Simulation study of individual cellular responses by bystander effects in cellular population

Hattori, Yuya; Yokoya, Akinari; Watanabe, Ritsuko

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.