Emergence of synchronized multicellular mechanosensing from spatiotemporal integration of heterogeneous single-cell information transfer.

Multicellular synchronization is a ubiquitous phenomenon in living systems. However, how noisy and heterogeneous behaviors of individual cells are integrated across a population toward multicellular synchronization is unclear. Here, we study the process of multicellular calcium synchronization of the endothelial cell monolayer in response to mechanical stimuli. We applied information theory to quantify the asymmetric information transfer between pairs of cells and defined quantitative measures to how single cells receive or transmit information within a multicellular network. Our analysis revealed that multicellular synchronization was established by gradual enhancement of information spread from the single cell to the multicellular scale. Synchronization was associated with heterogeneity in the cells' communication properties, reinforcement of the cells' state, and information flow. Altogether, we suggest a phenomenological model where cells gradually learn their local environment, adjust, and reinforce their internal state to stabilize the multicellular network architecture to support information flow from local to global scales toward multicellular synchronization.