Huang S, Ingber D E
Department of Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Exp Cell Res. 2000 Nov 25;261(1):91-103. doi: 10.1006/excr.2000.5044.
Development of characteristic tissue patterns requires that individual cells be switched locally between different phenotypes or "fates;" while one cell may proliferate, its neighbors may differentiate or die. Recent studies have revealed that local switching between these different gene programs is controlled through interplay between soluble growth factors, insoluble extracellular matrix molecules, and mechanical forces which produce cell shape distortion. Although the precise molecular basis remains unknown, shape-dependent control of cell growth and function appears to be mediated by tension-dependent changes in the actin cytoskeleton. However, the question remains: how can a generalized physical stimulus, such as cell distortion, activate the same set of genes and signaling proteins that are triggered by molecules which bind to specific cell surface receptors. In this article, we use computer simulations based on dynamic Boolean networks to show that the different cell fates that a particular cell can exhibit may represent a preprogrammed set of common end programs or "attractors" which self-organize within the cell's regulatory networks. In this type of dynamic network model of information processing, generalized stimuli (e.g., mechanical forces) and specific molecular cues elicit signals which follow different trajectories, but eventually converge onto one of a small set of common end programs (growth, quiescence, differentiation, apoptosis, etc.). In other words, if cells use this type of information processing system, then control of cell function would involve selection of preexisting (latent) behavioral modes of the cell, rather than instruction by specific binding molecules. Importantly, the results of the computer simulation closely mimic experimental data obtained with living endothelial cells. The major implication of this finding is that current methods used for analysis of cell function that rely on characterization of linear signaling pathways or clusters of genes with common activity profiles may overlook the most critical features of cellular information processing which normally determine how signal specificity is established and maintained in living cells.
特征性组织模式的形成要求单个细胞在不同表型或“命运”之间进行局部转换；当一个细胞增殖时，其相邻细胞可能分化或死亡。最近的研究表明，这些不同基因程序之间的局部转换是通过可溶性生长因子、不溶性细胞外基质分子和产生细胞形状畸变的机械力之间的相互作用来控制的。尽管精确的分子基础仍然未知，但细胞生长和功能的形状依赖性控制似乎是由肌动蛋白细胞骨架中张力依赖性变化介导的。然而，问题仍然存在：像细胞畸变这样的一般物理刺激如何能激活与那些与特定细胞表面受体结合的分子所触发的相同一组基因和信号蛋白呢？在本文中，我们使用基于动态布尔网络的计算机模拟来表明，一个特定细胞能够展现出的不同细胞命运可能代表了一组预先编程的共同终末程序或“吸引子”，它们在细胞调控网络内自我组织。在这种类型的信息处理动态网络模型中，一般刺激（例如机械力）和特定分子线索引发的信号沿着不同轨迹，但最终汇聚到一小组共同终末程序（生长、静止、分化、凋亡等）中的一个。换句话说，如果细胞使用这种类型的信息处理系统，那么细胞功能的控制将涉及选择细胞预先存在（潜在）的行为模式，而不是由特定结合分子进行指令。重要的是，计算机模拟的结果与用活内皮细胞获得的实验数据非常相似。这一发现的主要意义在于，目前用于分析细胞功能的方法，即依赖于线性信号通路或具有共同活性谱的基因簇的表征，可能会忽略细胞信息处理的最关键特征，而这些特征通常决定了活细胞中信号特异性是如何建立和维持的。
