Intercellular communication induces glycolytic synchronization waves between individually oscillating cells
Significance Many organs have densely packed cells divided in subpopulations that display coherent and spatially differentiated behavior. Using yeast cells packed in a microfluidic device, constructed to mimic an organ structure with peripheral blood flow, we show that cells coupled via diffusion of metabolites can lead to spatially differentiated subpopulations with temporally synchronized behavior. A detailed mathematical model for each yeast cell simulated in its precise architectural location within the microfluidic system correctly predicts the cells’ behavior as a function of an external stress solution. Our results provide us with a mechanistic understanding of this system and indicate how a relatively simple mechanism can underlie a yet poorly understood cellular differentiation process. Many organs have internal structures with spatially differentiated and sometimes temporally synchronized groups of cells. The mechanisms leading to such differentiation and coordination are not well understood. Here we design a diffusion-limited microfluidic system to mimic a multicellular organ structure with peripheral blood flow and test whether a group of individually oscillating yeast cells could form subpopulations of spatially differentiated and temporally synchronized cells. Upon substrate addition, the dynamic response at single-cell level shows glycolytic oscillations, leading to wave fronts traveling through the monolayered population and to synchronized communities at well-defined positions in the cell chamber. A detailed mechanistic model with the architectural structure of the flow chamber incorporated successfully predicts the spatial-temporal experimental data, and allows for a molecular understanding of the observed phenomena. The intricate interplay of intracellular biochemical reaction networks leading to the oscillations, combined with intercellular communication via metabolic intermediates and fluid dynamics of the reaction chamber, is responsible for the generation of the subpopulations of synchronized cells. This mechanism, as analyzed from the model simulations, is experimentally tested using different concentrations of cyanide stress solutions. The results are reproducible and stable, despite cellular heterogeneity, and the spontaneous community development is reminiscent of a zoned cell differentiation often observed in multicellular organs.