Caputo Kelly E, Lee Dooyoung, King Michael R, Hammer Daniel A
Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6321, USA.
Biophys J. 2007 Feb 1;92(3):787-97. doi: 10.1529/biophysj.106.082321. Epub 2006 Nov 3.
Many experiments have measured the effect of force on the dissociation of single selectin bonds, but it is not yet clear how the force dependence of molecular dissociation can influence the rolling of cells expressing selectin molecules. Recent experiments using constant-force atomic force microscopy or high-resolution microscopic observations of pause-time distributions of cells in a flow chamber show that for some bonds, the dissociation rate is high at low force and initially decreases with force, indicating a catch bond. As the force continues to increase, the dissociation rate increases again, like a slip bond. It has been proposed that this catch-slip bond leads to the shear threshold effect, in which a certain level of shear rate is required to achieve rolling. We have incorporated a catch-slip dissociation rate into adhesive dynamics simulations of cell rolling. Using a relatively simple model for the shear-controlled association rate for selectin bonds, we were able to recreate characteristics of the shear threshold effect seen most prominently for rolling through L-selectin. The rolling velocity as a function of shear rate showed a minimum near 100 s-1. Furthermore, cells were observed to roll at a shear rate near the threshold, but detach and move more quickly when the shear rate was dropped below the threshold. Finally, using adhesive dynamics, we were able to determine ranges of parameters necessary to see the shear threshold effect in the rolling velocity. In summary, we found through simulation that the catch-slip behavior of selectin bonds can be responsible for the shear threshold effect.
许多实验测量了力对单个选择素键解离的影响，但分子解离的力依赖性如何影响表达选择素分子的细胞滚动尚不清楚。最近使用恒力原子力显微镜或对流动腔中细胞暂停时间分布进行高分辨率显微镜观察的实验表明，对于某些键，在低力时解离速率较高，并且最初随力的增加而降低，这表明存在捕捉键。随着力持续增加，解离速率再次升高，类似于滑移键。有人提出这种捕捉-滑移键导致剪切阈值效应，即需要一定水平的剪切速率才能实现滚动。我们已将捕捉-滑移解离速率纳入细胞滚动的黏附动力学模拟中。使用一个相对简单的选择素键剪切控制缔合速率模型，我们能够重现通过L-选择素滚动时最显著的剪切阈值效应特征。滚动速度作为剪切速率的函数在接近100 s-1时显示出最小值。此外，观察到细胞在接近阈值的剪切速率下滚动，但当剪切速率降至阈值以下时会脱离并移动得更快。最后，使用黏附动力学，我们能够确定在滚动速度中观察到剪切阈值效应所需的参数范围。总之，我们通过模拟发现选择素键的捕捉-滑移行为可能是剪切阈值效应的原因。
