Emergent Behaviours of Stem Cells in Organogenesis Demonstrated by Hybrid Modelling

Abstract

The development of organs from stem cells is a complex process determined by spatial and temporal control mechanisms, to create well defined and complex 3D structures. In this process, a homeostasis between the processes of cell division and cell death is required. Executable biological models describe signalling and developmental processes at a high level of abstraction, allowing for mechanistic behaviour to be modelled in the absence of precise kinetic information. However, the physical process of 3D growth in the development of an organ is harder to abstract. Here we present a hybrid model of the development of the C. elegans germline from a pool of stem cells. The model combines a description of signalling and developmental processes using an executable model, developed in the BioModelAnalyzer tool (http://biomodelanalyzer.research.microsoft.com/), with a physical model of cell interactions described using Brownian dynamics simulation. This tool uniquely allows us to study the dynamics of organ development and growth, and here we will present new predictions arising from this model. We show how thermal mixing of the stem cell population presents a barrier to clonal dominance through tracking of cell lineages. By abstracting the new model, we demonstrate how invariant fate progression in developing cells is achieved in a complex, multi-stable system. Finally, we use the model to explore how different physical mechanisms of cell signalling, division and apoptosis are compatible with known behaviours.