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Abstract It is becoming increasingly clear that mechanical stress in adhesive junctions plays a significant role in dictating the fate of cell–cell attachment under physiological conditions. Targeted disruption of cell–cell junctions leads to multiple pathological conditions, among them the life‐threatening autoimmune blistering disease pemphigus vulgaris (PV). The dissociation of cell–cell junctions by autoantibodies is the hallmark of PV, however, the detailed mechanisms that result in tissue destruction remain unclear. Thus far, research and therapy in PV have focused primarily on immune mechanisms upstream of autoantibody binding, while the biophysical aspects of the cell–cell dissociation process leading to acantholysis are less well studied. In work aimed at illuminating the cellular consequences of autoantibody attachment, it is reported that externally applied mechanical stress mitigates antibody‐induced monolayer fragmentation and inhibits p38 MAPK phosphorylation activated by anti‐Dsg3 antibody. Further, it is demonstrated that mechanical stress applied externally to cell monolayers enhances cell contractility via RhoA activation and promotes the strengthening of cortical actin, which ultimately mitigates antibody‐induced cell–cell dissociation. The study elevates understanding of the mechanism of acantholysis in PV and shifts the paradigm of PV disease development from a focus solely on immune pathways to highlight the key role of physical transformations at the target cell. 

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.