Transition state characteristics during cell differentiation.
Transition state characteristics during cell differentiation.
复制标题
细胞分化过程中的过渡态特征。
DOI：
10.1371/journal.pcbi.1006405
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发表时间：
2018-09
影响因子：
4.3
通讯作者：
Stumpf MPH
中科院分区：
文献类型：
--
作者：
Brackston RD;Lakatos E;Stumpf MPH
描述干细胞分化过程的模型非常丰富，并且可以提供对潜在机制和实验观察到的行为的见解。沃丁顿的表观遗传景观一直提供了一个概念框架的分化过程，因为它的成立。然而，它也允许进行详细的数学和定量分析，因为景观至少在原则上与动力系统的数学模型有关。在这里，我们专注于一组动力系统的功能，是密切相关的细胞分化，通过考虑范例动力学模型，捕捉干细胞分化动力学的重要方面。这些模型使我们能够绘制细胞从一种命运转移到另一种命运时通过基因表达空间所采取的路径，例如从干细胞到更专门的细胞类型。我们的分析突出了过渡态（TS）的作用，分离不同的细胞命运，以及如何改变的TS的性质作为潜在的景观变化的变化，可以引起的，例如，细胞信号。我们证明，干细胞分化的模型可以解释为静态或短暂的景观。对于静态情况，TS代表所有细胞在分化期间接近的特定转录谱。或者，TS可以指当细胞经历随机转变时通常观察到的异质性时期。目前对单细胞分析的重点，特别是在人类和小鼠细胞图谱项目的背景下，是表征不同细胞状态的转录组特征。这显然是非常重要的，因为即使是不同细胞类型的数量，例如在人类中，也没有任何令人满意的确定性。在绘制这些状态的地图方面存在巨大的挑战，但这仍然只能提供部分答案。重要的是，细胞分化的方式，以及基因表达在分化过程中变化的方式仍然是未知的。在这里，我们使用动态系统的角度来考虑不同细胞类型（或细胞状态）之间的过渡的性质和动态。我们展示了如何发展景观（在沃丁顿的意义上）和过渡状态的性质变化，以响应外部刺激，并讨论这在干细胞分化的背景下（以及其潜在的逆转）。特别是，我们讨论了如何在过渡态的景观的性质，以及非梯度动力学的存在下，有很强的影响，从实验数据的分化动力学的可识别性。
Models describing the process of stem-cell differentiation are plentiful, and may offer insights into the underlying mechanisms and experimentally observed behaviour. Waddington’s epigenetic landscape has been providing a conceptual framework for differentiation processes since its inception. It also allows, however, for detailed mathematical and quantitative analyses, as the landscape can, at least in principle, be related to mathematical models of dynamical systems. Here we focus on a set of dynamical systems features that are intimately linked to cell differentiation, by considering exemplar dynamical models that capture important aspects of stem cell differentiation dynamics. These models allow us to map the paths that cells take through gene expression space as they move from one fate to another, e.g. from a stem-cell to a more specialized cell type. Our analysis highlights the role of the transition state (TS) that separates distinct cell fates, and how the nature of the TS changes as the underlying landscape changes—change that can be induced by e.g. cellular signaling. We demonstrate that models for stem cell differentiation may be interpreted in terms of either a static or transitory landscape. For the static case the TS represents a particular transcriptional profile that all cells approach during differentiation. Alternatively, the TS may refer to the commonly observed period of heterogeneity as cells undergo stochastic transitions. Current emphasis on single cell analysis, especially in the context of the human and mouse cell atlas projects, is on characterizing the transcriptomic signatures of different cell states. This is clearly of great importance, as even the number of different cell types, e.g. in humans, is not known with any satisfying degree of certainty. There are enormous challenges in mapping these states, but this will still only provide a partial answer. Importantly, the way in which cells differentiate, and the way in which gene expression changes over the course of differentiation will still be unknown. Here we use a dynamical systems perspective to consider the nature of, and dynamics during, the transition between different cell types (or cell states). We show how the developmental landscape (in Waddington’s sense) and the nature of the transition states change in response to external stimuli and discuss this in the context of stem cell differentiation (as well as its potential reversal). In particular, we discuss how the nature of the landscape at the transition state, as well as the presence of non-gradient dynamics, has strong implications for the identifiability of differentiation dynamics from experimental data.
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影响因子：
--
作者：
Bhattacharya S;Zhang Q;Andersen ME
通讯作者：
Andersen ME
影响因子：
--
作者：
Chickarmane V;Olariu V;Peterson C
通讯作者：
Peterson C
影响因子：
8.8
作者：
Filippi S;Barnes CP;Kirk PD;Kudo T;Kunida K;McMahon SS;Tsuchiya T;Wada T;Kuroda S;Stumpf MP
通讯作者：
Stumpf MP
影响因子：
4.4
作者：
Gillespie, DT
通讯作者：
Gillespie, DT
DOI：
10.1073/pnas.0506347102
发表时间：
2005-09-13
影响因子：
11.1
作者：
Kwon, C;Ao, P;Thouless, DJ
通讯作者：
Thouless, DJ