An extended model for culture-dependent heterogenous gene expression and proliferation dynamics in mouse embryonic stem cells.
An extended model for culture-dependent heterogenous gene expression and proliferation dynamics in mouse embryonic stem cells.
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DOI：
10.1038/s41540-017-0020-5
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发表时间：
2017
影响因子：
4
通讯作者：
Marucci L
中科院分区：
文献类型：
--
作者：
Godwin S;Ward D;Pedone E;Homer M;Fletcher AG;Marucci L
在发育过程中，多能性是描述细胞产生所有三个胚层和种系的能力的瞬时状态。最近的研究表明，在体外，多能性是高度动态的：外源刺激提供给小鼠胚胎干细胞的培养物，从植入前囊胚分离，显着影响多能性的频谱。2 i/LIF是最近定义的无血清培养基，其迫使小鼠胚胎干细胞进入多能性的基态，而血清/LIF培养物促进了基态样和引发样小鼠胚胎干细胞亚群的共存。后者的异质性与多能性标志物的时间波动相关，包括单细胞中的主调节因子Nanog。我们提出了一个数学模型的Nanog动力学在这两种媒体，占最近的实验数据显示，一个小的Nanog低亚群在基态多能性小鼠胚胎干细胞培养的持久性。该模型将存在于2 i/LIF（PD和Chiron）中的两种抑制剂以及与发现在两种培养基中差异表达的基因的反馈相互作用整合到核心多能性基因调控网络中。我们的模拟和分叉分析表明，在基态文化，Nanog动力学的结果从基因表达中的噪声减少和系统向单稳态，但仍然兴奋，监管的转变相结合。实验数据和基于代理的建模模拟表明，小鼠胚胎干细胞增殖动力学在两种介质中不同，并且不能通过仅考虑Nanog依赖的细胞周期调节来再现。我们进一步证明了PD和Chiron在调节转录因子表达的异质性和最终小鼠胚胎干细胞命运决定中起关键作用。小鼠胚胎干细胞（mESC）是多能细胞，具有转化为大多数其他细胞类型的潜力。由布里斯托大学的Lucia Marucci领导的一个团队，以及来自谢菲尔德大学的合作者，开发了数学模型来描述不同培养条件下mESC中多能性基因的时间动态。研究小组表明，基础基因调控网络中的反馈循环、噪音和培养条件的结合可以微调基因表达动态，从而微调mESCs的命运。实验和建模结果突出了多能性基因动力学和细胞增殖之间的相互作用。了解影响mESCs命运的动力学机制可以指导多能性和分化的培养方案的优化。
During development, pluripotency is a transient state describing a cell’s ability to give rise to all three germ layers and germline. Recent studies have shown that, in vitro, pluripotency is highly dynamic: exogenous stimuli provided to cultures of mouse embryonic stem cells, isolated from pre-implantation blastocysts, significantly affect the spectrum of pluripotency. 2i/LIF, a recently defined serum-free medium, forces mouse embryonic stem cells into a ground-state of pluripotency, while serum/LIF cultures promote the co-existence of ground-like and primed-like mouse embryonic stem cell subpopulations. The latter heterogeneity correlates with temporal fluctuations of pluripotency markers, including the master regulator Nanog, in single cells. We propose a mathematical model of Nanog dynamics in both media, accounting for recent experimental data showing the persistence of a small Nanog Low subpopulation in ground-state pluripotency mouse embryonic stem cell cultures. The model integrates into the core pluripotency Gene Regulatory Network both inhibitors present in 2i/LIF (PD and Chiron), and feedback interactions with genes found to be differentially expressed in the two media. Our simulations and bifurcation analysis show that, in ground-state cultures, Nanog dynamics result from the combination of reduced noise in gene expression and the shift of the system towards a monostable, but still excitable, regulation. Experimental data and agent-based modelling simulations indicate that mouse embryonic stem cell proliferation dynamics vary in the two media, and cannot be reproduced by accounting only for Nanog-dependent cell-cycle regulation. We further demonstrate that both PD and Chiron play a key role in regulating heterogeneity in transcription factor expression and, ultimately, mouse embryonic stem cell fate decision. Mouse embryonic stem cells (mESCs) are pluripotent cells, having the potential to turn into most other cell types. A team led by Lucia Marucci at the University of Bristol, and involving collaborators from the University of Sheffield, developed mathematical models to describe temporal dynamics of pluripotency genes in mESCs under different culture conditions. The team shows that the combination of feedback loops in the underlying gene regulatory networks, noise, and culture conditions fine-tunes gene expression dynamics and, consequently, the fate of mESCs. Experimental and modelling results highlight the interplay between pluripotency gene dynamics and cellular proliferation. Understanding the dynamical mechanisms that influence the fate of mESCs could guide the optimisation of culture protocols in both pluripotency and differentiation.
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