Greaves Richard B, Dietmann Sabine, Smith Austin, Stepney Susan, Halley Julianne D
York Centre for Complex Systems Analysis, University of York, York, United Kingdom.
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
PLoS Comput Biol. 2017 Sep 1;13(9):e1005713. doi: 10.1371/journal.pcbi.1005713. eCollection 2017 Sep.
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.
多能胚胎干细胞能够分化为体内任何细胞类型，这使得它们在再生医学领域具有极高价值。然而，由于核心多能性网络以及细胞命运计算过程的复杂性，目前尚无法控制干细胞的命运。我们提出了一种干细胞命运计算的理论模型，该模型基于哈雷和温克勒的分支过程理论（BPT）以及格里夫斯等人基于该理论模型推导的基于主体的计算机模拟。BPT将转录因子（TF）的复杂产生和作用抽象为一个单一的关键分支过程，该过程可能消散、维持或变为超临界状态。在此，我们将单一TF模型扩展到多个相互作用的TF，并构建了一个基于主体的多个TF模拟，以研究此类耦合系统的动态变化。我们以迭代方式共同开发了该模拟和理论模型，旨在更深入地理解干细胞命运计算，从而影响实验工作，而实验工作反过来可能影响细胞分化的结果。所使用的模型是自组织的一个例子，可能更广泛地适用于其他复杂系统的建模。基于该模型的模拟尽管目前在其所代表的生物学范围方面有限，但支持哈雷和温克勒分支过程模型在描述干细胞基因调控网络行为方面的实用性。我们的模拟展示了三个关键特征：（i）分支过程参数存在一个临界值，该值取决于所讨论的顺反子组的细节；（ii）活跃的顺反子组能够“点燃”原本完全消散的顺反子组，并将其驱动至临界状态；（iii）将顺反子组耦合在一起如何能够降低驱动它们达到临界状态所需的临界分支参数值。
