Abstract
The capacity of pluripotent embryonic stem cells to differentiate into any cell type in the body makes them invaluable in the field of regenerative medicine. However, because of the complexity of both the core pluripotency network and the process of cell fate computation it is not yet possible to control the fate of stem cells. We present a theoretical model of stem cell fate computation that is based on Halley and Winkler’s Branching Process Theory (BPT) and on Greaves et al.’s agent-based computer simulation derived from that theoretical model. BPT abstracts the complex production and action of a Transcription Factor (TF) into a single critical branching process that may dissipate, maintain, or become supercritical. Here we take the single TF model and extend it to multiple interacting TFs, and build an agent-based simulation of multiple TFs to investigate the dynamics of such coupled systems. We have developed the simulation and the theoretical model together, in an iterative manner, with the aim of obtaining a deeper understanding of stem cell fate computation, in order to influence experimental efforts, which may in turn influence the outcome of cellular differentiation. The model used is an example of self-organization and could be more widely applicable to the modelling of other complex systems. The simulation based on this model, though currently limited in scope in terms of the biology it represents, supports the utility of the Halley and Winkler branching process model in describing the behaviour of stem cell gene regulatory networks. Our simulation demonstrates three key features: (i) the existence of a critical value of the branching process parameter, dependent on the details of the cistrome in question; (ii) the ability of an active cistrome to “ignite” an otherwise fully dissipated cistrome, and drive it to criticality; (iii) how coupling cistromes together can reduce their critical branching parameter values needed to drive them to criticality.
Highlights
Stem cells present an important instance of the complexity of cellular function and gene regulation
We present a theoretical model of stem cell fate computation that is based on Halley and Winkler’s Branching Process Theory (BPT) and on Greaves et al.’s agent-based computer simulation derived from that theoretical model
From the simulation of the Transcription Factor Branching Process (TFBP), we can demonstrate the existence of mcrit values, values of the branching parameter below which the simulation rapidly dissipates and above which supercritical branching can take place; see Greaves et al [30] for details
Summary
Stem cells present an important instance of the complexity of cellular function and gene regulation. Pluripotent stem cells possess the capacity both to renew themselves indefinitely and to differentiate to any cell type in the body. This second capacity means that the ability to direct stem cell differentiation would have immense potential in regenerative medicine. High throughput datasets are available to facilitate understanding of stem cells, but such data provide only snapshots of biological complexity, with no dynamics. Modelling and understanding non-equilibrium gene regulatory networks flows and feedbacks. In the context of gene regulatory circuits, this is partly due to the often immense number of potential binding sites for key TFs in DNA. TF-DNA binding site data can provide information for static wiring diagram representations of regulatory circuits, but the dynamics of information flow within such circuitry remains challenging to understand
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