Emergence of multicellular calcium synchronization by information-transfer between individual cells

We quantitatively evaluated how noisy heterogeneous behavior of individual cells is integrated across a population toward multicellular calcium synchronization. By live calcium imaging of collective chemosensing monolayers of fibroblasts in response to periodic external ATP stimuli we found that the cells formed a multicellular communication network that gradually evolved and reinforced collective synchronization. We used information-theory to define quantitative measures to how single cells receive or transmit information in the multicellular network and found that cells take different roles in intercellular information-transfer. Initially short-range communication dominates, that gradually transitions to long-range communication as the network synchronizes. We hypothesized that this can be explained by gradual integration of spatial cues that reinforce the roles that cells take in collective synchronization. Indeed, cells maintained their roles in the communication network between consecutive stimuli cycles and reinforced them over time suggesting the existence of a cellular “phenotypic memory”. We identified a subpopulation of cells characterized with higher probability of both receiving and transmitting information. These “communication hub” cells tend to be most stable - not switching to other roles, thus leading to gradual enrichment in communication hubs that is associated with the gradual establishment synchronization. These results suggest that information is spreading more effectively in the multicellular network by gradual enrichment in “communication hubs” to establish effective collective synchronization. And thus we propose that synchronization emerges from division of labor of the individual cells that gradually reinforces synchronized calcium signaling from the local to the global scale.