Biomechanics and Modeling in Mechanobiology

, Volume 9, Issue 5, pp 613–627 | Cite as

Multi-scale simulation of L-selectin–PSGL-1-dependent homotypic leukocyte binding and rupture

  • V. K. Gupta
  • Ihab A. Sraj
  • Konstantinos Konstantopoulos
  • Charles D. Eggleton
Original Paper


L-selectin–PSGL-1-mediated polymorphonuclear (PMN) leukocyte homotypic interactions potentiate the extent of PMN recruitment to endothelial sites of inflammation. Cell–cell adhesion is a complex phenomenon involving the interplay of bond kinetics and hydrodynamics. As a first step, a 3-D computational model based on the Immersed Boundary Method is developed to simulate adhesion-detachment of two PMN cells in quiescent conditions. Our simulations predict that the total number of bonds formed is dictated by the number of available receptors (PSGL-1) when ligands (L-selectin) are in excess, while the excess amount of ligands influences the rate of bond formation. Increasing equilibrium bond length results in a higher number of receptor–ligand bonds due to an increased intercellular contact area. On-rate constants determine the rate of bond formation, while off-rates control the average number of bonds by modulating bond lifetimes. Application of an external pulling force leads to time-dependent on- and off-rates and causes bond rupture. Moreover, the time required for bond rupture in response to an external force is inversely proportional to the applied load and decreases with increasing off-rate.


Cell adhesion Cell deformation Immersed boundary method Monte Carlo simulation Receptor–ligand bond kinetics 


