Department of Basic Science and Research Center for Complex Systems Biology, University of Tokyo, Meguro-ku, Tokyo, Japan.
PLoS One. 2011;6(11):e27232. doi: 10.1371/journal.pone.0027232. Epub 2011 Nov 3.
The lack of understanding of stem cell differentiation and proliferation is a fundamental problem in developmental biology. Although gene regulatory networks (GRNs) for stem cell differentiation have been partially identified, the nature of differentiation dynamics and their regulation leading to robust development remain unclear. Herein, using a dynamical system modeling cell approach, we performed simulations of the developmental process using all possible GRNs with a few genes, and screened GRNs that could generate cell type diversity through cell-cell interactions. We found that model stem cells that both proliferated and differentiated always exhibited oscillatory expression dynamics, and the differentiation frequency of such stem cells was regulated, resulting in a robust number distribution. Moreover, we uncovered the common regulatory motifs for stem cell differentiation, in which a combination of regulatory motifs that generated oscillatory expression dynamics and stabilized distinct cellular states played an essential role. These findings may explain the recently observed heterogeneity and dynamic equilibrium in cellular states of stem cells, and can be used to predict regulatory networks responsible for differentiation in stem cell systems.
干细胞分化和增殖的理解不足是发育生物学中的一个基本问题。尽管已经部分确定了干细胞分化的基因调控网络（GRNs），但导致稳健发育的分化动力学的本质及其调控仍不清楚。在此，我们使用一个细胞动力学系统建模方法，使用少量基因的所有可能的 GRNs 进行了发育过程的模拟，并筛选出能够通过细胞间相互作用产生细胞类型多样性的 GRNs。我们发现，既能增殖又能分化的模型干细胞总是表现出振荡的表达动力学，并且这种干细胞的分化频率受到调控，从而产生稳健的数量分布。此外，我们揭示了干细胞分化的常见调控基序，其中产生振荡表达动力学并稳定不同细胞状态的调控基序组合起着至关重要的作用。这些发现可以解释最近观察到的干细胞中细胞状态的异质性和动态平衡，并可用于预测干细胞系统中负责分化的调控网络。
