Pushing, pulling, and squeezing our way to understanding mechanotransduction

Abstract

Mechanotransduction is often described in the context of force-induced changes in molecular conformation, but molecular-scale mechanical stimuli arise in vivo in the context of complex, multicellular tissue structures. For this reason, we highlight and review experimental methods for investigating mechanotransduction across multiple length scales. We begin by discussing techniques that probe the response of individual molecules to applied force. We then move up in length scale to highlight techniques aimed at uncovering how cells transduce mechanical stimuli into biochemical activity. Finally, we discuss approaches for determining how these stimuli arise in multicellular structures. We expect that future work will combine techniques across these length scales to provide a more comprehensive understanding of mechanotransduction.

Measurement of dynamic cell-induced 3D displacement fields in vitro for traction force optical coherence microscopy

“…This feature, in combination with rapid acquisition, enables an unprecedented temporal sampling frequency for volumetric imaging that may be maintained for extended experiment times in both low-and highly-scattering biological samples. As such, OCM may enable the study of large 3D cell populations and/or collectives for both long term processes like migration, division, and ECM remodeling, as well as short term dynamics such as environmental probing with filopodia and mechanotransduction events [27]. Further down the line, OCM may enable novel mechanobiology research in in vivo settings using endogenous scattering contrast.…”

“…This means that particle or feature tracking algorithms will have smaller search spaces to analyze and may return more robust results due to less structure decorrelation between timepoints [23]. It is also possible that new dynamic processes on the minute-to-second timescales may be revealed by these high spatiotemporal resolution acquisitions [3,27]. Finally, the high phase sensitivity of frequency domain OCT methods may allow the detection of subwavelength (down to subnanometer) displacements at time scales up to the order of the system line scan rate [36].…”

“…Mechanical signals, and the responses they invoke, span a wide range of spatiotemporal scales-from individual molecules to entire tissues and organs, and from collective cell migration over hours, days, or weeks, to cellular mechanotransduction events on the order of seconds to minutes [3,6,[27][28][29]. To understand how all of these systems interact, it is crucial that TFM and other methods in mechanobiology capture information over a large range of spatiotemporal scales.…”

“…To understand how all of these systems interact, it is crucial that TFM and other methods in mechanobiology capture information over a large range of spatiotemporal scales. Moreover, as cellular behavior can strongly depend on the composition and dimensionality of surrounding substrates, the ability to observe cellular behavior within 3D models of the ECM is of high priority [3,6,27,28]. High spatiotemporal coverage-the ability to capture large volumes at high resolution, with rapid acquisition that may be maintained for extended times-is therefore a key trait required for the advancement of 3D TFM research.…”

E-cadherin and LGN align epithelial cell divisions with tissue tension independently of cell shape

“…In addition, cells are subject to diverse mechanical forces, including tensile forces exerted by neighboring cells and by contraction of the intracellular actomyosin cytoskeleton (10,11). These mechanical forces are sensed by cells and transduced into an intracellular response, which triggers changes in cellular behaviors, including cell proliferation, differentiation, and migration (12,13).…”