Theoretical Investigation of Architecture-Dependent Calcium Signaling in Multicellular Network

Abstract

Calcium signal can be found in many types of cell. It has been treated as a life and death signal in cell-level for triggering life at fertilization, controlling the development and differentiation of cells into specialized types, mediating the subsequent activity, and finally affecting the cell death. In tissues, intercellular calcium wave is thought to serve as a long-range signaling, affected by the cell architecture. The aim of this thesis is to provide insight into the intercellular calcium waves in multicellular complex structures subjected to mechano- or chemical-stimuli. In the mechano-stimulated study, we combine the development of theoretical and experimental study of the propagation of calcium signals in multicellular structures composed of human endothelial cells. This analysis provides evidence for an effect of architecture on the propagation of calcium signals and the effect of single and dual stimulation on the multicellular structures. A simple model was established based on the calcium release/intake reaction and diffusion through gap junction from stimulated cell to the downstream cells. The simulation result shows similar results as what is shown in experiments. In the chemical-stimulated model, we studied computationally the interdependence between intracellular calcium and inositol-1,4,5-trisphosphate (IP₃) pathway and cell-cell communication via gap junction. We investigate the influence of the microenvironment of cells on the frequency of intracellular calcium oscillation. The simulation result shows that the oscillation frequency of an isolated cell is lower than that of a cell embedded in a cell-chain. This phenomenon is attributed to retrograde diffusion of calcium and IP₃ originating from a widening range of cells in the chain undergoing oscillations. It further demonstrates the important influence of microenvironment on the bio-signaling propagation.