We are investigating how intercellular adhesion proteins sense and transmit mechanical signals between cells in tissues. Using precision force probes, we established that cadherin complexes, which are crucial cell-cell adhesion proteins are mechanosensors. We are investigating how force-induced conformational changes in proteins in this complex trigger molecular and signaling cascades that regulate cell functions in tissues and in engineered scaffolds. Using a systems level approach, we are also establishing how integrins and cadherins coordinate functions to regulate global cell properties and broader tissue mechanics.
Our approach combines nanomechanical measurements and live cell imaging to follow dynamic force-actuated changes in cells. We are collaborating with Cara Gottardi and with J. de Rooij to identify key cellular components required for mechanosensing. In addition, we use single molecular AFM studies and molecular dynamics simulations to determine how forces alter protein conformations in order to identify possible mechanisms of molecular force sensing.
Cell adhesion research focuses on molecular mechanisms of cell adhesion and on the impact of adhesion on critical cell functions such as migration and signaling. Our work spans length scales ranging from atomistic simulations to cell adhesion and migration in engineered environments. At the atomic level, steered molecular dynamics simulations identify structural features crucial to the mechanical functions of these proteins. Sensitive, molecular level force-measurement techniques experimentally test predictions of the simulations, and investigate relationships between the protein structures, their mechanisms and strengths of binding, and their response to mechanical force-at the single molecule level. Using single cell manipulation, we also determine quantitative relationships betwen the properties of single protein bonds and the dynamics and strength of adhesion between living cells.
Polarized cells on gradients.
To determine how adhesive cues control cell functions, we use microfabrication and surface chemistry to generate controlled, concentration fields of adhesive cues. A recent study assessed how these signals direct cell migration or alter such cell functions as differentiation or proliferation. With nanopatterned materials we ask whether cells sense nanoscale features as well as the spatial distribution of defined cues. How many molecules are required to trigger cell signaling? On what length scales do cells sense biochemical or mechanical differences?
Recent studies combine live cell imaging with surface patterning to visualize directly how specifically patterned biologically active molecules trigger real-time spatiotemporal changes in cells. This powerful combination of precision surface engineering with state of the art imaging will identify crucial biological design rules that define how cells read their environment to instruct cell behavior.