Abstract
The mechanisms of pattern formation during embryonic development remain poorly understood. Embryonic stem cells in culture self-organise to form spatial patterns of gene expression upon geometrical confinement indicating that patterning is an emergent phenomenon that results from the many interactions between the cells. Here, we applied an agent-based modelling approach in order to identify plausible biological rules acting at the meso-scale within stem cell collectives that may explain spontaneous patterning. We tested different models involving differential motile behaviours with or without biases due to neighbour interactions. We introduced a new metric, termed stem cell aggregate pattern distance (SCAPD) to probabilistically assess the fitness of our models with empirical data. The best of our models improves fitness by 70% and 77% over the random models for a discoidal or an ellipsoidal stem cell confinement respectively. Collectively, our findings show that a parsimonious mechanism that involves differential motility is sufficient to explain the spontaneous patterning of the cells upon confinement. Our work also defines a region of the parameter space that is compatible with patterning. We hope that our approach will be applicable to many biological systems and will contribute towards facilitating progress by reducing the need for extensive and costly experiments.
Highlights
The mechanisms of pattern formation during embryonic development remain poorly understood
We developed a new metric to quantify the difference in the constellation of the cell patterns between the model results and the empirical data, which we call the stem cell aggregate pattern distance (SCAPD)
We focused on specific pattern formation in embryonic stem cells (ESCs) and constructed 16 agent-based stem cell pattern formation models to test all combinations of four biologically plausible rules of cell motility that we have defined
Summary
The mechanisms of pattern formation during embryonic development remain poorly understood. Our findings show that a parsimonious mechanism that involves differential motility is sufficient to explain the spontaneous patterning of the cells upon confinement. Decades of research in model animals have permitted to uncover molecular players responsible for the patterning of the mammalian embryo These include diffusible signals secreted by the cells such as Nodal, BMP4, Wnt and their respective inhibitors engaged in a complex molecular interplay that involves many feedback mechanisms[3,4]. New insights have been gained with embryonic stem cells (ESCs) in vitro. ESCs-based in vitro systems have made it possible to investigate signalling dynamics using both experimental perturbations and computational modelling approaches to better understand how distinct domains of cell fates are specified over t ime[9,10,11].
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