title: Cellular population dynamics control the robustness of the stem cell niche.
abstract: Within populations of cells, fate decisions are controlled by an indeterminate combination of cell-intrinsic and cell-extrinsic factors. In the case of stem cells, the stem cell niche is believed to maintain 'stemness' through communication and interactions between the stem cells and one or more other cell-types that contribute to the niche conditions. To investigate the robustness of cell fate decisions in the stem cell hierarchy and the role that the niche plays, we introduce simple mathematical models of stem and progenitor cells, their progeny and their interplay in the niche. These models capture the fundamental processes of proliferation and differentiation and allow us to consider alternative possibilities regarding how niche-mediated signalling feedback regulates the niche dynamics. Generalised stability analysis of these stem cell niche systems enables us to describe the stability properties of each model. We find that although the number of feasible states depends on the model, their probabilities of stability in general do not: stem cell-niche models are stable across a wide range of parameters. We demonstrate that niche-mediated feedback increases the number of stable steady states, and show how distinct cell states have distinct branching characteristics. The ecological feedback and interactions mediated by the stem cell niche thus lend (surprisingly) high levels of robustness to the stem and progenitor cell population dynamics. Furthermore, cell-cell interactions are sufficient for populations of stem cells and their progeny to achieve stability and maintain homeostasis. We show that the robustness of the niche - and hence of the stem cell pool in the niche - depends only weakly, if at all, on the complexity of the niche make-up: simple as well as complicated niche systems are capable of supporting robust and stable stem cell dynamics.
authors.affiliation: Theoretical Systems Biology, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Adam L
authors.initials: AL
authors.lastname: MacLean
authors.affiliation: MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge CB2 0SR, UK.
authors.forename: Paul D W
authors.initials: PD
authors.lastname: Kirk
authors.affiliation: Theoretical Systems Biology, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK m.stumpf@imperial.ac.uk.
authors.forename: Michael P H
authors.initials: MP
authors.lastname: Stumpf
keywords: Asymmetric division; Cell fate; Self-renewal; Stability analysis; Stem cell niche