Robert Corentin, Prista von Bonhorst Francisco, De Decker Yannick, Dupont Geneviève, Gonze Didier
Unit of Theoretical Chronobiology and Université Libre de Bruxelles (ULB), Brussels CP 231, Belgium.
Nonlinear Physical Chemistry Unit, Université Libre de Bruxelles (ULB), Brussels CP 231, Belgium.
Interface Focus. 2022 Jun 10;12(4):20220010. doi: 10.1098/rsfs.2022.0010. eCollection 2022 Aug 6.
During development, cells from a population of common progenitors evolve towards different fates characterized by distinct levels of specific transcription factors, a process known as cell differentiation. This evolution is governed by gene regulatory networks modulated by intercellular signalling. In order to evolve towards distinct fates, cells forming the population of common progenitors must display some heterogeneity. We applied a modelling approach to obtain insights into the possible sources of cell-to-cell variability initiating the specification of cells of the inner cell mass into epiblast or primitive endoderm cells in early mammalian embryo. At the single-cell level, these cell fates correspond to three possible steady states of the model. A combination of numerical simulations and bifurcation analyses predicts that the behaviour of the model is preserved with respect to the source of variability and that cell-cell coupling induces the emergence of multiple steady states associated with various cell fate configurations, and to a distribution of the levels of expression of key transcription factors. Statistical analysis of these time-dependent distributions reveals differences in the evolutions of the variance-to-mean ratios of key variables of the system, depending on the simulated source of variability, and, by comparison with experimental data, points to the rate of synthesis of the key transcription factor NANOG as a likely initial source of heterogeneity.
在发育过程中，一群共同祖细胞中的细胞朝着不同命运演化，这些命运由特定转录因子的不同水平所表征，这一过程称为细胞分化。这种演化受细胞间信号传导调节的基因调控网络支配。为了朝着不同命运演化，构成共同祖细胞群体的细胞必须表现出一定的异质性。我们应用一种建模方法，以深入了解在早期哺乳动物胚胎中启动内细胞团细胞分化为上胚层或原始内胚层细胞的细胞间变异性的可能来源。在单细胞水平上，这些细胞命运对应于模型的三种可能稳态。数值模拟和分岔分析的结合预测，模型的行为在变异性来源方面得以保留，并且细胞间耦合诱导与各种细胞命运配置相关的多个稳态的出现，以及关键转录因子表达水平的分布。对这些时间依赖性分布的统计分析揭示了系统关键变量的方差均值比的演化差异，这取决于模拟的变异性来源，并且通过与实验数据比较，指出关键转录因子NANOG的合成速率可能是异质性的初始来源。
