On cooperativity in cellular habitats, with quantitative experiments and modelling

Tales of a Fountain of Youth and the invention of medicine illustrate our age-long obsession with two themes: life and death. What it takes to stay alive, and not to be dead, is a basic question in science that is easy to state, and yet difficult to address at a profound level. One striking feature of many living organisms is the ability of individuals to behave in unison by communicating with each other. At life’s microscopic level, living cells can also send and receive chemical signals to communicate with each other in their habitat but for a population of many thousands of cells it remains enigmatic who is communicating with whom, what are the signals, and how the signals work over space and time. We used quantitative experiments and mathematical modelling to systematically explore how mouse Embryonic Stem (ES) cells might cooperate by communicating when differentiating into the first two lineages. We discovered that differentiating mouse ES cells scattered across many centimeters on a dish form one macroscopic entity that either survives or dies in unison if and only if its population-density is above a threshold value. This switch-like behavior is determined by cells that secrete and sense FGF4 that diffuses over many millimeters to activate YAP1-induced survival mechanisms. Our work shows that living cells (in vitro) can rely on macroscopic cooperation to stay alive.