Mathematical model of adult stem cell regeneration with cross-talk between genetic and epigenetic regulation
Mathematical model of adult stem cell regeneration with cross-talk between genetic and epigenetic regulation
复制标题
遗传与表观遗传调控之间相互作用的成体干细胞再生数学模型
DOI：
10.1073/pnas.1324267111
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发表时间：
2014-03-11
影响因子：
11.1
通讯作者：
Nie, Qing
中科院分区：
文献类型：
--
作者：
Lei, Jinzhi;Levin, Simon A.;Nie, Qing
本文研究了成体干细胞如何维持其执行一系列复杂任务的能力，包括组织再生和替换缺陷细胞。为此，干细胞群必须协调分化、增殖和细胞死亡（凋亡），以维持表观遗传状态的适当分布。利用应用数学的工具，并借鉴资源代际转移理论，本文展示了如何选择细胞分裂过程中的控制策略，以最大化预期性能，利用遗传和表观遗传调控之间的串扰以及稳态过程中的性能标准。异质增殖是一种混合策略，在这种策略中，并非所有细胞都具有相同的增殖概率，它被证明可以增加稳健性，从而提高长期性能。成体干细胞存在于人体的各个部位，通过细胞分裂进行增殖，以补充垂死的细胞或促进受损组织的再生。为了在器官或组织的生命周期中发挥这些功能，干细胞需要将其种群保持在其表观遗传状态的忠实分布中，这些状态容易受到每次细胞分裂期间的随机波动、意外损伤和许多细胞分裂期间发生的潜在基因突变的影响。然而，目前尚不清楚干细胞的分化、增殖和凋亡这三个过程如何共同完成这些具有挑战性的任务。在这里，不考虑分子细节，我们提出了一个成人干细胞再生的遗传最优控制模型，包括三个基本过程，以及基于表型差异适应度的细胞分裂和适应。在该模型中，需要具有表观遗传状态分布的干细胞在每次细胞分裂后最大化预期性能。我们表明，依赖于干细胞表观遗传状态的异质增殖可以改善干细胞分布的维持，以创造平衡的种群。在每个细胞分裂过程中的控制策略导致一个涉及异质增殖的反馈机制，可以加速再生，减少干细胞群体的波动。当允许突变时，细胞凋亡进化为在多次细胞分裂后的稳态中发挥最大作用。总体结果强调了遗传和表观遗传调控之间的串扰以及在表观遗传状态下形成理想的干细胞异质分布的稳态过程中的性能目标的重要性。
Significance This paper examines how adult stem cells maintain their ability to carry out a complex set of tasks, including tissue regeneration and replacement of defective cells. To do so, stem cell populations must coordinate differentiation, proliferation, and cell death (apoptosis) to maintain an appropriate distribution of epigenetic states. Using the tools of applied mathematics, and borrowing from the theory of intergenerational transfer of resources, this paper shows how control strategies during cell division should be chosen to maximize expected performance, utilizing cross-talk between genetic and epigenetic regulation and performance criteria during homeostasis. Heterogeneous proliferation, a mixed strategy in which not all cells have the same proliferation probability, is shown to increase robustness, and hence long-term performance. Adult stem cells, which exist throughout the body, multiply by cell division to replenish dying cells or to promote regeneration to repair damaged tissues. To perform these functions during the lifetime of organs or tissues, stem cells need to maintain their populations in a faithful distribution of their epigenetic states, which are susceptible to stochastic fluctuations during each cell division, unexpected injury, and potential genetic mutations that occur during many cell divisions. However, it remains unclear how the three processes of differentiation, proliferation, and apoptosis in regulating stem cells collectively manage these challenging tasks. Here, without considering molecular details, we propose a genetic optimal control model for adult stem cell regeneration that includes the three fundamental processes, along with cell division and adaptation based on differential fitnesses of phenotypes. In the model, stem cells with a distribution of epigenetic states are required to maximize expected performance after each cell division. We show that heterogeneous proliferation that depends on the epigenetic states of stem cells can improve the maintenance of stem cell distributions to create balanced populations. A control strategy during each cell division leads to a feedback mechanism involving heterogeneous proliferation that can accelerate regeneration with less fluctuation in the stem cell population. When mutation is allowed, apoptosis evolves to maximize the performance during homeostasis after multiple cell divisions. The overall results highlight the importance of cross-talk between genetic and epigenetic regulation and the performance objectives during homeostasis in shaping a desirable heterogeneous distribution of stem cells in epigenetic states.