Division of Applied Mathematics, Brown University, Providence, Rhode Island.
Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Biophys J. 2018 Apr 24;114(8):2014-2023. doi: 10.1016/j.bpj.2018.03.004.
Reticulocytes, the precursors of erythrocytes, undergo drastic alterations in cell size, shape, and deformability during maturation. Experimental evidence suggests that young reticulocytes are stiffer and less stable than their mature counterparts; however, the underlying mechanism is yet to be fully understood. Here, we develop a coarse-grained molecular-dynamics reticulocyte membrane model to elucidate how the membrane structure of reticulocytes contributes to their particular biomechanical properties and pathogenesis in blood diseases. First, we show that the extended cytoskeleton in the reticulocyte membrane is responsible for its increased shear modulus. Subsequently, we quantify the effect of weakened cytoskeleton on the stiffness and stability of reticulocytes, via which we demonstrate that the extended cytoskeleton along with reduced cytoskeleton connectivity leads to the seeming paradox that reticulocytes are stiffer and less stable than the mature erythrocytes. Our simulation results also suggest that membrane budding and the consequent vesiculation of reticulocytes can occur independently of the endocytosis-exocytosis pathway, and thus, it may serve as an additional means of removing unwanted membrane proteins from reticulocytes. Finally, we find that membrane budding is exacerbated when the cohesion between the lipid bilayer and the cytoskeleton is compromised, which is in accord with the clinical observations that erythrocytes start shedding membrane surface at the reticulocyte stage in hereditary spherocytosis. Taken together, our results quantify the stiffness and stability change of reticulocytes during their maturation and provide, to our knowledge, new insights into the pathogenesis of hereditary spherocytosis and malaria.
网织红细胞是红细胞的前体，在成熟过程中细胞大小、形状和变形能力会发生剧烈变化。实验证据表明，年轻的网织红细胞比成熟的网织红细胞更硬、更不稳定；然而，其潜在机制尚未完全理解。在这里，我们开发了一个粗粒化的分子动力学网织红细胞膜模型，以阐明网织红细胞膜的结构如何导致其在血液疾病中的特殊生物力学特性和发病机制。首先，我们表明网织红细胞膜中伸展的细胞骨架是导致其剪切模量增加的原因。随后，我们通过量化细胞骨架减弱对网织红细胞刚性和稳定性的影响，证明了伸展的细胞骨架和减少的细胞骨架连接性导致网织红细胞比成熟红细胞更硬和更不稳定的似乎矛盾的现象。我们的模拟结果还表明，膜出芽和随后的网织红细胞囊泡化可以独立于内吞作用-外排作用途径发生，因此，它可能是从网织红细胞中去除不需要的膜蛋白的另一种手段。最后，我们发现当脂质双层和细胞骨架之间的内聚力受到损害时，膜出芽会加剧，这与遗传性球形红细胞增多症中临床观察到的红细胞从网织红细胞阶段开始脱落膜表面的结果一致。总之，我们的结果量化了网织红细胞在成熟过程中的刚性和稳定性变化，并为遗传性球形红细胞增多症和疟疾的发病机制提供了新的见解。
