Monte-Carlo Simulation of a Multi-Dimensional Switch-Like Model of Stem Cell Differentiation

TL;DR

This paper introduces a multi-dimensional switch-like model for stem cell differentiation that explains both cell fate decisions and multi-lineage priming, supported by analytical and Monte-Carlo simulation results.

Contribution

It presents a novel model capturing multi-lineage priming and cell fate decision processes through a degenerate bifurcation and symmetry breaking, extending prior bifurcation approaches.

Findings

Identifies a critical hyperplane supporting multi-lineage priming states.

Shows symmetry breaking explains cell fate decisions.

Monte-Carlo simulations confirm analytical bifurcation results.

Abstract

The process controlling the diferentiation of stem, or progenitor, cells into one specific functional direction is called lineage specification. An important characteristic of this process is the multi-lineage priming, which requires the simultaneous expression of lineage-specific genes. Prior to commitment to a certain lineage, it has been observed that these genes exhibit intermediate values of their expression levels. Multi-lineage differentiation has been reported for various progenitor cells, and it has been explained through the bifurcation of a metastable state. During the differentiation process the dynamics of the core regulatory network follows a bifurcation, where the metastable state, corresponding to the progenitor cell, is destabilized and the system is forced to choose between the possible developmental alternatives. While this approach gives a reasonable interpretation of the cell fate decision process, it fails to explain the multi-lineage priming characteristic. Here, we describe a new multi-dimensional switch-like model that captures both the process of cell fate decision and the phenomenon of multi-lineage priming. We show that in the symmetrical interaction case, the system exhibits a new type of degenerate bifurcation, characterized by a critical hyperplane, containing an infinite number of critical steady states. This critical hyperplane may be interpreted as the support for the multi-lineage priming states of the progenitor. Also, the cell fate decision (the multi-stability and switching behavior) can be explained by a symmetry breaking in the parameter space of this critical hyperplane. These analytical results are confirmed by Monte-Carlo simulations of the corresponding chemical master equations.