In silico and in vitro study of the adhesion dynamics of erythrophagocytosis in sickle cell disease.
In silico and in vitro study of the adhesion dynamics of erythrophagocytosis in sickle cell disease.
复制标题
镰状细胞病中红细胞吞噬作用的粘附动力学的计算机和体外研究。
DOI：
10.1016/j.bpj.2023.05.022
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发表时间：
2023
影响因子：
3.4
通讯作者：
Karniadakis,GeorgeEm
中科院分区：
文献类型：
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作者：
Li,Guansheng;Qiang,Yuhao;Li,He;Li,Xuejin;Dao,Ming;Karniadakis,GeorgeEm
发生在脾内的红细胞吞噬作用是将衰老和患病的红细胞从微循环中移除的关键过程。尽管在理解生物信号通路如何调节吞噬过程方面已经取得了一些进展，但红细胞和巨噬细胞之间的生物物理相互作用的作用，特别是在镰状细胞病等病理条件下的作用，还没有得到充分的研究。在这里，我们结合计算模拟和微流体实验来量化流动条件下的红细胞-巨噬细胞黏附动力学，与脾的红髓中的黏附动力学相当。我们还研究了常氧和低氧条件下红细胞与巨噬细胞的相互作用。首先，我们利用微流控实验对常氧和低氧条件下正常红细胞和镰刀状红细胞的黏附模型中的关键模型参数进行了标定。然后，我们研究了红细胞和巨噬细胞之间的黏附动力学。我们的模拟显示了三种典型的黏附状态，每一种状态都以红细胞的明显动态运动为特征，即牢固黏附、翻转黏附和不黏附(要么是由于不与巨噬细胞接触，要么是因为从巨噬细胞上分离)。我们还跟踪了红细胞和巨噬细胞接触时形成的键的数量，以及两个相互作用的细胞之间的接触面积，为在模拟和微流体实验中观察到的三种粘连状态提供了机制解释。此外，据我们所知，我们首次量化了不同充氧条件下红细胞(正常和镰刀状)与巨噬细胞之间的粘附力。结果表明，常氧下镰状细胞与巨噬细胞的粘附力分别为33-58和53-92，缺氧时为155170。综上所述，我们的微流体和模拟结果加深了我们对镰状细胞病中红细胞和巨噬细胞之间的生物物理相互作用的理解，并为研究生理和病理条件下脾巨噬细胞的过滤功能提供了坚实的基础。
Erythrophagocytosis occurring in the spleen is a critical process for removing senescent and diseased red blood cells (RBCs) from the microcirculation. Although some progress has been made in understanding how the biological signaling pathways mediate the phagocytic processes, the role of the biophysical interaction between RBCs and macrophages, particularly under pathological conditions such as sickle cell disease, has not been adequately studied. Here, we combine computational simulations with microfluidic experiments to quantify RBC-macrophage adhesion dynamics under flow conditions comparable to those in the red pulp of the spleen. We also investigate the RBC-macrophage interaction under normoxic and hypoxic conditions. First, we calibrate key model parameters in the adhesion model using microfluidic experiments for normal and sickle RBCs under normoxia and hypoxia. We then study the adhesion dynamics between the RBC and the macrophage. Our simulation illustrates three typical adhesion states, each characterized by a distinct dynamic motion of the RBCs, namely firm adhesion, flipping adhesion, and no adhesion (either due to no contact with macrophages or detachment from the macrophages). We also track the number of bonds formed when RBCs and macrophages are in contact, as well as the contact area between the two interacting cells, providing mechanistic explanations for the three adhesion states observed in the simulations and microfluidic experiments. Furthermore, we quantify, for the first time to our knowledge, the adhesive forces between RBCs (normal and sickle) and macrophages under different oxygenated conditions. Our results show that the adhesive forces between normal cells and macrophages under normoxia are in the range of 33–58and 53–92for sickle cells under normoxia and 155170for sickle cells under hypoxia. Taken together, our microfluidic and simulation results improve our understanding of the biophysical interaction between RBCs and macrophages in sickle cell disease and provide a solid foundation for investigating the filtration function of the splenic macrophages under physiological and pathological conditions.