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  1. Alon R, Hammer DA, Springer TA (1995) Lifetime of the P-selectin-carbohydrate bond and its response to tensile force in hydrodynamic flow. Nature 374: 539–542CrossRefGoogle Scholar
  2. Alon R, Fuhlbrigge RC, Finger ER, Springer TA (1996) Interactions through L-selectin between leukocytes and adherent leukocytes nucleate rolling adhesions on selectins and VCAM-1 in shear flow. J Cell Biol 135(3): 849–865CrossRefGoogle Scholar
  3. Bargatze RF, Kurk S, Butcher EC, Jutila MA (1994) Neutrophils roll on adherent netrophils bond to cytokine-induced endothelial cells via L-selectin on rolling cells. J Exp Med 180: 1785–1792CrossRefGoogle Scholar
  4. Bell GI (1978) Models for the specific adhesion of cells to cells. Science 200: 618–627CrossRefGoogle Scholar
  5. Bruehl RE, Springer TA, Bainton DF (1996) Quantification of L-selectin distribution on human leukocyte microvilli by immunogold labeling and electron microscopy. J Histochem Cytochem 44(8): 835–844Google Scholar
  6. Charrier JM, Shrivastava S, Wu R (1989) Free and constrained inflation of elastic membranes in relation to thermoforming non-axisymmetric problems. J Strain Anal 24(2): 55–74CrossRefGoogle Scholar
  7. Chen S, Springer TA (1999) An automatic braking system that stabilizes leukocyte rolling by an increase in selectin bond number with shear. J Cell Biol 144: 185–200CrossRefGoogle Scholar
  8. Chen W, Zarnitsyna VI, Sarangapani KK, Huang J, Zhu C (2008) Measuring receptor-ligand binding kinetics on cell surfaces: from adhesion frequency to thermal fluctuation methods. Cell Mol Bioeng 1(4): 276–288CrossRefGoogle Scholar
  9. Chesla SE, Selvaraj P, Zhu C (1998) Measuring two-dimensional receptor-ligand binding kinetics by micropipette. Biophys J 75: 1553–1572CrossRefGoogle Scholar
  10. Cozen-Roberts C, Lauffenburger DA, Quinn JA (1990) Receptor- mediated cell attachment and detachment kinetics. I. Probabilistic model and analysis. Biophys J 58: 841–856CrossRefGoogle Scholar
  11. Dembo M (1994) On peeling an adherent cell from a surface. In: vol 24 of series: Lectures on Mathematics in the Life Sciences, Some Mathematical Problems in Biology. American Mathematical Society, Providence, RI. pp 51–77Google Scholar
  12. Eggleton CD, Popel AS (1998) Large deformation of red blood cell ghosts in a simple shear flow. Phys Fluids 10: 1834–1845CrossRefGoogle Scholar
  13. Evans E, Ritchie K (1997) Dynamic strength of molecular adhesion bonds. Biophys J 72: 1541–1555CrossRefGoogle Scholar
  14. Evans EA, Leung A, Hammer D, Simon S (2001) Chemically distinct transition states govern rapid dissociation of single L-selectin bonds under force. Proc Natl Acad Sci 98(7): 3784–3789CrossRefGoogle Scholar
  15. Evans EA, Calderwood DA (2007) Forces and bond dynamics in cell adhesion. Science 316: 1148–1153CrossRefGoogle Scholar
  16. Fritz J, Katopodis AG, Kolbinger F, Anselmetti D (1998) Force- mediated kinetics of single P-selectin/ligand complexes observed by atomic force microscopy. Proc Natl Acad Sci 95: 12283–12288CrossRefGoogle Scholar
  17. Girdhar G, Shao J-Y (2007) Simultaneous tether extraction from endothelial cells and leukocytes: observation, mechanics, and significance. Biophys J 93: 4041–4052CrossRefGoogle Scholar
  18. Goldsmith HL, Quinn TA, Drury G, Spanos C, McIntosh FA, Simon SI (2001) Dynamics of neutrophil aggregation in Couette flow revealed by videomicroscopy: effect of shear rate on two-body collision efficiency and doublet lifetime. Biophys J 81: 2020– 2034CrossRefGoogle Scholar
  19. Guo S, Ray C, Kirkpatrick A, Lad N, Akhremitchev BB (2008) Effects of multiple-bond ruptures on kinetic parameters extracted from force spectroscopy measurements: revisiting biotin-streptavidin interactions. Biophys J 95: 3964–3976CrossRefGoogle Scholar
  20. Guo S, Lad N, Ray C, Akhremitchev BB (2009) Association kinetics from single molecule force spectroscopy measurements. Biophys J 96: 3412–3422CrossRefGoogle Scholar
  21. Hammer DA, Apte SM (1992) Simulation of cell rolling and adhesion on surfaces in shear flow: general results and analysis of selectin-mediated neutrophil adhesion. Biophys J 63: 35–57CrossRefGoogle Scholar
  22. Hinterdorfer P, Baumgartner W, Gruber HJ, Schilcher K, Schindler H (1996) Detection and localization of individual antibody-antigen recognition events by atomic force microscopy. PNAS 93: 3477–3481CrossRefGoogle Scholar
  23. Jadhav S, Eggleton CD, Konstantopoulos K (2005) A 3-D computational model predicts that cell deformation affects selectin-mediated leukocyte rolling. Biophy J 88: 96–104CrossRefGoogle Scholar
  24. Jadhav S, Chan KY, Eggleton CD, Konstantopoulos K (2007) Shear modulation of intercellular contact area between two deformable cells colliding under flow. J Biomech 40: 2891–2897CrossRefGoogle Scholar
  25. Kadash KE, Lawrence MB, Diamond SL (2004) Neutrophil string formation: hydrodynamic thresholding and cellular deformation during cell collisions. Biophys J 86: 4030–4039CrossRefGoogle Scholar
  26. Khismatullin DB, Truskey GA (2005) Three-dimensional numerical simulation of receptor-mediated leukocyte adhesion to surfaces: effects of cell deformability and viscoelasticity. Phys Fluids 17: 031505CrossRefGoogle Scholar
  27. Konstantopoulos K, Kukreti S, McIntire LV (1998) Biomechanics of cell interactions in shear fields. Adv Drug Deliv Rev 33: 141–164CrossRefGoogle Scholar
  28. Kuhner F, Costa LT, Bisch PM, Thalhammer S, Heckl WM, Gaub HE (2004) LexA-DNA bond strength by single molecule force spectroscopy. Biophys J 87: 2683–2690CrossRefGoogle Scholar
