Pivkin Igor V, Peng Zhangli, Karniadakis George E, Buffet Pierre A, Dao Ming, Suresh Subra
Institute of Computational Science, Faculty of Informatics, University of Lugano, 6900 Lugano, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland;
Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556; Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):7804-9. doi: 10.1073/pnas.1606751113. Epub 2016 Jun 27.
Red blood cells (RBCs) can be cleared from circulation when alterations in their size, shape, and deformability are detected. This function is modulated by the spleen-specific structure of the interendothelial slit (IES). Here, we present a unique physiological framework for development of prognostic markers in RBC diseases by quantifying biophysical limits for RBCs to pass through the IES, using computational simulations based on dissipative particle dynamics. The results show that the spleen selects RBCs for continued circulation based on their geometry, consistent with prior in vivo observations. A companion analysis provides critical bounds relating surface area and volume for healthy RBCs beyond which the RBCs fail the "physical fitness test" to pass through the IES, supporting independent experiments. Our results suggest that the spleen plays an important role in determining distributions of size and shape of healthy RBCs. Because mechanical retention of infected RBC impacts malaria pathogenesis, we studied key biophysical parameters for RBCs infected with Plasmodium falciparum as they cross the IES. In agreement with experimental results, surface area loss of an infected RBC is found to be a more important determinant of splenic retention than its membrane stiffness. The simulations provide insights into the effects of pressure gradient across the IES on RBC retention. By providing quantitative biophysical limits for RBCs to pass through the IES, the narrowest circulatory bottleneck in the spleen, our results offer a broad approach for developing quantitative markers for diseases such as hereditary spherocytosis, thalassemia, and malaria.
当红细胞（RBCs）的大小、形状和可变形性发生改变时，它们可从循环中被清除。这种功能由内皮间裂隙（IES）的脾脏特异性结构调节。在此，我们通过基于耗散粒子动力学的计算模拟，量化红细胞穿过IES的生物物理极限，为红细胞疾病预后标志物的开发提供了一个独特的生理框架。结果表明，脾脏根据红细胞的几何形状选择其继续循环，这与先前的体内观察结果一致。一项配套分析提供了健康红细胞表面积和体积之间的关键界限，超过此界限，红细胞就无法通过“身体适应性测试”以穿过IES，这支持了独立实验。我们的结果表明，脾脏在决定健康红细胞的大小和形状分布方面起着重要作用。由于受感染红细胞的机械滞留会影响疟疾发病机制，我们研究了恶性疟原虫感染的红细胞穿过IES时的关键生物物理参数。与实验结果一致，发现受感染红细胞的表面积损失比其膜硬度更是脾脏滞留的一个重要决定因素。模拟结果揭示了跨IES的压力梯度对红细胞滞留的影响。通过为红细胞穿过脾脏中最狭窄的循环瓶颈IES提供定量生物物理极限，我们的结果为开发遗传性球形红细胞增多症、地中海贫血和疟疾等疾病的定量标志物提供了一种广泛的方法。
