The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA.
Gladstone Institute of Cardiovascular Disease, San Francisco, CA, 94158, USA.
Nat Commun. 2018 Oct 5;9(1):4111. doi: 10.1038/s41467-018-06693-1.
The initiation of heterogeneity within a population of phenotypically identical progenitors is a critical event for the onset of morphogenesis and differentiation patterning. Gap junction communication within multicellular systems produces complex networks of intercellular connectivity that result in heterogeneous distributions of intracellular signaling molecules. In this study, we investigate emergent systems-level behavior of the intercellular network within embryonic stem cell (ESC) populations and corresponding spatial organization during early neural differentiation. An agent-based model incorporates experimentally-determined parameters to yield complex transport networks for delivery of pro-differentiation cues between neighboring cells, reproducing the morphogenic trajectories during retinoic acid-accelerated mouse ESC differentiation. Furthermore, the model correctly predicts the delayed differentiation and preserved spatial features of the morphogenic trajectory that occurs in response to intercellular perturbation. These findings suggest an integral role of gap junction communication in the temporal coordination of emergent patterning during early differentiation and neural commitment of pluripotent stem cells.
群体中表型相同的祖细胞异质性的起始是形态发生和分化模式开始的关键事件。多细胞系统中的间隙连接通讯产生细胞间连接的复杂网络，导致细胞内信号分子的异质分布。在这项研究中，我们研究了胚胎干细胞 (ESC) 群体中细胞间网络的新兴系统级行为以及早期神经分化过程中的相应空间组织。基于代理的模型结合了实验确定的参数，为相邻细胞之间传递促分化信号产生复杂的传输网络，复制了维甲酸加速的小鼠 ESC 分化过程中的形态发生轨迹。此外，该模型正确预测了细胞间干扰时出现的分化延迟和形态发生轨迹的空间特征得以保留，这表明间隙连接通讯在早期分化过程中新兴模式的时间协调以及多能干细胞的神经定向中起着重要作用。
