Ooi Hsu Kiang, Ma Lan
Department of Bioengineering, University of Texas at Dallas, Richardson, TX 75080, USA.
Annu Int Conf IEEE Eng Med Biol Soc. 2012;2012:5498-501. doi: 10.1109/EMBC.2012.6347239.
Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Dependent on the type of stimulus, apoptosis can be propagated by intrinsic pathway or extrinsic pathway. Previously, we have proposed a deterministic model of intrinsic apoptosis pathway which is bistable in a robust parameter region. Cellular networks, however, are inherently stochastic and significant cell-to-cell variability in apoptosis response has been observed at single cell level. In this work, we examine the impact of intrinsic stochastic fluctuations as well as variation of protein concentrations on behavior of the intrinsic apoptosis network. First, Gillespie Stochastic Simulation Algorithm (SSA) of the model is implemented to account for intrinsic noise. Using histograms of steady-state output at varying input levels, we show that the intrinsic noise in the apoptosis network elicits a wider region of bistability. We further analyze the dependence of system stochasticity due to intrinsic fluctuations, such as steady-state noise level and random response delay time, on the input signal. We find however that the intrinsic noise is insufficient to generate significant stochastic variations at physiologically relevant level of molecular numbers. Finally, extrinsic fluctuation represented by variations of two key proteins is modeled and the resultant stochasticity of apoptosis timing is analyzed. Indeed, these protein variations can induce cell-to-cell stochastic variability at a quantitative level agreeing with experiments. Therefore, we conclude that the heterogeneity in intrinsic apoptosis responses among individual cells plausibly arises from extrinsic rather than intrinsic origin of fluctuations.
细胞凋亡是一种细胞自杀机制，它使后生动物能够控制组织中的细胞数量，并清除威胁动物生存的单个细胞。根据刺激类型的不同，细胞凋亡可以通过内源性途径或外源性途径进行传播。此前，我们提出了一种内源性凋亡途径的确定性模型，该模型在一个稳健的参数区域内是双稳态的。然而，细胞网络本质上是随机的，并且在单细胞水平上已经观察到凋亡反应中存在显著的细胞间变异性。在这项工作中，我们研究了内源性随机波动以及蛋白质浓度变化对内在凋亡网络行为的影响。首先，我们实现了该模型的 Gillespie 随机模拟算法（SSA）来考虑内源性噪声。通过使用不同输入水平下稳态输出的直方图，我们表明凋亡网络中的内源性噪声引发了更广泛的双稳态区域。我们进一步分析了由于内源性波动导致的系统随机性，如稳态噪声水平和随机响应延迟时间，对输入信号的依赖性。然而，我们发现内源性噪声不足以在生理相关的分子数量水平上产生显著的随机变化。最后，我们对由两种关键蛋白质的变化所代表的外源性波动进行建模，并分析由此产生的凋亡时间的随机性。事实上，这些蛋白质变化可以在定量水平上诱导细胞间的随机变异性，这与实验结果一致。因此，我们得出结论，单个细胞之间内在凋亡反应的异质性可能源于外源性而非内源性的波动起源。
