*; Noguchi, Miho; Yokoya, Akinari
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Kaminaga, Kiichi; Noguchi, Miho; Narita, Ayumi; Sakamoto, Yuka; Kanari, Yukiko; Yokoya, Akinari
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Hattori, Yuya; Yokoya, Akinari; Watanabe, Ritsuko
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When only a limited number of cells in a population are hit by radiation, non-irradiated cells might receive from the irradiated cells intercellular signals that induce biological effects known as "bystander effects". To understand the responses of each cell in the inhomogeneous population, we have developed a mathematical model of intercellular signaling and individual cellular responses, particularly focusing on cell cycle progression, cell cycle arrest, and cell death. In our model, the cellular population was described by grids. Each grid represented each cell. We assumed that absorbed dose was given in each grid (cell). The intercellular-signals emitted from the cells were assumed to be transferred through culture medium and gap junctions, and their concentrations in each grid were calculated based on a diffusion equation. We assumed that individual cell have targets which are necessary to progress the cell cycle. Both irradiation and the intercellular signals were assumed to inactivate "targets" in the cell. The number of inactivated targets decides cellular state, cell cycle progression, cell cycle arrest or cell death. The cell cycle was described as a virtual clock with cyclic stages (G1, S, G2, M phases) and several check-points. In the condition of normal cell-cycle progression and proliferation, our model successfully reproduced growth curves of experimental data previously reported for non-irradiated cellular population. When we irradiated one cell in the center of cellular population, some of non-irradiated cells caused inactivation of the targets by the intercellular signals, resulting in cell cycle arrest and cell death. Based on the simulation and analysis of the temporal and spatial dynamics of intercellular signaling, inactivated targets, cell cycle arrest and cell death, we will discuss the mechanism of radiation-induced responses in inhomogeneous cellular populations.
Hattori, Yuya; Yokoya, Akinari; Watanabe, Ritsuko
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It is widely recognized that bystander phenomena are caused by two intercellular signaling pathways, via culture medium and gap junctions. We consider that modeling the bystander effect on cell-cycle progression is the first step toward investigating the mechanism of transgenerational effects, which ultimately trigger radiation-induced carcinogenesis. Our model describes the cultured cellular population as two-dimensional grids. The simulation algorithm consists of four steps: (1) irradiation, (2) generation and diffusion of intercellular signals, (3) induction of DNA damage by direct irradiation and intercellular signals, (4) response on cell cycle for DNA damage. The cell cycle is represented as a virtual clock that includes several checkpoint pathways within a cyclic process. Using this model, we simulated how affect the intercellular signals on cellular responses in sparsely and densely cultured conditions. In this work, we adopted life-time and diffusion constant of cytokine and calcium ion for signals via culture medium and signals via gap-junction, respectively. The simulation shows that the signals increased cell-cycle modification with increase of dose. The bystander effect on cell-cycle was significant for cells in sparse condition than in dense condition, showing that the model works reasonably. However, the effect of signals via gap-junction was unexpectedly small. It was caused by the short life-time of calcium ion. It indicates that other mechanism as reemission of other substances should be considered for the model of gap-junction. Obtaining the experimental data comparable with our simulation can be of great help to understand the mechanism of bystander effect.
Kaminaga, Kiichi; Shinoda, Kohei; Fukuoka, Sotaro; Nakaue, Hiroki; Yokoya, Akinari
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Yokoya, Akinari; Kaminaga, Kiichi; Hattori, Yuya; Watanabe, Ritsuko; Noguchi, Miho; Fujii, Kentaro
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Kaminaga, Kiichi; Usami, Noriko*; Noguchi, Miho; Yokoya, Akinari
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no abstracts in English
