We develop a model-based theoretical framework to shed light on the phenomenon of cross-level interactions in complex and dynamic multicellular structures with a focus on calcium signaling via calcium waves. In particular, we investigate computationally the interdependence between intracellular calcium and inositol-1,4,5-trisphosphate (IP3) pathway and cell-cell communication via gap junction intercellular diffusion of Ca2+ and IP3. To enable the propagation of calcium waves in a one-dimensional chain of cells, we introduce a calcium concentration-dependent threshold-based mechanism to trigger calcium oscillations of individual cells. Our model shows that the dynamics of cells embedded in a multicellular network is significantly different from that of an isolated cell. In particular, we have demonstrated that the transient and steady state frequency of calcium oscillations of a cell stimulated with an agonist depends on its microenvironment, in this case, its cell neighbors. The neighborhood of the stimulated cell forms a “signaling niche” that acts on the stimulated cell itself and dynamically regulates its oscillation frequency. This effect is attributed to a crosstalk between the stimulated cell and its environment through retrograde diffusion of calcium and IP3.
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