Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis
Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis
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DOI：
10.1073/pnas.1516503113
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发表时间：
2016-02-09
影响因子：
11.1
通讯作者：
Levchenko, Andre
中科院分区：
文献类型：
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作者：
Ellison, David;Mugler, Andrew;Levchenko, Andre
细胞对外源性信号的集体反应依赖于细胞间的相互作用。原则上，这些可以导致对微弱和嘈杂刺激的敏感性增强。然而，这还没有被实验证明，并且关于多细胞信号处理如何调节单细胞对细胞外信号输入的敏感性知之甚少，包括那些指导组织形式和功能的复杂变化。在这里，我们探讨了细胞间通讯是否可以增强细胞系的感知能力，并对趋化性线索的弱梯度作出反应。使用乳腺上皮细胞和数学建模的实验相结合，我们发现，多细胞传感能够检测和响应浅表皮生长因子（EGF）梯度是无法检测到的单细胞。然而，这种类型的梯度传感的优点是有限的信号传递的噪声，必要的整合空间分布的配体浓度信息。我们计算的基本感官的限制所施加的这种通信噪声和联合收割机将它们与实验数据估计的有效大小的多细胞感觉集团参与梯度传感。功能实验强烈暗示通过间隙连接的细胞间通信和钙从细胞内存储的集体梯度传感介质的释放。由此产生的综合分析提供了一个框架，了解感官信息处理的化学耦合细胞的继电器的优点和局限性。
Collective cell responses to exogenous cues depend on cell-cell interactions. In principle, these can result in enhanced sensitivity to weak and noisy stimuli. However, this has not yet been shown experimentally, and little is known about how multicellular signal processing modulates single-cell sensitivity to extracellular signaling inputs, including those guiding complex changes in the tissue form and function. Here we explored whether cell-cell communication can enhance the ability of cell ensembles to sense and respond to weak gradients of chemotactic cues. Using a combination of experiments with mammary epithelial cells and mathematical modeling, we find that multicellular sensing enables detection of and response to shallow epidermal growth factor (EGF) gradients that are undetectable by single cells. However, the advantage of this type of gradient sensing is limited by the noisiness of the signaling relay, necessary to integrate spatially distributed ligand concentration information. We calculate the fundamental sensory limits imposed by this communication noise and combine them with the experimental data to estimate the effective size of multicellular sensory groups involved in gradient sensing. Functional experiments strongly implicated intercellular communication through gap junctions and calcium release from intracellular stores as mediators of collective gradient sensing. The resulting integrative analysis provides a framework for understanding the advantages and limitations of sensory information processing by relays of chemically coupled cells.