Hall Benjamin A, Piterman Nir, Hajnal Alex, Fisher Jasmin
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, United Kingdom; Microsoft Research Cambridge, Cambridge, UK.
Department of Computer Science, University of Leicester, Leicester, UK.
Biophys J. 2015 Jul 21;109(2):428-38. doi: 10.1016/j.bpj.2015.06.007.
The establishment of homeostasis among cell growth, differentiation, and apoptosis is of key importance for organogenesis. Stem cells respond to temporally and spatially regulated signals by switching from mitotic proliferation to asymmetric cell division and differentiation. Executable computer models of signaling pathways can accurately reproduce a wide range of biological phenomena by reducing detailed chemical kinetics to a discrete, finite form. Moreover, coordinated cell movements and physical cell-cell interactions are required for the formation of three-dimensional structures that are the building blocks of organs. To capture all these aspects, we have developed a hybrid executable/physical model describing stem cell proliferation, differentiation, and homeostasis in the Caenorhabditis elegans germline. Using this hybrid model, we are able to track cell lineages and dynamic cell movements during germ cell differentiation. We further show how apoptosis regulates germ cell homeostasis in the gonad, and propose a role for intercellular pressure in developmental control. Finally, we use the model to demonstrate how an executable model can be developed from the hybrid system, identifying a mechanism that ensures invariance in fate patterns in the presence of instability.
细胞生长、分化和凋亡之间稳态的建立对于器官发生至关重要。干细胞通过从有丝分裂增殖转变为不对称细胞分裂和分化来响应时间和空间上调控的信号。信号通路的可执行计算机模型通过将详细的化学动力学简化为离散的有限形式，能够准确地重现广泛的生物现象。此外，协调的细胞运动和物理性细胞间相互作用对于形成作为器官构建块的三维结构是必需的。为了涵盖所有这些方面，我们开发了一个混合的可执行/物理模型，描述秀丽隐杆线虫生殖系中的干细胞增殖、分化和稳态。使用这个混合模型，我们能够追踪生殖细胞分化过程中的细胞谱系和动态细胞运动。我们进一步展示了凋亡如何调节性腺中的生殖细胞稳态，并提出细胞间压力在发育控制中的作用。最后，我们使用该模型来演示如何从混合系统开发可执行模型，确定一种在存在不稳定性时确保命运模式不变性的机制。
