A Synthetic Multifunctional Mammalian pH Sensor and CO2 Transgene-Control Device
A Synthetic Multifunctional Mammalian pH Sensor and CO2 Transgene-Control Device
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DOI：
10.1016/j.molcel.2014.06.007
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发表时间：
2014-08-07
期刊：
影响因子：
16
通讯作者：
Fussenegger, Martin
中科院分区：
文献类型：
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作者：
Auslaender, David;Auslaender, Simon;Fussenegger, Martin
所有代谢活动都在由CO2-碳酸氢盐缓冲系统控制的狭窄pH范围内进行。我们假设pH值可以作为替代信号来监测和响应生理状态。通过将人类质子激活的细胞表面受体TDAG 8功能性地重新连接到嵌合启动子，我们创建了一种合成的信号级联，可以精确地监测生理范围内的细胞外pH值。合成pH传感器可以通过有机酸以及气态CO2来调节，其将CO2-碳酸氢盐平衡向氢离子转移。这使得气体可编程逻辑门的设计成为可能，提供了对微流体设备内细胞行为的远程控制，并允许在标准生物反应器中进行CO2触发的生物制药生产。当将含有与胰岛素产生相关的合成pH传感器的细胞植入发展为糖尿病酮症酸中毒的1型糖尿病小鼠时，假体网络自动对酸性pH进行评分，并协调纠正酮症酸中毒的胰岛素表达反应。
All metabolic activities operate within a narrow pH range that is controlled by the CO2-bicarbonate buffering system. We hypothesized that pH could serve as surrogate signal to monitor and respond to the physiological state. By functionally rewiring the human proton-activated cell-surface receptor TDAG8 to chimeric promoters, we created a synthetic signaling cascade that precisely monitors extracellular pH within the physiological range. The synthetic pH sensor could be adjusted by organic acids as well as gaseous CO2 that shifts the CO2-bicarbonate balance toward hydrogen ions. This enabled the design of gas-programmable logic gates, provided remote control of cellular behavior inside microfluidic devices, and allowed for CO2-triggered production of biopharmaceuticals in standard bioreactors. When implanting cells containing the synthetic pH sensor linked to production of insulin into type 1 diabetic mice developing diabetic ketoacidosis, the prosthetic network automatically scored acidic pH and coordinated an insulin expression response that corrected ketoacidosis.