  29. Lasky LA (1992) Selectins: interpreters of cell-specific carbohydrate information during inflammation. Science 258: 964–969CrossRefGoogle Scholar
  30. Lawrence MB, Springer TA (1991) Leukocytes roll on a selectin at physiologic flow rates: distinction from the prerequisite for adhesion through integrins. Cell 65: 859–873CrossRefGoogle Scholar
  31. Marshall BT, Sarangapani KK, Wu J, Lawrence MB, McEver RP (2006) Measuring molecular elasticity by atomic force microscope cantilever fluctuations. Biophys J 90: 681–692CrossRefGoogle Scholar
  32. Merkel R, Nassoy P, Leung A, Ritchie K, Evans E (1999) Energy landscapes of receptor-ligand bonds explored with dynamic force spectroscopy. Nature 397: 50–53CrossRefGoogle Scholar
  33. Moore KL, Varki A, McEver RP (1991) GMP-140 binds to a glycoprotein receptor on human neutrophils: evidence for a lectin-like interaction. J Cell Biol 112: 491–499CrossRefGoogle Scholar
  34. Moore KL, Patel KD, Bruehl RE, Li F, Johnson DA, Lichenste HS, Cummings RD, Bainton DF, McEver RP (1995) P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin. J Cell Biol 128: 661–671CrossRefGoogle Scholar
  35. Mustard JF, Packham MA, Kinlough-Rathbone RL, Perry DW, Regoeczi E (1978) Fibrinogen and ADP-induced platelet aggregation. Blood 52: 453–466Google Scholar
  36. Neelamegham S, Taylor AD, Shankaran H, Smith CW, Simon SI (2000) Shear and time-dependent changes in Mac-1, LFA-1, and ICAM-3 binding regulate neutrophil homotypic adhesion. J Immunol 164: 3798–3805Google Scholar
  37. Nicolson GL (1988) Organ specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev 7: 143–188CrossRefGoogle Scholar
  38. Osborn L (1990) Leukocyte adhesion to endothelium in inflammation. Cell 62: 3–6CrossRefGoogle Scholar
  39. Paschall CD, Guilford WH, Lawrence MB (2008) Enhancement of L-selectin, but not P-selectin, bond formation frequency by convective flow. Biophys J 94: 1034–1045CrossRefGoogle Scholar
  40. Patel KD, Nollert MU, McEver RP (1995) P-selectin must extend a sufficient length from the plasma membrane to mediate rolling of neutrophils. J Cell Biol 131(6): 1893–1902CrossRefGoogle Scholar
  41. Pawar P, Jadhav S, Eggleton CD, Konstantopoulos K (2008) Roles of cell and microvillus deformation and receptor-ligand binding kinetics in cell rolling. Am J Physiol Heart Circ Physiol 295: H1439–H1450CrossRefGoogle Scholar
  42. Pereverzev YV, Prezhdo OV, Forero M, Sokurenko EV, Thomas WE (2005) The two-pathway model for the catch-slip transition in biological adhesion. Biophys J 89: 1446–1454CrossRefGoogle Scholar
  43. Peskin CS, McQueen DM (1989) A three dimensional computational method for blood flow in the heart. I. Immersed elastic fibers in a viscous incompressible fluid. J Comput Phys 81: 372CrossRefMathSciNetMATHGoogle Scholar
  44. Puri KD, Finger EB, Springer TA. (1997) The faster kinetics of L-selectin than of E-selectin and P-selectin rolling at comparable binding strength. J Immunol 158: 405–413Google Scholar
  45. Rinko LJ, Lawrence MB, Guilford WH (2004) The molecular mechanics pf P- and L-selectin lectin domains binding to PSGL-1. Biophys J 86: 544–554CrossRefGoogle Scholar
  46. Shao JY, Xu JB (2002) A modified micropipette aspiration technique and its application to tether formation from human neutrophils. J Biomech Eng-T ASME 124: 388–396CrossRefGoogle Scholar
  47. Shao JY, Ting-Beall HP, Hochmuth RM (1998) Static and dynamic lengths of neutrophil microvilli. Proc Natl Acad Sci USA 95: 6797–6802CrossRefGoogle Scholar
  48. Shrivastava S, Tang J (1993) Large deformation finite element analysis of non-linear viscoelastic membranes with reference to thermoforming. J Strain Anal 28(1): 31–51CrossRefGoogle Scholar
  49. Simon SI, Green CE (2005) Molecular mechanics and dynamics of leukocyte recruitment during inflammation. Annu Rev Biomed Eng 7: 151–185CrossRefGoogle Scholar
  50. Tandon P, Diamond SL (1998) Kinetics of β 2-integrin and L-selectin bonding during neutrophile aggregation in shear flow. Biophys J 75: 3163–3178CrossRefGoogle Scholar
  51. Taylor AD, Neelamegham S, Hellums JD, Smith CW, Simon SI (1996) Molecular dynamics of the transition from L-selectin to β 2-integrin dependent neutrophil adhesion under defined hydrodynamic shear. Biophys J 71: 3488–3500CrossRefGoogle Scholar
  52. Tolentino TP, Wu J, Zarnitsyna VI, Fang Y, Dustin ML, Zhu C (2008) Measuring diffusion and binding kinetics by contact area FRAP. Biophys J 95: 920–930CrossRefGoogle Scholar
  53. Williams PM (2003) Analytical descriptions of dynamic force spectroscopy: behaviour of multiple connections. Anal Chim Acta 479: 107–115CrossRefGoogle Scholar
  54. Yago T, Zarnitsyna VI, Klopocki AG, McEver RP, Zhu C (2007) Transport governs flow-enhanced cell tethering through L-selectin at threhold shear. Biophys J 92: 330–342CrossRefGoogle Scholar
  55. Zhang X, Bogorin DF, Moy VT (2004) Molecular basis of the dynamic strength of the sialyl Lewis X-selectin interaction. Chemphyschem 5: 175–182CrossRefGoogle Scholar
  56. Zhao Y, Chien S, Weinbaum S (2001) Dynamic contact forces on leukocyte microvilli and their penetration of the endothelial glycocalyx. Biophys J 80: 1124–1140CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • V. K. Gupta
    • 1
  • Ihab A. Sraj
    • 1
  • Konstantinos Konstantopoulos
    • 2
  • Charles D. Eggleton
    • 1
  1. 1.Department of Mechanical EngineeringUniversity of Maryland, Baltimore CountyBaltimoreUSA
  2. 2.Department of Chemical and Biomolecular EngineeringThe John Hopkins UniversityBaltimoreUSA

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