Appreciating force and shape—the rise of mechanotransduction in cell biology

Abstract

Although the shapes of organisms are encoded in their genome, the developmental processes that lead to the final form of vertebrates involve a constant feedback between dynamic mechanical forces, and cell growth and motility. Mechanobiology has emerged as a discipline dedicated to the study of the effects of mechanical forces and geometry on cell growth and motility—for example, during cell-matrix adhesion development—through the signalling process of mechanotransduction.

Figure 1 ∣. Mechanotransduction.

Mechanotransduction converts mechanical stimuli — such as substrate rigidity (through contractile units or mature integrin adhesions), stretching (through cell–cell contacts or integrin adhesions) or shear stress (not shown) — into chemical signals to regulate cell behaviour and function. Typically, the pathway involves receptors at focal adhesions or cell–cell contacts (for example, integrins and cadherins), mechanosensors (for example, stretchable proteins such as talin and p130CAS) and nuclear signalling factors to change gene and protein expression profiles. Nuclear deformation (the shape of the nucleus before force is applied is indicated by the dashed line) can also lead to changes in gene expression patterns. The timescale of these events ranges from milliseconds to seconds for the stretching of mechanosensors, hours for altered gene expression, days for changes in cell behaviour and function, and weeks for tissue development. FAK, focal adhesion kinase; MLP, muscle LIM protein; MRTFA, myocardin-related transcription factor A; YAP, Yes-associated protein.

Figure 2 ∣. Timeline of milestones in the history of mechanotransduction research.

Image of the front cover of the 1992 edition of On Growth and Form by D’Arcy Thompson. Image of integrin protein structure in autoinhibited conformation (left) and active conformation (right) reprinted with permission from David S. Goodsell and the Research Collaboratory for Structural Bioinformatics (RCSB), Protein Data Bank (PDB). Image of vinculin binding to stretched talin from del Rio, A. et al. Stretching single talin rod molecules activates vinculin binding. Science 323, 638–641 (2009). Reprinted with permission from AAAS. Image of submicrometre pillar array courtesy of Nicolas Biais and Luis Santos, Columbia University, New York, USA.

Figure 3 ∣. Experimental tools in mechanobiology.

Pillar arrays can be made to varying dimensions, thereby allowing the determination of substrate rigidity and force resolution. Pillar displacement is measured in live cells and is used to determine cellular forces that are applied to the substrate. Traction force microscopy uses embedded fluorescent beads (often of two colours) and finite element analysis to measure substrate deformations by the cell. Magnetic tweezers create magnetic fields that cause magnetic beads to apply forces to molecules in vitro or in vivo (for example, to integrins with fibronectin-coated beads). Optical traps use a focused laser beam to provide lateral or axial forces onto micrometre-diameter beads and thus apply forces to molecules; dielectric objects such as beads are attracted to the centre of the beam. If the bead is shifted laterally or axially out of the trap centre, the diffraction of the beam results in a restoration force on the bead, pulling it back into the centre. Each tool has advantages in terms of spatial resolution and maximum force that can be applied or experimental data analysis, and thus they are each suitable for specific applications. ∇B, magnetic field gradient; d, distance; F, force; k, spring constant; μ, magnetic moment.