Tunable synthetic phenotypic diversification on Waddington's landscape through autonomous signaling
Tunable synthetic phenotypic diversification on Waddington's landscape through autonomous signaling
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DOI：
10.1073/pnas.1105901108
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发表时间：
2011-11-01
影响因子：
11.1
通讯作者：
Kiga, Daisuke
中科院分区：
文献类型：
--
作者：
Sekine, Ryoji;Yamamura, Masayuki;Kiga, Daisuke
细胞的表型多样化对于多细胞生物的发育和再生过程至关重要。多样化的概念被描述为运动的大理石滚下沃丁顿的景观，其中的稳定状态的数量随着发展的进展而变化。与这个简单的概念相反，自然生物分子过程的复杂性阻碍了对其设计原理的理解。我们已经在大肠杆菌中构建了一个只有四个基因的合成电路，它通过细胞间的通信编程细胞自主地多样化，就像景观上的运动一样。电路设计是基于一个双向拨动开关与细胞间信号系统的组合。当所有细胞都从低状态开始时，具有电路的细胞在体内和计算机中分化成两种不同的细胞状态，“高”和“低”。合成多样化不仅受到电路设计所确定的景观形状的影响，包括信号分子的合成速率，还受到实验中细胞数量的影响。这种细胞数量依赖性让人想起“群落效应”：发育中的细胞的命运由它们的数量决定。我们的合成回路可以成为研究高等生物多样性和分化的模型系统。因此，我们的电路与不同细胞功能的进一步整合将为在组织工程中在群体水平上指导细胞命运提供独特的工具。
Phenotypic diversification of cells is crucial for developmental and regenerative processes in multicellular organisms. The diversification concept is described as the motion of marbles rolling down Waddington's landscape, in which the number of stable states changes as development proceeds. In contrast to this simple concept, the complexity of natural biomolecular processes prevents comprehension of their design principles. We have constructed, in Escherichia coli, a synthetic circuit with just four genes, which programs cells to autonomously diversify as the motion on the landscape through cell-cell communication. The circuit design was based on the combination of a bistable toggle switch with an intercellular signaling system. The cells with the circuit diversified into two distinct cell states, "high" and "low," in vivo and in silico, when all of the cells started from the low state. The synthetic diversification was affected by not only the shape of the landscape determined by the circuit design, which includes the synthesis rate of the signaling molecule, but also the number of cells in the experiments. This cell-number dependency is reminiscent of the " community effect": The fates of developing cells are determined by their number. Our synthetic circuit could be a model system for studying diversification and differentiation in higher organisms. Prospectively, further integrations of our circuit with different cellular functions will provide unique tools for directing cell fates on the population level in tissue engineering.