Synthetic mammalian signaling circuits for robust cell population control.
Synthetic mammalian signaling circuits for robust cell population control.
复制标题
用于鲁棒细胞群控制的合成哺乳动物信号电路。
DOI：
10.1016/j.cell.2022.01.026
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发表时间：
2022-03-17
期刊：
影响因子：
64.5
通讯作者：
Elowitz MB
中科院分区：
文献类型：
--
作者：
Ma Y;Budde MW;Mayalu MN;Zhu J;Lu AC;Murray RM;Elowitz MB
在多细胞生物中，细胞主动感知和控制自己的种群密度。人工合成的哺乳动物群体感应电路可以提供对种群控制原理的深入了解，并扩展细胞疗法。然而，一个关键的挑战是降低它们对逃避控制的“作弊”突变的固有敏感性。在这里，我们重新利用植物激素生长素，使正交哺乳动物细胞间的通信和群体感应。我们设计了一个矛盾的人口控制电路，称为Paradaux，其中生长素刺激和抑制不同浓度的净细胞生长。这种循环在长达42天的连续培养的延长时间尺度上限制了种群大小。相比之下，当在一个非矛盾的制度，人口控制变得更容易突变逃逸。这些结果建立生长素作为一个多功能的“私人”通信系统，并表明矛盾的电路架构可以提供强大的人口控制。哺乳动物细胞被改造为具有植物激素系统和稳健的合成信号传导途径，植物激素系统提供扩散通信通道，稳健的合成信号传导途径允许通过生长素进行群体感测和控制。
In multicellular organisms, cells actively sense and control their own population density. Synthetic mammalian quorum sensing circuits could provide insight into principles of population control and extend cell therapies. However, a key challenge is reducing their inherent sensitivity to “cheater” mutations that evade control. Here, we repurposed the plant hormone auxin to enable orthogonal mammalian cell-cell communication and quorum sensing. We designed a paradoxical population control circuit, termed Paradaux, in which auxin stimulates and inhibits net cell growth at different concentrations. This circuit limited population size over extended timescales, of up to 42 days of continuous culture. By contrast, when operating in a non-paradoxical regime, population control became more susceptible to mutational escape. These results establish auxin as a versatile “private” communication system, and demonstrate that paradoxical circuit architectures can provide robust population control. Mammalian cells were engineered with both a plant hormone system, which provides a diffusive communication channel, and robust synthetic signaling pathways that allow for population sensing and control through auxin.
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