Deborah Leckband Research
Bioengineering and Biophysics
In the BioInterfaces and Cellular Mechanics Laboratory, broad goals of our research are to establish physical mechanisms of biological adhesion and mechanotransduction and their implications for human health and tissue development. Intercellular adhesion is essential for the organization and function of all multicellular organisms, and regulates biological processes from tissue generation to tumor metastasis.
How cells sense and interpret mechanical information through adhesion receptors is postulated to be as important for guiding tissue formation and function as soluble signals such as growth factors. Our objectives are to identify the basic mechanisms of mechanotransduction and their role in tissue engineering and human pathology. We are also exploiting this new knowledge to understand and treat disease, engineer tissues, and improve human health.
The Mechano-Biology group investigates how cells transduce mechanical signals across membranes to regulate tissue functions. For example, we are determining how arterial stiffness contributes to increased vascular leakage, which is a key marker of cardiovascular disease. Related studies are exploring how mechanical ventilation may alter pulmonary endothelial barrier permeability, in acute lung injury. We are also investigating how mechanical forces alter gene expression and differentiation, both in tissue engineering and in embryonic development.
Using mechanical probes and dynamic imaging, we visualize mechanotransduction in live cells in real time, and are identifying immediate molecular events in force transduction. We are developing and using protein biosensors to directly image force actuated, spatiotemporal changes in cells in real time. We also visualize coupled reactions in cells as well as integrated signaling through tissue. This systems level approach reveals how coupled, mechanically sensitive signaling networks coordinately regulate tissue functions such as vascular leakiness or the barrier integrity of kidney epithelium.
Our research identified mechanotransduction events in pulmonary endothelial cells that trigger the local reinforcement of cell-cell adhesive contacts, and activate signals that propagate through the cell. We demonstrated that these global signals are even transmitted across cell-cell boundaries to affect distant cells in the endothelium. These very exciting results demonstrate that tissues are mechanically integrated systems where force regulates biochemistry and biochemistry reciprocally regulates tissue mechanics.
The Cell and Molecular Biophysics group investigates the biophysical mechanisms of protein recognition, adhesion, and the mechanochemical force transduction across cell membranes. We use atomistic simulations, single molecule measurements, fluorescent protein sensors, and protein engineering.
A current focus is on the protein alpha catenin, which is a postulated molecular strain gauge at cell-cell adhesive junctions. Our atomistic simulations with Emad Tajkhorshid (Biochemistry) identified key structural features that may determine the force sensitivity of this protein, as well as a family of related molecules. Single protein mechanics measurements are testing these predictions and determining how mutations associated with developmental disorders and cancer affect the mechanical properties and force sensitive interactions of alpha catenin with other proteins in the cell.
We study the biophysical properties of adhesion receptors. With cadherin as a model adhesion receptor, atomistic simulations and single bond rupture measurements (atomic force microscopy) established structural determinants of adhesion strength, binding kinetics, and adhesion mechanisms. We identified different cadherin adhesive bonds with different mechanical and kinetic properties, and demonstrated how these different interactions contribute to the assembly and mechanics of intercellular junctions.
Using micropipettes to manipulate adhesion between cell pairs, we quantify the kinetics and affinities of adhesion receptors at the cell surface. Our research established how single protein properties control cell adhesion, and conversely, how intracellular signals can switch off cell adhesion. We demonstrated quantitatively that intracellular signals allosterically regulate cadherin affinity, and identified a physical mechanism contributing to metastasis in colorectal cancer. Our work also revealed how glycosylation regulates intercellular adhesion. We are currently collaborating with a theory group (Yinghao Wu, Einstein) to model the binding kinetics of confined receptors in intercellular gaps.
The Biointerfaces Group develops microfabrication to manipulate cell behavior and to study mechanotransduction and adhesion. Microfabrication offers a range of tools to generate mechanical and chemical gradients as well as modulate the mechanical properties of cell substrates. We use different microfabricated platforms to investigate the effect of disease-linked mutations on adhesion and wound healing.
Using a microfabricated stencil to generate defects in cell monolayers, we established how genetic variations affect endothelial wound healing in cardiovascular disease. We also use micropillar arrays and hydrogels with tunable stiffness to investigate the impact of intercellular tension on signaling and intercellular barrier regulation. In collaboration with Joon Kong, we are investigating how biomaterial mechanics and composition influence intercellular interactions, gene expression, and differentiation in 2D and in 3D environments.
Finally, we use microfabrication and surface chemistry to establish design principles for tuning cell interactions with biomaterials. Recent studies established a physical chemical mechanism controlling thermally switchable cell attachment and release from temperature responsive polymer coatings. Our results differ from a commonly held view, but our results generated new design criteria that achieve more efficient, thermally controlled cell harvesting from polymer coated substrates.