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, the same cells limited population growth, but were 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.

中文翻译：

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用于稳健细胞群控制的合成哺乳动物信号电路

在多细胞生物中，细胞主动感知和控制自己的种群密度。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洞察并扩展细胞疗法。然而，一个关键挑战是降低它们对逃避控制的“欺骗”突变的固有敏感性。在这里，我们重新利用植物激素生长素来实现正交哺乳动物细胞间通讯和群体感应。我们设计了一个矛盾的人口控制电路，称为Paradaux，其中生长素在不同浓度下刺激和抑制净细胞生长。该电路在延长的时间尺度上限制了种群规模，长达 42 天的连续培养。相比之下，当在非矛盾状态下运行时，相同的细胞限制了种群增长，但更容易受到突变逃逸的影响。这些结果将生长素确立为一种多功能的“私人”通信系统，并证明矛盾的电路架构可以提供强大的种群控制。