Robustness and timing of cellular differentiation through population-based symmetry breaking

Abstract

Although coordinated behavior of multicellular organisms relies on intercellular communication, the dynamical mechanism that underlies symmetry breaking in homogeneous populations, thereby giving rise to heterogeneous cell types remains unclear. In contrast to the prevalent cell-intrinsic view of differentiation where multistability on the single cell level is a necessary pre-requisite, we propose that heterogeneous cellular identities emerge and are maintained cooperatively on a population level. Identifying a generic symmetry breaking mechanism, we demonstrate that robust proportions between differentiated cell types are intrinsic features of this inhomogeneous steady state solution. Critical organization in the vicinity of the symmetry breaking bifurcation on the other hand, suggests that timing of cellular differentiation emerges for growing populations in a self-organized manner. Setting a clear distinction between pre-existing asymmetries and symmetry breaking events, we thus demonstrate that emergent symmetry breaking, in conjunction with organization near criticality necessarily leads to robustness and accuracy during development.

Cell-cell communication through FGF4 generates and maintains robust proportions of differentiated cell types in embryonic stem cells

“…In the simulations, we considered several different scenarios of initial conditions, ranging from all cells being GATA-positive initially to all cells being NANOG-positive initially, to mimic the experimental settings ( Figure 3E Bifurcation analysis of a minimal system of N = 2 communicating cells indicated that the robust proportioning of the two differentiated cell types in the wild type is a consequence of a new joint dynamical state of the system, characterized with an inhomogeneous steady state (IHSS, Figure S6B). An IHSS is generated at the population level, it is characterized by mutually exclusive gene expression patterns in the population, and has recently been proposed as a generic mechanism for robust cell type proportioning (Stanoev et al, 2019). This suggests that the emergence of an IHSS as a new dynamical solution in the population of FGF-coupled NANOG-GATA mutually repressive circuits is a possible dynamical basis for robust cell type proportioning in differentiating ESCs.…”

“…A central characteristic of a population-based mechanism for cell differentiation, such as the IHSS, is the interdependence of different cell types (Koseska and Bastiaens, 2017). It has been theoretically demonstrated that this property of the IHSS solution manifests in the regeneration of heterogeneous populations following separation of cell types after differentiation (Stanoev et al, 2019). We asked whether a similar behavior could be observed when PrE-like cells are isolated after both cell types have been established, using a live reporter for Gata6 expression as a proxy to isolate PrE-like cells, and to subsequently monitor their differentiation state in different media ( Figure 5A).…”

“…The model of the intercellular communication system ( Figure 3D) is adapted from Stanoev et al (2019), and is described with the following set of equations:…”

“…Population-level mechanisms for cell differentiation are an attractive solution to the problem of developmental canalization, as it has been shown theoretically that populations of communicating cells can re-establish specific cell type proportions following perturbations (Stanoev et al, 2019). This theory furthermore predicts that the differentiation outcomes are robust towards initial conditions, since the heterogeneous cell identities are generated and maintained on the level of the communicating population, rather than being specified intrinsically in each cell.…”

“…Mutant analysis identifies recursive cell-cell communication via local FGF4 signaling as the minimal molecular mechanism for this emergent property of cell type proportioning. These experimental observations can be described as a dynamical property of an inhomogeneous steady state (IHSS), a population-based solution that is characterized with mutually exclusive gene expression patterns (Stanoev et al, 2019).…”