Not just a number: What cells feel depends on how they grab it

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Cell adhesion is fundamental for multicellular life. Many physiological processes, including organism development, wound healing, and the immune response, depend on the cells’ ability to form delicate, adaptive attachment sites connecting them mechanically to their environment. Over the past decades, we have learned that cells are, in situ, highly sensitive to geometrical constraints (1,2,3) and the mechanical rigidity of their microenvironment (4,5,6). For example, in vitro experiments, during which cells are placed on micropatterned substrates, revealed that edges and corners in the patterns promote formation of contractile cytoskeletal structures (3). Complementary to this finding is the well-established fact that cells upregulate their contractility and the size of the adhesive structures on substrates with increasing rigidity (4,5).

How do cells sense the rigidity of their microenvironment? In general, our understanding of cellular mechanotransduction is dominated by a molecular view. Mechanosensitive molecules at the cell membrane, including stretch-activated ion channels, G protein-coupled receptors, integrins, and cytoskeletal proteins such as talin cooperate to transduce the mechanical signal into a chemical response. Despite these sensory inputs being highly localized, they are globally coupled via the cytoskeleton and the membrane. Therefore, one may argue that a systemic view of mechanosensing, integrating geometry and micromechanics on various scales, is appropriate. However, the notion that a cell's perception of the mechanical properties of its environment depends per se on how it attached to the environment is clearly understudied, at least from the theoretical point of view.

In this issue of Biophysical Journal, Solowiej-Wedderburn and Dunlop provide compelling theoretical evidence of the central role of micro-adhesion geometry in the cell’s ability to sense the rigidity of a planar substrate (7). The employed framework is an idealized continuum model wherein the cell is treated as a thin, elastic layer coupled to a surface. Cellular contraction is modeled by an isotropic, homogeneous active stress, a description that is formally equivalent to continuum models of thermoelasticity. The model has been shown previously to be able to predict cell-substrate traction at the edge of cellular monolayers (8,9). In agreement with experimental observations, cells modeled in this way spread more on stiff substrates with cell-substrate traction localized in regions with high curvature at the boundary of the cell (10,11).

Solowiej-Wedderburn and Dunlop show that the substrate rigidity cannot be considered a single, independent control parameter but, instead, the apparent substrate stiffness perceived by the cell is a function of the distribution of adhesion sites and the “real” stiffness. This leads to introduction of a new concept of “effective substrate stiffness.” Intriguingly, the model predicts that different stiffness environments can be made to feel similar for cells by altering adhesion geometry, a prediction that can be tested experimentally in future work.

A related question that can be studied uniquely with theoretical methods is whether the mechanics of cells obey certain optimization principles. In this regard, the recent work points to the possibility that the organization and size of cell adhesions minimizes the elastic energy stored in the system. Naturally, it will have to be seen whether nature’s varying designs for cell adhesion actually obey such mechanical optimization principles. The prospects remain exciting.

Editor: Alexander Fletcher