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Simultaneous Tether Extraction from Endothelial Cells and Leukocytes: Observation, Mechanics, and Significance

Department of Biomedical Engineering, Washington University, Saint Louis, Missouri

Correspondence: Address reprint requests to Jin-Yu Shao, PhD, Dept. of Biomedical Engineering, Washington University in St. Louis, Campus Box 1097, Rm. 290E, Whitaker Hall, One Brookings Dr., St. Louis, MO 63130-4899. Tel.: 314-935-7467; Fax: 314-935-7448; E-mail: shao{at}biomed.wustl.edu.

It has been hypothesized, from earlier studies on single-tether extraction from individual leukocytes and human umbilical vein endothelial cells, that during rolling of leukocytes on the endothelium, simultaneous extraction of membrane nanotubes (tethers) occurs, resulting in enhancement of the force decrease on the adhesive bond. In this study, using the micropipette aspiration technique and fluorescence microscopy, we show that tethers are indeed extracted simultaneously when an endothelial cell and a leukocyte are separated after brief contact and adhesion, and the endothelial cell contributes much more to the composite tether length. In addition, the constitutive relationship for simultaneous tether extraction is determined with neutrophils and T-lymphocytes as force transducers, and cytokine-stimulated human umbilical vein and dermal microvascular endothelial cells as substrates, respectively. This relationship is consistent with that derived theoretically from the constitutive equations for single-tether extraction from either cell alone. Moreover, we show that simultaneous tether extraction was likely terminated by receptor-ligand bond dissociation. With a biomechanical model of leukocyte rolling, we predict the force history of the adhesive receptor-ligand bond and show that it is remarkably similar for different leukocyte-endothelial cell pairs. Simultaneous tether extraction therefore represents a generic mechanism for stabilizing leukocyte rolling on the endothelium.