Simulations of neutrophil rolling dynamics and the transition to firm adhesion

Cell adhesion under flow occurs throughout the body in processes such as inflammation, lymphocyte homing, and cancer metastasis. Understanding this process is critical to developing better therapies that exploit the body's natural function or inhibit it when it is detrimental. This thesis focuses on neutrophil adhesion during inflammation, which progresses from capture from the bloodstream and rolling via selectin bonds, to firm adhesion mediated by activated integrins, and finally transmigration through the endothelium to the injured tissue. Towards this goal of better understanding the details of cell adhesion, we have enhanced the Adhesive Dynamics model previously developed in the lab to allow for a more realistic simulation of the process. The basic model consists of a hard sphere in shear flow with elastic adhesion molecules on the tips of microvilli. Bonds form and break between the cell and adhesive surface according to reaction probability sampling, and the net force determines the motion of the cell. Neutrophil morphology was addressed by incorporating the measured rheology of microvillus deformation into a model of rolling. As expected, cells with deformable microvilli rolled more slowly than cells with stiff microvilli and accurately recreated the rolling trajectories observed for real cells opposed to fixed cells. We also updated the models for selectin bond kinetics to an experimentally-motivated catch-slip dissociation rate and an association rate that increases with shear rate. Simulations suggested that the catch-slip dissociation rate is the main source of the shear threshold effect for rolling, which could prevent undesired cell accumulation. As a final step in recreating cell adhesion, we incorporated a G-protein signaling mechanism inside the cell that transforms extracellular chemokine binding to integrin activation through diffusion and reaction of intracellular signaling elements. As integrins became active, cells briefly paused before stopping in a time that correlated with the time scale for integrin activation. By including novel neutrophil features in the Adhesive Dynamics model, simulations revealed otherwise unseen characteristics of adhesion and were used to explore the effects of model parameters on the observed behavior. The insights gained can steer experiments aimed at better understanding the details of cell adhesion.