Cell signalling regulates dynamics of Nanog distribution in embryonic stem cell populations.
Cell signalling regulates dynamics of Nanog distribution in embryonic stem cell populations.
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DOI：
10.1098/rsif.2012.0525
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发表时间：
2013-01-06
期刊：
影响因子：
--
通讯作者：
Wernisch L
中科院分区：
文献类型：
--
作者：
Luo Y;Lim CL;Nichols J;Martinez-Arias A;Wernisch L
小鼠胚胎干（ES）细胞群体的特征是Nanog的分布，Nanog是一种表达与多能性程度相关的基因。表现出高水平Nanog的细胞保持多能性状态，而具有低水平Nanog的细胞更可能经历分化。使用具有Nanog的荧光标签的细胞系使得能够测量处于静止状态或扰动后的ES细胞培养物中Nanog的分布。为了模拟系统的动力学，我们假设单个细胞的Nanog-GFP分布显示Nanog水平的不同吸引子稳态，单个细胞随机在这些状态之间移动。添加合成的信号转导抑制剂诱导Nanog分布的强烈变化。特别是，添加Chiron和PD 03（ERK和GSK 3信号通路的抑制剂）诱导高水平的Nanog。在这项研究中，我们将ES细胞置于不同的培养条件下，包括上述抑制剂，并记录了几天内Nanog-GFP分布的变化。为了解释Nanog水平的测量，我们提出了一种新的随机建模策略的动态系统不需要详细的知识的监管或信号机制，同时仍然捕捉随机和确定性的随机动态系统的组成部分。尽管其相对简单，该模型提供了一个洞察的关键特征的细胞群体在各种条件下，包括噪声水平和占用和位置的吸引子稳定状态，而不需要强有力的假设有关的细胞机制。通过将该模型应用于我们的实验数据，我们推断Nanog水平存在三个稳定的稳态，这些稳态在细胞培养基的所有不同条件下都是相同的。另一方面，噪声和每个稳定状态下的细胞比例会发生很大的变化。令人惊讶的是，PD 03和Chiron对系统的噪声和动力学的单独影响与它们的组合效果截然不同。我们的结果表明，信号传导决定了每个状态的占据，GSK 3在调节整个人群的噪音中发挥着特殊作用。
A population of mouse embryonic stem (ES) cells is characterized by a distribution of Nanog, a gene whose expression is associated with the degree of pluripotency. Cells exhibiting high levels of Nanog maintain a state of pluripotency, while those with low levels are more likely to undergo differentiation. Using a cell line with a fluorescence tag for Nanog enables measurements of the distribution of Nanog in an ES cell culture in a stationary state or after a perturbation. In order to model the dynamics of the system, we assume that the distribution of Nanog-GFP for single cells shows distinct attractor steady states of Nanog levels, with individual cells moving between these states stochastically. The addition of synthetic inhibitors of signal transduction induces strong shifts in the distribution of Nanog. In particular, the addition of Chiron and PD03, inhibitors for the ERK and GSK3 signalling pathways, induces a high level of Nanog. In this study, we placed ES cells in different culture conditions, including the above inhibitors, and recorded the change in Nanog-GFP distribution over several days. In order to interpret the measurements of Nanog levels, we propose a new stochastic modelling strategy for the dynamics of the system not requiring detailed knowledge of regulatory or signalling mechanisms, while still capturing the stochastic and the deterministic components of the stochastic dynamical system. Despite its relative simplicity, the model provides an insight into key features of the cell population under various conditions, including the level of noise and occupancy and location of attractor steady states, without the need for strong assumptions about the underlying cellular mechanisms. By applying the model to our experimental data, we infer the existence of three stable steady states for Nanog levels, which are the same in all the different conditions of the cell-culture medium. Noise, on the other hand, and the proportion of cells in each steady state are subject to large shifts. Surprisingly, the isolated effects of PD03 and Chiron on noise and dynamics of the system are quite different from their combined effect. Our results show that signalling determines the occupancy of each state, with a particular role for GSK3 in the regulation of the noise across the population.
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影响因子：
64.5
作者：
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通讯作者：
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DOI：
10.1073/pnas.0806007105
发表时间：
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