Model and simulation for spatial cell fate pattering in mouse blastocysts based on an advection-diffusion mechanism for intercellular signalling

基于细胞间信号传导的平流扩散机制的小鼠囊胚空间细胞命运模式的模型和模拟

• 批准号: 470129398
• 负责人: Professorin Dr. Sabine Fischer
• 金额: --
• 依托单位: Center for Computational and Theoretical Biology (CTB)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/470129398?language=en
• 关键词: Model; simulation; spatial; cell; fate

During mammalian preimplantation development, intercellular signalling controls the differentiation of multilineage primed stem cells. The arising cell fates are arranged in ordered patterns, which contain the information for studying the spatial coordination of cell fate specification. We focus on the activity range of the intercellular signalling and investigate its interplay with cell division and cell sorting. Motivated by the fibroblast growth factor (FGF) signalling pathway, which regulates primitive endoderm and epiblast differentiation in the mouse embryo, we develop a mathematical modelling framework with tuneable signalling range. We aim at showing that an advection-diffusion mechanism can provide a physical explanation for achieving different signal activity ranges. We include cell division and cell sorting in the model following the hypothesis that the three mechanisms act in parallel. Implementation of a pair correlation function facilitates a quantitative comparison of the simulation results with at least 590 biological samples from four published experimental data sets from three different laboratories. This will tell us whether the three mechanisms indeed act in parallel or whether we have to let the mechanisms overlap or even work consecutively. Hence, as a final outcome, we will obtain the characteristics and timing of cell signalling, cell division and cell sorting. The key additions of our work to existing models of mouse blastocyst development are introducing a signalling range based on the physics of the signalling molecule; and a detailed analysis of the relative contributions of signalling, cell division and cell sorting through a thorough comparison of the model with three-dimensional spatial experimental data. Our approach is deliberately general in nature to facilitate an extension to other mammalian species.

在哺乳动物植入前发育过程中，细胞间信号传导控制着多谱系致敏干细胞的分化。出现的细胞命运是有序排列的，其中包含了研究细胞命运指定的空间协调的信息。我们专注于细胞间信号传导的活动范围，并研究其与细胞分裂和细胞分选的相互作用。由成纤维细胞生长因子（FGF）信号通路，调节原始内胚层和上胚层分化的小鼠胚胎的动机，我们开发了一个数学建模框架与可调信号范围。我们的目的是表明，对流扩散机制可以提供一个物理解释实现不同的信号活动范围。我们在模型中包括细胞分裂和细胞分选，假设这三种机制并行作用。一对相关函数的实现有利于模拟结果与来自三个不同实验室的四个已公布的实验数据集的至少590个生物样品的定量比较。这将告诉我们，这三个机制是否确实平行运作，或者我们是否必须让这些机制重叠，甚至连续运作。因此，作为最终结果，我们将获得细胞信号传导、细胞分裂和细胞分选的特征和时间。我们的工作的关键补充现有的小鼠囊胚发育模型的基础上引入了信号传导分子的物理范围;和信号传导，细胞分裂和细胞分选的相对贡献的详细分析，通过一个彻底的比较模型与三维空间的实验数据。我们的方法是故意一般性的，以促进扩展到其他哺乳动物物种。