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

Abstract

During mammalian development and homeostasis, cells often transition from a multilineage primed state to one of several differentiated cell types that are marked by the expression of mutually exclusive genetic markers. These observations have been classically explained by single-cell multistability as the dynamical basis of differentiation, where robust cell type proportioning relies on preexisting cell-to-cell differences. We propose a conceptually different dynamical mechanism in which cell types emerge and are maintained collectively by cell-cell communication, as a novel inhomogeneous state of the coupled system. Differentiation can be triggered by cell number increase as the population grows in size, through organisation of the initial homogeneous population before the symmetry-breaking bifurcation point. Robust proportioning and reliable recovery of the differentiated cell types following a perturbation is an inherent feature of the inhomogeneous state that is collectively maintained. This dynamical mechanism is valid for systems with steady-state or oscillatory single-cell dynamics. Our results therefore suggest that timing and subsequent differentiation in robust cell type proportions can emerge from the cooperative behaviour of growing cell populations during development.

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

“…6C, first and second panel, Movies S1, S2). Similar transitions have been predicted in silico as a generic feature of the IHSS solution (Stanoev et al, 2021). The transient downregulation of VNP expression was not observed when supplementing the culture medium with FGF4, but instead reporter expression was maintained in the majority of cells (Fig.…”

“…6E). Taken together, these (Stanoev et al, 2021). Our results suggest a new function for FGF signalling, which is to generate and maintain robust proportions of differentiated cell types.…”

“…S8 " type="url"/> ). An IHSS is composed of mutually exclusive gene expression patterns, is generated and dynamically maintained via communication at the population level and has recently been proposed as a generic mechanism for robust cell-type proportioning ( Stanoev et al, 2021 ). The emergence of an IHSS is therefore 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 demonstrated theoretically that this property of the IHSS solution manifests in the regeneration of heterogeneous populations following separation of cell types after differentiation ( Stanoev et al, 2021 ). To test whether a similar behavior could be observed in isolated PrE-like cells, we used a short-lived Venus-NLS-PEST reporter ( Abranches et al, 2013 ; Nagoshi et al, 2004 ) knocked into the Gata6 locus of a GATA4-mCherry inducible cell line as a proxy to isolate PrE-like cells, and subsequently to monitor their differentiation state ( Fig.…”

“…Population-level mechanisms for cell differentiation are an attractive solution to the problem of developmental canalization, because it has been shown theoretically that populations of communicating cells can re-establish specific cell-type proportions following perturbations ( Stanoev et al, 2021 ). This theory furthermore predicts that the differentiation outcomes are insensitive to initial conditions, because the heterogeneous cell identities represent a collective state that is generated and maintained at the level of the communicating population, rather than being specified intrinsically in each cell.…”