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Integrin-based force transduction at the molecular and cellular scales Dunn, Alex


In this talk I describe our work to understand how cells sense and exert mechanical force across multiple length and time scales. Current models for cellular mechanics and cell motility have been derived largely from observations of cells adhering to hard, flat surfaces. In contrast, relatively little is known about how cells adhere to, deform, and migrate through soft, three-dimensional (3D) environments such as are commonly found in vivo. We used multicolor, time-lapse confocal imaging to quantify cytoskeletal motion and cell-generated matrix deformations for human fibroblasts embedded in soft, porous fibrin matrices, an environment that cells encounter during wound healing. Quantitative analysis of cytoskeletal and cell adhesion dynamics suggests that a modified version of the molecular clutch model of cytoskeletal force transduction, which was originally developed to describe cell migration on hard, flat surfaces, can be extended to understand cell migration in some 3D contexts. In a complementary project, we sought to understand how cells regulate force transmission at the level of single integrins, heterodimeric, transmembrane proteins that mediate cell attachment to the extracellular matrix (ECM). To do so, we developed fluorescent molecular tension sensors to visualize and measure the forces exerted by single integrins in living cells. We found that a large fraction of integrins transmitted modest loads of less than 3 pN, while subpopulations bearing higher loads were enriched within adhesions. Further, our data indicate that integrin engagement with the fibronectin synergy site, a secondary binding site for α5β1 integrin, increased cells’ resistance to physical detachment by externally applied loads, but did not alter cellular force output at either the whole-cell or single-integrin level. These and other observations suggest that a substantial population of integrins experiencing loads well below their peak capacities can provide cells and tissues with physical integrity in the presence of widely varying external loads. More broadly, observations from these two projects support a common understanding of the physical mechanisms by which cells adhere to and exert force on the ECM in a wide variety of contexts.

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