Chaotic expression dynamics implies pluripotency: when theory and experiment meet.
Chaotic expression dynamics implies pluripotency: when theory and experiment meet.
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DOI：
10.1186/1745-6150-4-17
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发表时间：
2009-05-15
期刊：
影响因子：
5.5
通讯作者：
Kaneko K
中科院分区：
文献类型：
--
作者：
Furusawa C;Kaneko K
在正常发育过程中，细胞经历单向分化过程，逐渐减少它们可能成为的细胞类型的数量。多能干细胞可以分化成多种类型的细胞，但终末分化的细胞不能进一步分化。干细胞生物学的一个基本问题是多能干细胞和终末分化细胞之间细胞状态差异的表征，例如基因表达谱。为了解决这个问题，我们开发了一个细胞动力学系统模型，具有细胞内蛋白质表达动力学和相互相互作用。根据广泛的模拟，基因表达动态中具有不规则（混乱）振荡的细胞有可能分化成其他细胞类型。在发育过程中，这种复杂的振荡逐渐丢失，导致多能性丧失。这些模拟结果，加上最近在干细胞中的单细胞水平测量，使我们得出以下关于多能性的假设：一些基因表达的混沌振荡导致细胞多能性并提供细胞状态异质性，这是由准稳定状态的巡回性支持的。分化稳定了这些状态，导致多能性丧失。为了检验这一假设，通过荧光显微镜和荧光激活细胞分选 (FACS) 分析测量单细胞水平基因表达水平的时间过程至关重要。通过分析单细胞水平表达数据的时间序列，我们可以区分蛋白质表达水平随时间的变化是仅由于表达动力学的随机性还是源于细胞固有的混沌动力学，正如我们的假设所预测的那样。通过进一步分析分化细胞类型中的表达，人们可以检查多能性的丧失是否伴随着振荡的丧失。从科学和临床角度来看，从确定的细胞中恢复多能性是一个长期的愿望。我们的假设提出了恢复分化潜力的可行途径，即通过增加表达基因的多样性来恢复混乱的表达动态，这与最近一代的诱导多能干（iPS）细胞一致。本文由 David Krakauer、Jeroen van Zon（由 Rob de Boer 提名）和 Williams S. Hlavacek 审阅。
During normal development, cells undergo a unidirectional course of differentiation that progressively decreases the number of cell types they can potentially become. Pluripotent stem cells can differentiate into several types of cells, but terminally differentiated cells cannot differentiate any further. A fundamental problem in stem cell biology is the characterization of the difference in cellular states, e.g., gene expression profiles, between pluripotent stem cells and terminally differentiated cells. To address the problem, we developed a dynamical systems model of cells with intracellular protein expression dynamics and interactions with each other. According to extensive simulations, cells with irregular (chaotic) oscillations in gene expression dynamics have the potential to differentiate into other cell types. During development, such complex oscillations are lost successively, leading to a loss of pluripotency. These simulation results, together with recent single-cell-level measurements in stem cells, led us to the following hypothesis regarding pluripotency: Chaotic oscillation in the expression of some genes leads to cell pluripotency and affords cellular state heterogeneity, which is supported by itinerancy over quasi-stable states. Differentiation stabilizes these states, leading to a loss of pluripotency. To test the hypothesis, it is crucial to measure the time course of gene expression levels at the single-cell level by fluorescence microscopy and fluorescence-activated cell sorting (FACS) analysis. By analyzing the time series of single-cell-level expression data, one can distinguish whether the variation in protein expression level over time is due only to stochasticity in expression dynamics or originates from the chaotic dynamics inherent to cells, as our hypothesis predicts. By further analyzing the expression in differentiated cell types, one can examine whether the loss of pluripotency is accompanied by a loss of oscillation. Recovery of pluripotency from determined cells is a long-standing aspiration, from both scientific and clinical perspectives. Our hypothesis suggests a feasible route to recover the potential to differentiate, i.e., by increasing the variety of expressed genes to restore chaotic expression dynamics, as is consistent with the recent generation of induced pluripotent stem (iPS) cells. This article was reviewed by David Krakauer, Jeroen van Zon (nominated by Rob de Boer), and Williams S. Hlavacek.
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