Cell fate specification and transitions in multicellular systems

In complex organisms, large numbers of cells must precisely coordinate their phenotypes for proper tissue self-organization during development, homeostasis, and the immune response. This coordination is mediated by a combination of intracellular gene regulation and cell-cell signaling, which leads to phenotypic transitions in single cells. However, as each cell shifts its phenotype, it may in turn contribute new signals to the tissue microenvironment, leading to complex collective behavior. We have developed a generalized model of multicellular gene expression which accounts for intracellular and intercellular gene regulation. The model is a type of spin glass where each spin describes the expression state of a gene in a particular cell. Intracellular gene interactions are defined using a Hopfield network, which enforces the stability of certain cell types in the absence of signaling. We represent multicellular tissue by a graph of Hopfield networks interacting through cell-cell signaling. Local minima of the collective gene expression landscape correspond to different stable tissue configurations. We characterize how the space of stable gene expression patterns evolves as the strength of signaling is tuned. Counterintuitively, we find that random signaling networks tend to stabilize tissue states which are spatially and compositionally simple [1]. These results provide new perspectives on cell fate within a collective tissue context.