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Living cells are out of equilibrium active materials. Cell-generated forces are transmitted across the cytoskeleton network and to the extracellular environment. These active force interactions shape cellular mechanical behavior, trigger mechano-sensing, regulate cell adaptation to the microenvironment and can affect disease outcomes. In recent years, the mechanobiology community has witnessed the emergence of many experimental and theoretical approaches to study cells as mechanically active materials. In this review, we highlight recent advancements in incorporating active characteristics of cellular behavior at different length scales into classic viscoelastic models by either adding an active tension-generating element or by adjusting the resting length of an elastic element in the model. Summarizing the two groups of approaches, we will review the formulation, and application of these models to understand cellular adaptation mechanisms in response to various types of mechanical stimuli, such as the effect of extracellular matrix properties and external loadings or deformations. 

Epithelial cells experience long lasting loads of different magnitudes and rates. How they adapt to these loads strongly impacts tissue health. Yet, much remains unknown about their stress evolution under sustained strain. Here, by subjecting cell pairs to sustained strain, we report a bimodal stress response, where in addition to the typically observed stress relaxation, a subset of cells exhibits a dynamic tensioning process with significant elevation in stress within 100s, resembling active pulling-back in muscle fibers. Strikingly, the fraction of cells exhibiting tensioning increases with increasing strain rate. The tensioning response is accompanied by actin remodeling, and perturbation to actin abrogates it, supporting cell contractility’s role in the response. Collectively, our data show that epithelial cells adjust their tensional states over short timescales in a strain-rate dependent manner to adapt to sustained strains, demonstrating that the active pulling-back behavior could be a common protective mechanism against environmental stress. 

Binding of autoantibodies to keratinocyte surface antigens, primarily desmoglein 3 (Dsg3) of the desmosomal complex, leads to the dissociation of cell-cell adhesion in the blistering disorder pemphigus vulgaris (PV). After the initial disassembly of desmosomes, cell-cell adhesions actively remodel in association with the cytoskeleton and focal adhesions. Growing evidence highlights the role of adhesion mechanics and mechanotransduction at cell-cell adhesions in this remodeling process, as their active participation may direct autoimmune pathogenicity. However, a large part of the biophysical transformations after antibody binding remains underexplored. Specifically, it is unclear how tension in desmosomes and cell-cell adhesions changes in response to antibodies, and how the altered tensional states translate to cellular responses. Here, we showed a tension loss at Dsg3 using fluorescence resonance energy transfer (FRET)-based tension sensors, a tension loss at the entire cell-cell adhesion, and a potentially compensatory increase in junctional traction force at cell-extracellular matrix adhesions after PV antibody binding. Further, our data indicate that this tension loss is mediated by the inhibition of RhoA at cell-cell contacts, and the extent of RhoA inhibition may be crucial in determining the severity of pathogenicity among different PV antibodies. More importantly, this tension loss can be partially restored by altering actomyosin based cell contractility. Collectively, these findings provide previously unattainable details in our understanding of the mechanisms that govern cell-cell interactions under physiological and autoimmune conditions, which may open the window to entirely new therapeutics aimed at restoring physiological balance to tension dynamics that regulates the maintenance of cell-cell adhesion. 

Significance Cell–cell junctions are essential components in multicellular structures and often experience strains of different magnitudes and rates. However, their mechanical behavior is currently underexplored due to the lack of techniques to quantitatively characterize junctional stress–strain relationships. We developed a polymeric microstructure to strain the mutual junction of a single cell pair while simultaneously recording the junction stress and observed previously unseen strain-rate–dependent junction responses. We showed that cytoskeleton growth could relax the stress buildup and prevent junction failure at low strain rates, while high strain rates led to synchronized junction failures at remarkably large strains (over 200%). We expect this platform and our biophysical understanding to form the foundation for the rate-dependent mechanics of cell–cell junctions.