Catch bonds in sickle cell disease: Shear-enhanced adhesion of red blood cells to laminin
Catch bonds in sickle cell disease: Shear-enhanced adhesion of red blood cells to laminin
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DOI：
10.1016/j.bpj.2023.05.010
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发表时间：
2023-06-20
影响因子：
3.4
通讯作者：
Gurkan，Umut A.
中科院分区：
文献类型：
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作者：
Goreke，Utku;Iram，Shamreen;Gurkan，Umut A.
在镰状细胞病中，异常红细胞（RBC）粘附阻碍了血液流动，这种现象是否会在镰状细胞病中发挥作用？在这里，我们调查的动态镰刀形红细胞粘附到表面功能化的蛋白质层粘连蛋白（血管周围的细胞外基质的一个组成部分）在生理相关的微尺度流动。首先，使用全内反射显微镜，我们的特点的空间波动的红细胞膜以上的层粘连蛋白表面分离前。我们观察到的复杂的动力学表明捕获键合的可能性，其中细胞从表面的平均脱离时间最初增加到最大值，然后作为剪切力的函数减小。接下来，我们对来自25名镰状细胞病患者的血液样品进行了一系列剪切诱导的分离实验，量化了在突然的力跳跃和线性力斜坡下粘附细胞的数量和持续时间。实验表明，一部分患者确实表现出了捕捉结合。通过将数据拟合到键动力学的理论模型，我们可以提取每个患者的平均键寿命与力。结果表明，患者之间的异质性，无论是在定性行为（是否有捕获绑定）和寿命的大小。在生理力作用下具有长键寿命的患者更可能具有某些不良临床特征，如肺动脉高压和心内分流的诊断。通过引入一个体外平台来全面表征RBC-层粘连蛋白粘附动力学，我们的方法可以有助于镰状细胞病患者特异性抗粘附疗法的开发。该实验装置也很容易推广到研究其他细胞类型（例如白细胞或癌细胞）的粘附动力学，并且可以结合与疾病相关的环境条件，例如缺氧。
Could the phenomenon of catch bonding—force-strengthened cellular adhesion—play a role in sickle cell disease, where abnormal red blood cell (RBC) adhesion obstructs blood flow? Here, we investigate the dynamics of sickle RBCs adhering to a surface functionalized with the protein laminin (a component of the extracellular matrix around blood vessels) under physiologically relevant microscale flow. First, using total internal reflectance microscopy we characterize the spatial fluctuations of the RBC membrane above the laminin surface before detachment. The complex dynamics we observe suggest the possibility of catch bonding, where the mean detachment time of the cell from the surface initially increases to a maximum and then decreases as a function of shear force. We next conduct a series of shear-induced detachment experiments on blood samples from 25 sickle cell disease patients, quantifying the number and duration of adhered cells under both sudden force jumps and linear force ramps. The experiments reveal that a subset of patients does indeed exhibit catch bonding. By fitting the data to a theoretical model of the bond dynamics, we can extract the mean bond lifetime versus force for each patient. The results show a striking heterogeneity among patients, both in terms of the qualitative behavior (whether or not there is catch bonding) and in the magnitudes of the lifetimes. Patients with large bond lifetimes at physiological forces are more likely to have certain adverse clinical features, like a diagnosis of pulmonary arterial hypertension and intracardiac shunts. By introducing anin vitroplatform for fully characterizing RBC-laminin adhesion dynamics, our approach could contribute to the development of patient-specific antiadhesive therapies for sickle cell disease. The experimental setup is also easily generalizable to studying adhesion dynamics in other cell types, for example, leukocytes or cancer cells, and can incorporate disease-relevant environmental conditions like oxygen deprivation.