Intercellular communication induces glycolytic synchronization waves between individually oscillating cells

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.

Automated summary

This study utilized a diffusion-limited microfluidic system to mimic the structure of a multicellular organ, demonstrating that a group of oscillating yeast cells can form subpopulations of spatially differentiated and temporally synchronized cells under certain conditions. The intricate interplay of intracellular biochemical reaction networks and intercellular communication, along with the fluid dynamics of the reaction chamber, plays a critical role in generating the synchronized cell populations. The results of the study, which were experimentally tested and reproducible, suggest that the observed spontaneous community development resembles zoned cell differentiation in multicellular organs.