Department of Chemistry , Stanford University , Stanford , California 94305 , United States.
School of Chemical and Biomedical Engineering , Nanyang Technological University , Singapore 637457 , Singapore.
Acc Chem Res. 2018 May 15;51(5):1046-1053. doi: 10.1021/acs.accounts.7b00594. Epub 2018 Apr 12.
Over the past decade, there has been growing interest in developing biosensors and devices with nanoscale and vertical topography. Vertical nanostructures induce spontaneous cell engulfment, which enhances the cell-probe coupling efficiency and the sensitivity of biosensors. Although local membranes in contact with the nanostructures are found to be fully fluidic for lipid and membrane protein diffusions, cells appear to actively sense and respond to the surface topography presented by vertical nanostructures. For future development of biodevices, it is important to understand how cells interact with these nanostructures and how their presence modulates cellular function and activities. How cells recognize nanoscale surface topography has been an area of active research for two decades before the recent biosensor works. Extensive studies show that surface topographies in the range of tens to hundreds of nanometers can significantly affect cell functions, behaviors, and ultimately the cell fate. For example, titanium implants having rough surfaces are better for osteoblast attachment and host-implant integration than those with smooth surfaces. At the cellular level, nanoscale surface topography has been shown by a large number of studies to modulate cell attachment, activity, and differentiation. However, a mechanistic understanding of how cells interact and respond to nanoscale topographic features is still lacking. In this Account, we focus on some recent studies that support a new mechanism that local membrane curvature induced by nanoscale topography directly acts as a biochemical signal to induce intracellular signaling, which we refer to as the curvature hypothesis. The curvature hypothesis proposes that some intracellular proteins can recognize membrane curvatures of a certain range at the cell-to-material interface. These proteins then recruit and activate downstream components to modulate cell signaling and behavior. We discuss current technologies allowing the visualization of membrane deformation at the cell membrane-to-substrate interface with nanometer precision and demonstrate that vertical nanostructures induce local curvatures on the plasma membrane. These local curvatures enhance the process of clathrin-mediated endocytosis and affect actin dynamics. We also present evidence that vertical nanostructures can induce significant deformation of the nuclear membrane, which can affect chromatin distribution and gene expression. Finally, we provide a brief perspective on the curvature hypothesis and the challenges and opportunities for the design of nanotopography for manipulating cell behavior.
在过去的十年中，人们对开发具有纳米级和垂直形貌的生物传感器和设备产生了浓厚的兴趣。垂直纳米结构诱导细胞自发吞噬，从而提高了细胞-探针的耦合效率和生物传感器的灵敏度。尽管与纳米结构接触的局部膜对于脂质和膜蛋白的扩散是完全流体的，但细胞似乎能够主动感知和响应垂直纳米结构所呈现的表面形貌。为了未来生物设备的发展，了解细胞如何与这些纳米结构相互作用以及它们的存在如何调节细胞功能和活动非常重要。细胞如何识别纳米级表面形貌是近十年来生物传感器工作之前二十年的一个活跃研究领域。大量研究表明，几十到几百纳米范围内的表面形貌可以显著影响细胞功能、行为，最终影响细胞命运。例如，具有粗糙表面的钛植入物比具有光滑表面的植入物更有利于成骨细胞附着和宿主-植入物整合。在细胞水平上，大量研究表明，纳米级表面形貌可以调节细胞的附着、活性和分化。然而，细胞如何相互作用并响应纳米级形貌特征的机制仍不清楚。在本报告中，我们重点介绍了一些支持新机制的最新研究，该机制认为纳米形貌引起的局部膜曲率直接作为生化信号诱导细胞内信号转导，我们称之为曲率假说。曲率假说提出，一些细胞内蛋白可以识别细胞-材料界面处一定范围内的膜曲率。这些蛋白然后募集并激活下游组件来调节细胞信号转导和行为。我们讨论了当前允许以纳米级精度可视化细胞膜在细胞膜-基底界面上的变形的技术，并证明垂直纳米结构会在质膜上诱导局部曲率。这些局部曲率增强了网格蛋白介导的内吞作用过程并影响肌动蛋白动力学。我们还提供了证据表明，垂直纳米结构可以诱导核膜的显著变形，从而影响染色质分布和基因表达。最后，我们简要地讨论了曲率假说以及设计用于操纵细胞行为的纳米形貌的挑战和机遇。
