Cells both sense and exert mechanical force. In vivo, force is likely to be important, in many and varied ways, in the development and maintenance of tissue function. Toward understanding this as-yet relatively unexplored biology, methods to map cellular forces are of great interest.

Adhesion molecules are major players in the ways cells push and pull on each other and on the extracellular matrix. Imaging-based methods with designed sensors are now being used to measure force exerted by these molecules.

Tools to measure biological forces. Credit: Katie Vicari

Earlier versions of such tools were variations on the theme of force-sensitive fluorescence resonance energy transfer (FRET) sensors. For instance, researchers placed a sequence encoding a force-sensitive domain from a spider silk protein between genes encoding two fluorescent proteins that undergo FRET and then expressed the entire cassette spliced into the sequence encoding vinculin (Nature 466, 263–266, 2010). Upon calibration, the FRET signal provided a measure of the forces across vinculin at the cell surface. Another group constructed a slightly different tool: a ligand of interest was linked via a tension-sensitive polymer to the extracellular substrate; tension on the cognate cell-surface receptor could then be measured by monitoring the extent of quenching of a conjugated fluorophore by quencher at the substrate (Nat. Methods 9, 64–67, 2011). Force sensors based on imaging can be combined with other high-resolution imaging to map forces to cellular structure.

In a recent twist, researchers dispensed with the fluorescence readout altogether. They constructed cell tethers by conjugating a ligand of interest to DNA, exploiting its well-studied mechanical properties to tune the tether strength (i.e., the force at which it ruptures). By simply monitoring whether a cell can adhere to a surface presenting the ligand with a tether of a given strength, the researchers measured the force exerted at a single receptor-ligand pair (Science 340, 991–994, 2013).

Also very recently, cellular force measurements have moved in vivo. Using tiny ligand-conjugated oil droplets with known mechanical properties, researchers measured, via imaging, the forces exerted by cells in living tissues (Nat. Methods doi:10.1038/nmeth.2761).

Microscale and nanoscale imaging tools to monitor biological forces will undoubtedly continue to develop. Unanticipated biological vistas are likely to open up as a result.