Nano-to-Micro Scale Dynamics of P-selectin Detachment from Leukocyte Interfaces: III. Numerical Simulation of Tethering Under Flow

¹ University of Rochester
² Boston University
³ University of Pennsylvania

^* To whom correspondence should be addressed. E-mail: mike_king{at}urmc.rochester.edu.

Submitted on August 23, 2004
Revised on October 4, 2004
Accepted on 19 November 2004

	Abstract

Transient capture of cells or model microspheres from flow over substrates sparsely coated with adhesive ligands has provided significant insight into the unbinding kinetics of leukocyte:endothelium adhesion complexes under external force. Whenever a cell is stopped by a point attachment, the full hydrodynamic load is applied to the adhesion site within an exceptionally short time-less than the reciprocal of the hydrodynamic shear rate (e.g. typically < 0.01 sec). The decay in numbers of cells or beads that remain attached to a surface has been used as a measure of the kinetics of molecular bond dissociation under constant force, revealing a modest increase in detachment rate at growing applied shear stresses. On the other hand, when detached under steady ramps of force with mechanical probes (e.g. the atomic force microscope AFM and biomembrane force probe BFP), P-selectin:PSGL-1 adhesion bonds break at rates that increase enormously under rising force, yielding hundred fold faster off rates at force levels comparable to high shear. The comparatively weak effect of force on tether survival in flow chamber experiments could be explained by a possible partition of the load amongst several bonds. However, a comprehensive understanding of the difference in kinetic behavior requires us to also inspect other factors affecting the dynamics of attachment-force buildup, such as the interfacial compliance of all linkages supporting the adhesion complex. Here, combining the mechanical properties of the leukocyte interface measured in probe tests with single-bond kinetics and the kinetics of cytoskeletal dissociation, we show that for the leukocyte adhesion complex P-selectin:PSGL-1, a detailed adhesive dynamics simulation accurately reproduces the tethering behavior of cells observed in flow chambers [Park et al., Biophys. J. 82:1835 (2002)]. Surprisingly, a mixture of 10% single bonds and 90% dimeric bonds is sufficient to fully match the data of the P-selectin:PSGL-1 experiments, with the calculated decay in fraction of attached cells still appearing exponential.

Key Words: P-selectin, PSGL-1, adhesive dynamics, cell tethering, leukocyte

This article has been cited by other articles:

				J. Schmitz, M. Benoit, and K.-E. Gottschalk The Viscoelasticity of Membrane Tethers and Its Importance for Cell Adhesion Biophys. J., August 1, 2008; 95(3): 1448 - 1459. [Abstract] [Full Text] [PDF]

				G. Girdhar and J.-Y. Shao Simultaneous Tether Extraction from Endothelial Cells and Leukocytes: Observation, Mechanics, and Significance Biophys. J., December 1, 2007; 93(11): 4041 - 4052. [Abstract] [Full Text] [PDF]

				V. Heinrich and C. Ounkomol Force versus Axial Deflection of Pipette-Aspirated Closed Membranes Biophys. J., July 15, 2007; 93(2): 363 - 372. [Abstract] [Full Text] [PDF]

				Y. Yu and J.-Y. Shao Simultaneous Tether Extraction Contributes to Neutrophil Rolling Stabilization: A Model Study Biophys. J., January 15, 2007; 92(2): 418 - 429. [Abstract] [Full Text] [PDF]

				K. E. Edmondson, W. S. Denney, and S. L. Diamond Neutrophil-Bead Collision Assay: Pharmacologically Induced Changes in Membrane Mechanics Regulate the PSGL-1/P-Selectin Adhesion Lifetime Biophys. J., November 1, 2005; 89(5): 3603 - 3614. [Abstract] [Full Text] [PDF]

				E. Evans, V. Heinrich, A. Leung, and K. Kinoshita Nano- to Microscale Dynamics of P-Selectin Detachment from Leukocyte Interfaces. I. Membrane Separation from the Cytoskeleton Biophys. J., March 1, 2005; 88(3): 2288 - 2298. [Abstract] [Full Text] [PDF]

				V. Heinrich, A. Leung, and E. Evans Nano- to Microscale Dynamics of P-Selectin Detachment from Leukocyte Interfaces. II. Tether Flow Terminated by P-Selectin Dissociation from PSGL-1 Biophys. J., March 1, 2005; 88(3): 2299 - 2308. [Abstract] [Full Text] [PDF]