Adhesive Dynamics Simulations of Sialyl-Lewisx/E-selectin-Mediated Rolling in a Cell-Free System

Abstract

Selectin-mediated leukocyte rolling is crucial for the proper function of the immune response. Recently, selectin-mediated rolling was recreated in a cell-free system (Biophysical Journal 71:2902-2907 (1996)); it was shown that sialyl Lewis(x) (sLe(x))-coated microspheres roll over E-selectin-coated surfaces under hydrodynamic flow. The cell-free system removes many confounding cellular features, such as cell deformability and signaling, allowing us to focus on the role of carbohydrate/selectin physical chemistry in mediating rolling. In this paper, we use adhesive dynamics, a computational method that allows us to simulate adhesion, to analyze the experimental data produced in the cell-free system. We simulate the effects of shear rate, ligand density, and number of receptors per particle on rolling velocity and compare them with experimental results obtained with the cell-free system. If we assume the population of particles is homogeneous in receptor density, we predict that particle rolling velocity calculated in simulations is more sensitive to shear rate than found in experiments. Also, the calculated rolling velocity is more sensitive to the number of receptors on the microspheres than to the ligand density on the surface, again in contrast to experiment. We argue that heterogeneity in the distribution of receptors throughout the particle population causes these discrepancies. We improve the agreement between experiment and simulation by calculating the average rolling velocity of a population whose receptors follow a normal distribution, suggesting heterogeneity among particles significantly affects the experimental results. Further comparison between theory and experiment yields an estimate of the reactive compliance of sLe(x)/E-selectin interactions of 0.25 A, close to that reported in the literature for E-selectin and its natural ligand (0.3 A). We also provide an estimate of the value of the intrinsic association rate (between 10(4) and 10(5) s(-1)) for the formation of sLe(x)/E-selectin bonds.

Mechanical properties of hepatocellular carcinoma cells

“…For HCC cells, the viscoelasticity has probably significant bearing on tumor cell invasion and metastasis, in which it determines the flowing behavior of tumor cells in the circulation and whether such cells can be arrested to form metastasis. In addition, mechanical stiffness is closely related to cell adhesion behavior [26,27] , which is the first step in tumor cell invasion. With the three-element standard linear solid viscoelastic model, we clearly showed that HCC cells have higher values for the elastic coefficients but not the viscous coefficient than hepatocytes.…”

L-selectin Dimerization Enhances Tether Formation to Properly Spaced Ligand

“…The biophysical basis for the exceptional ability of selectins to mediate cell capture (tethering) and rolling adhesions under highly disruptive forces is still obscure (3)(4)(5)(6). This ability has been primarily attributed to fast formation rates of selectin bonds and to the ability of selectin tethers to tolerate rupture by elevated shear forces (7)(8)(9)(10).…”

Adhesive Dynamics

“…This calculation was done for a hard sphere rolling over a ligand-coated substrate in Couette flow. The approximation of a hard sphere was appropriate because we had developed "cell-free" rolling in which the dynamics of rolling was recreated by decorating hard spheres with a selectin ligand, such as the tetra-saccharide sialyl-Lewis x [17]; we have made rigorous comparisons between the dynamics of bead rolling and the results of simulations [18] to verify that the model was correct. The left panel shows a spatio-temporal map of bonds in the contact zone between a bead and surface, in the reference frame of the bead, with each line segment indicating a bond, and red bonds under strain.…”