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.@en

Communicating is crucial for cells to coordinate their behaviors. Immunological processes, involving diverse cytokines and cell types, are ideal for developing frameworks for modeling coordinated behaviors of cells. Here, we review recent studies that combine modeling and experiments to reveal how immune systems use autocrine, paracrine, and juxtacrine signals to achieve behaviors such as controlling population densities and hair regenerations. We explain that models are useful because one can computationally vary numerous parameters, in experimentally infeasible ways, to evaluate alternate immunological responses. For each model, we focus on the length-scales and time-scales involved and explain why integrating multiple length-scales and time-scales in a model remain challenging. We suggest promising modeling strategies for meeting this challenge and their practical consequences.@en

Cells can secrete molecules that help each other’s replication. In cell cultures, chemical signals might diffuse only within a cell colony or between colonies. A chemical signal’s interaction length—how far apart interacting cells are—is often assumed to be some value without rigorous justifications because molecules’ invisible paths and complex multicellular geometries pose challenges. Here we present an approach, combining mathematical models and experiments, for determining a chemical signal’s interaction length. With murine embryonic stem (ES) cells as a testbed, we found that differentiating ES cells secrete FGF4, among others, to communicate over many millimeters in cell culture dishes and, thereby, form a spatially extended, macroscopic entity that grows only if its centimeter-scale population density is above a threshold value. With this ‘macroscopic quorum sensing’, an isolated macroscopic, but not isolated microscopic, colony can survive differentiation. Our integrated approach can determine chemical signals’ interaction lengths in generic multicellular communities. [Figure not available: see fulltext.].@en