Recent progress in cell surface nanoscopy: Light and force in the near-field

SummaryA hot topic in current cell biology is to understand the specific nanometer-scale organization and distribution of the surface machinery of living cells and the role these molecular properties play in the spatiotemporal control of different cellular processes. In the past years, near-field nanoscopy – using near-field scanning optical microscopy (NSOM) and atomic force microscopy (AFM) – has enabled key breakthroughs in this fast moving area. These two highly-sensitive surface scanning probe techniques go far beyond nano-imaging, by enabling researchers to localize and manipulate individual molecules on cell surfaces with nanoscale spatial resolution. Specifically, nanophotonic approaches and dynamic measurements in ultra-confined volumes allow nowadays the visualization of dynamic processes on cell membranes with optical spatial resolution down to 30 nm and sub-millisecond time resolution. These NSOM approaches are now exploited to reveal the existence of pre-assembled nanoplatforms of multi-molecular components on mammalian cells, to understand the molecular mechanisms responsible for the well-defined architecture of the cell surface and to decipher the molecular bases of diverse cellular processes, ranging from cell adhesion to pathogen recognition. In parallel, remarkable progress in AFM techniques now provides new opportunities for localizing single molecules in living cells and for analyzing their adhesive and mechanical properties in relation to function. Notably, the ability to observe and force-probe the cell surface machinery at molecular resolution has lead to the discovery of functional protein nanocomplexes that form under mechanical stress to activate cell signaling and cell adhesion.

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► We review recent progress in cell surface nanoscopy.
► Near-field scanning optical microscopy images protein nanoclusters on cells.
► Atomic force microscopy localizes and force-probes single molecules in living cells.
► We survey key discoveries in cell surface biology using these two tools.