Emergent Criticality in Coupled Boolean Networks.

Early embryonic development involves forming all specialized cells from a fluid-like mass of identical stem cells. The differentiation process consists of a series of symmetry-breaking events, starting from a high-symmetry state (stem cells) to a low-symmetry state (specialized cells). This scenario closely resembles phase transitions in statistical mechanics. To theoretically study this hypothesis, we model embryonic stem cell (ESC) populations through a coupled Boolean network (BN) model. The interaction is applied using a multilayer Ising model that considers paracrine and autocrine signaling, along with external interventions. It is demonstrated that cell-to-cell variability can be interpreted as a mixture of steady-state probability distributions. Simulations have revealed that such models can undergo a series of first- and second-order phase transitions as a function of the system parameters that describe gene expression noise and interaction strengths. These phase transitions result in spontaneous symmetry-breaking events that generate new types of cells characterized by various steady-state distributions. Coupled BNs have also been shown to self-organize in states that allow spontaneous cell differentiation.

Self-Regulated Symmetry Breaking Model for Stem Cell Differentiation.

In conventional disorder-order phase transitions, a system shifts from a highly symmetric state, where all states are equally accessible (disorder) to a less symmetric state with a limited number of available states (order). This transition may occur by varying a control parameter that represents the intrinsic noise of the system. It has been suggested that stem cell differentiation can be considered as a sequence of such symmetry-breaking events. Pluripotent stem cells, with their capacity to develop into any specialized cell type, are considered highly symmetric systems. In contrast, differentiated cells have lower symmetry, as they can only carry out a limited number of functions. For this hypothesis to be valid, differentiation should emerge collectively in stem cell populations. Additionally, such populations must have the ability to self-regulate intrinsic noise and navigate through a critical point where spontaneous symmetry breaking (differentiation) occurs. This study presents a mean-field model for stem cell populations that considers the interplay of cell-cell cooperativity, cell-to-cell variability, and finite-size effects. By introducing a feedback mechanism to control intrinsic noise, the model can self-tune through different bifurcation points, facilitating spontaneous symmetry breaking. Standard stability analysis showed that the system can potentially differentiate into several cell types mathematically expressed as stable nodes and limit cycles. The existence of a Hopf bifurcation in our model is discussed in light of stem cell differentiation.