Animal cells use an unknown mechanism to control their growth and physical size. Here, using the fluorescence exclusion method, we measure cell volume for adherent cells on substrates of varying stiffness. We discover that the cell volume has a complex dependence on substrate stiffness and is positively correlated with the size of the cell adhesion to the substrate. From a mechanical force-balance condition that determines the geometry of the cell surface, we find that the observed cell volume variation can be predicted quantitatively from the distribution of active myosin through the cell cortex. To connect cell mechanical tension with cell size homeostasis, we quantified the nuclear localization of YAP/TAZ, a transcription factor involved in cell growth and proliferation. We find that the level of nuclear YAP/TAZ is positively correlated with the average cell volume. Moreover, the level of nuclear YAP/TAZ is also connected to cell tension, as measured by the amount of phosphorylated myosin. Cells with greater apical tension tend to have higher levels of nuclear YAP/TAZ and a larger cell volume. These results point to a size-sensing mechanism based on mechanical tension: the cell tension increases as the cell grows, and increasing tension feeds back biochemically to growth and proliferation control.

The application of flow visualization in biological systems is becoming increasingly common in studies ranging from intracellular transport to the movements of whole organisms. In cell biology, the standard method for measuring cell-scale flows and/or displacements has been particle image velocimetry (PIV); however, alternative methods exist, such as optical flow constraint. Here we review PIV and optical flow, focusing on the accuracy and efficiency of these methods in the context of cellular biophysics. Although optical flow is not as common, a relatively simple implementation of this method can outperform PIV and is easily augmented to extract additional biophysical/chemical information such as local vorticity or net polymerization rates from speckle microscopy.

Under the microscope, eukaryotic animal cells can adopt a variety of different shapes and sizes. These cells also move and deform, and the physical mechanisms driving these movements and shape changes are important in fundamental cell biology, tissue mechanics, as well as disease biology. This article reviews some of the basic mechanical concepts in cells, emphasizing continuum mechanics description of cytoskeletal networks and hydrodynamic flows across the cell membrane. We discuss how cells can generate movement and shape changes by controlling mass fluxes at the cell boundary. These mass fluxes can come from polymerization/depolymerization of actin cytoskeleton, as well as osmotic and hydraulic pressure-driven flow of water across the cell membrane. By combining hydraulic pressure control with force balance conditions at the cell surface, we discuss a quantitative mechanism of cell shape and volume control. The broad consequences of this model on cell mechanosensation and tissue mechanics are outlined.

The spirochetes that cause Lyme disease (Borrelia burgdorferi) and syphilis (Treponema pallidum) swim through viscous fluids, such as blood and interstitial fluid, by undulating their bodies as traveling, planar waves. These undulations are driven by rotation of the flagella within the periplasmic space, the narrow (∼20-40 nm in width) compartment between the inner and outer membranes. We show here that the swimming speeds of B. burgdorferi and T. pallidum decrease with increases in viscosity of the external aqueous milieu, even though the flagella are entirely intracellular. We then use mathematical modeling to show that the measured changes in speed are consistent with the exertion of constant torque by the spirochetal flagellar motors. Comparison of simulations, experiments, and a simple model for power dissipation allows us to estimate the torque and resistive drag that act on the flagella of these major spirochetal pathogens.

Morphogenesis during human development relies on the interplay between physiochemical cues that are mediated in part by cellular density and cytoskeletal tension. Here, we interrogated these factors on vascular lineage specification during human-induced pluripotent stem-cell (hiPSC) fate decision. We found that independent of chemical cues, spatially presented physical cues induce the self-organization of Brachyury-positive mesodermal cells, in a RhoA/Rho-associated kinase (ROCK)-dependent manner. Using unbiased support vector machine (SVM) learning, we found that density alone is sufficient to predict mesodermal fate. Furthermore, the long-withstanding presentation of spatial confinement during hiPSC differentiation led to an organized vascular tissue, reminiscent of native blood vessels, a process dependent on cell density as found by SVM analysis. Collectively, these results show how tension and density relate to vascular identity mirroring early morphogenesis. We propose that such a system can be applied to study other aspects of the stem-cell niche and its role in embryonic patterning.

The Lyme disease spirochete, Borrelia burgdorferi, swims by undulating its cell body in the form of a traveling flat-wave, a process driven by rotating internal flagella. We study B. burgdorferi ’s swimming by treating the cell body and flagella as linearly elastic filaments. The dynamics of the cell are then determined from the balance between elastic and resistive forces and moments. We find that planar, traveling waves only exist when the flagella are effectively anchored at both ends of the bacterium and that these traveling flat-waves rotate as they undulate. The model predicts how the undulation frequency is related to the torque from the flagellar motors and how the stiffness of the cell body and flagella affect the undulations and morphology.

Physics reveals how swimming bacteria can mimic washing machine spin cycles.

To elucidate pathogen-host interactions during early Lyme disease, we developed a mathematical model that explains the spatiotemporal dynamics of the characteristic first sign of the disease, a large (≥5-cm diameter) rash, known as an erythema migrans. The model predicts that the bacterial replication and dissemination rates are the primary factors controlling the speed that the rash spreads, whereas the rate that active macrophages are cleared from the dermis is the principle determinant of rash morphology. In addition, the model supports the clinical observations that antibiotic treatment quickly clears spirochetes from the dermis and that the rash appearance is not indicative of the efficacy of the treatment. The quantitative agreement between our results and clinical data suggest that this model could be used to develop more efficient drug treatments and may form a basis for modeling pathogen-host interactions in other emerging infectious diseases.