Mechanosensing at cell-cell and cell-matrix adhesions

Understanding how hundreds to millions of cells work together to form or repair tissues and organs represents a central challenge in cell and developmental biology. Recent studies demonstrate that tissue growth and patterning are inherently physical processes, and that individual cells are exquisitely sensitive to stretch, fluid flow, and extracellular matrix (ECM) stiffness. However, the molecular mechanisms by which living cells sense mechanical stimuli remain poorly understood. In this talk I describe our work to understand the protein-based molecular machines that cells use to sense and transduce mechanical force at cell-cell and cellmatrix adhesions. We used a single-molecule optical trap assay to determine a probable mechanism by which cells sense mechanical stretch at cell-cell contacts, a physical cue that is thought to be central in controlling growth and patterning in living tissues (Buckley et al., Science, 2014). In related work, we developed fluorescent molecular tension sensors to visualize the nanometer-scale structures that link cells to the extracellular matrix (Morimatsu et al., Nano Lett. 2015). We find that individual integrins exert relatively modest forces, consistent with a collective model for cellular force generation and force sensing. These observations, together with those from projects investigating the biophysical basis for the sense of touch (Krieg et al., Nat. Cell Biol., 2014) and cell motility in three-dimensional matrices, suggest deep underlying commonalities in how cells may detect and respond to mechanical force in a wide variety of physiological circumstances.