Cell-Cell Adhesion Mechanics and Mechanotransduction at the Single Cell Level

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For cells to remain attached to their neighbors, there are cell-cell 'adhesion complexes.' These complexes are parts of the cell surface made up of very large adhesive molecules that transfer forces between the cells and hold them together. Mechanical coupling at adhesion complexes is necessary for many of the healthy behaviors of cells. Changes in the structure of the adhesion complex or of how the molecules change shape during stretching can cause diseases of the heart, joints (arthritis), and is part of the cellular story in cancer. The cell-cell junctions also are part of the cell's ability to detect how large the forces are on the tissue (mechanotransduction). One type of these junctions between cells, the 'desmosome', connects to the fiber network inside the cell to transmit forces and is not understood very well since most previous adhesion complex research has been done on the 'adherens' junction, which has different molecules and is associated with different diseases. This research project will reduce the huge knowledge gap about desmosomes with respect to their potential roles in mechanotransduction and disease control. The research will further the goals of the United States in developing the basic knowledge needed to understand and eventually treat medical conditions that are caused by failure of the desmosome to properly function. The research study will be integrated with existing University of Nebraska educational programs to offer undergraduate students experiences in mechanics, robotics, and cell biology. The PIs will also translate the research methodologies into a new course, "Cell Mechanics", in order to bring bioengineering-intensive knowledge into the current curriculum.Data from the PI's group have demonstrated the role of the desmosome-intermediate filament linkage in regulating cell mechanics, a role that has long been regarded to belong solely to the adherens junction. The research will determine the role that desmosomes play in cell-cell adhesion mechanics and in mechanotransduction. To achieve this goal, a novel device will be developed to provide in situ stimulation and interrogation of cell-cell junctions through defined mechanical tension. The platform will be able to stretch the mutual junction of a single pair of cells and simultaneously perform mechanical measurement, which will address the current challenge in interrogating cell-cell adhesion (i.e., difficulties in applying defined mechanical stimuli and conducting mechanical measurements at the same time). More importantly, integrated within an imaging system, the effect of mechanical stimuli on mechanotransduction pathways at the cell-cell junction can be monitored in real-time under applied load. With the platform, two fundamental scientific questions will be answered: (1) what is the contribution of desmosome and its link to intermediate filaments in maintaining cell-cell adhesion strength and (2) does the desmosome junction include mechanosensors that convert applied mechanical cues into biochemical signals to regulate cell behavior?This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.