Paul Kirk | Search bioRxiv

bioRxiv2015

Cellular Population Dynamics Control the Robustness of the Stem Cell Niche

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.

Systems Biology↗

bioRxiv2015

Origins of cell-to-cell variability, kinetic proof-reading and the robustness of MAPK signal transduction

Cellular signalling processes can exhibit pronounced cell-to-cell variability in genetically identical cells. This affects how individual cells respond differentially to the same environmental stimulus. However, the origins of cell-to-cell variability in cellular signalling systems remain poorly understood. Here we measure the temporal evolution of phosphorylated MEK and ERK dynamics across populations of cells and quantify the levels of population heterogeneity over time using high-throughput image cytometry. We use a statistical modelling framework to show that upstream noise is the dominant factor causing cell-to-cell variability in ERK phosphorylation, rather than stochasticity in the phosphorylation/dephosphorylation of ERK. In particular, the cell-to-cell variability during sustained phosphorylation stems from random fluctuations in the background upstream signalling processes, while during transient phosphorylation, the heterogeneity is primarily due to noise in the intensity of the upstream signal(s). We show that the core MEK/ERK system uses kinetic proof-reading to faithfully and robustly transmits these variable inputs. The MAPK cascade thus propagates cell-to-cell variability at the population level, rather than attenuating or increasing it.

Systems Biology↗