Dynamic cross-links tune the solid-fluid behavior of living cells.

To keep the mechanical integrity of an organism it seems obvious that cells, as the building blocks, must be solid. Although it is clear that switching to a fluid would be catastrophic for organization of the body, it turns out that living cells do change their mechanical properties to a more fluid-like behavior when it comes to migration and force generation. Being fluid-like allows cells to adapt to any arbitrary shape posed by the environment, which is crucial for movement through complex tissue. The mechanical integrity of healthy cells is therefore closely regulated to ensure that cells are solid enough to maintain tissue shape while also being fluid enough to allow dynamic remodeling. Physics provides powerful tools in the framework of viscoelasticity to characterize this fundamental solid and fluid-like behavior (1), and it is evident that cells need to dynamically regulate their viscoelastic properties to support physiological pressures and forces generated during lung expansion, muscle contraction, blood filtration, etc., while still allowing growth, remodeling, and repair over the lifetime of the organism. However, when this precise mechanical regulation is disturbed, cells often transition to diseased states (2). In PNAS, Ehrlicher et al. (3) study a genetic defect in the actin crosslinker alpha-actinin 4 that is known to lead to the severe kidney disease focal segmental glomerulosclerosis. Their study shows that the mutation affects cell movement, force generation, and cytoplasmic mobility, thus providing a connection between physical properties at the molecular scale and human disease. Thanks to a number of fundamental physical studies in simplified in vitro model systems (4–7), the mechanical properties of actin networks have been well characterized, thus setting the stage to understand cellular viscoelasticity. Two important ingredients control the mechanical properties of actin networks in cells: cross-linkers and molecular motors (Fig. 1A). Permanent cross-linking of actin networks (via scruin) is known to cause a dominantly elastic behavior (4). In contrast, transient cross-linking (via heavy meromyosin) allowed stress relaxation in the network, hence resulting in a dominantly viscous behavior at long timescales (5). These previous studies hint that cross-link kinetics provides a mechanism to tune the viscoelastic properties of the actin network. Groundbreaking in vitro studies of myosin-II in actin networks further emphasized the importance of crosslinking dynamics (6, 7). At low cross-linking density, the activity of myosin-II motors allowed faster stress relaxation to occur transient crosslinks (control mechanical properties) myosin motors (internal force generators)