Tal Sneh is an undergraduate researcher working in the Shenoy lab this summer. He is researching computational models of cell-cell junctions. After graduation from Arizona State University, Tal plans to pursue graduate school in materials science engineering.
Recruitment of the Arp2/3 Complex Reverses Cadherin-driven Contractile Cytoskeletal Reorganization and Contributes to the Closing of Endothelial Gaps
Endothelial junction gaps are involved in a range of processes, from angiogenesis to cancer cell extravasation, and have garnered interest as a potential target for the prevention of tumor metastases. It has been experimentally realized that chemo-mechanical positive feedback signaling regulates cell contractility and junction behavior, with high contractility facilitating the opening of regular gaps bordered by regions of highly aligned actin stress fibers. However, it remains unclear what produces cytoskeletal re-organization into stress fibers or by what mechanism these fibers start to reduce in contractility, eventually disassemble, and close endothelial gaps. The Arp2/3 complex has been observed to act as a nucleation site for actin polymerization near the cell boundary, with such polymerization producing forces that may act counter to stress fiber contractility. In this study, we develop a continuum model of a symmetric two-cell junction to investigate Arp2/3-induced polymerization as a candidate mechanism for countering the positive cell contractility feedback loop, leading to the closing of endothelial gaps. The model is solved using COMSOL finite element analysis software. We demonstrate that increased polymerization at the junction can disassemble stress fibers and allow endothelial gaps to close. We further show that junction stability requires a specific balance of contractility and Arp2/3 recruitment. This work provides an important mechanistic understanding of mechanical signaling and cytoskeletal endothelial restructuring, demonstrating the key role of cadherin-complex strain-stiffening behavior in determining cell behavior and explaining that of Arp2/3 in recovering paracellular junction gaps to maintain endothelial integrity.