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

We quantitatively characterize how noisy and heterogeneous behaviors of individual cells are integrated across a population toward multicellular synchronization by studying the calcium dynamics in mechanically stimulated monolayers of endothelial cells. We used information-theory to quantify the asymmetric information-transfer between pairs of cells and define quantitative measures of how single cells receive or transmit information in the multicellular network. We find that cells take different roles in intercellular information-transfer and that this heterogeneity is associated with synchronization. Cells tended to maintain their roles between consecutive cycles of mechanical stimuli and reinforced them over time, suggesting the existence of a cellular "memory" in intercellular information transfer. Interestingly, we identified a subpopulation of cells characterized by higher probability of both receiving and transmitting information. These "communication hub" roles were stable - once a cell switched to a "communication hub" role it was less probable to switch to other roles. This stableness property of the cells led to gradual enrichment of communication hubs that was associated with the establishment of synchronization. Our analysis demonstrated that multicellular synchronization was established by effective information spread from the (local) single cell to the (global) group scale in the multicellular network. Altogether, we suggest that multicellular synchronization is driven by single cell communication properties, including heterogeneity, functional memory and information flow.