Patient-specific modeling of individual sickle cell behavior under transient hypoxia.
Patient-specific modeling of individual sickle cell behavior under transient hypoxia.
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DOI：
10.1371/journal.pcbi.1005426
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发表时间：
2017-03
影响因子：
4.3
通讯作者：
Karniadakis GE
中科院分区：
文献类型：
--
作者：
Li X;Du E;Dao M;Suresh S;Karniadakis GE
镰状细胞病（SCD）是一种高度复杂的遗传性血液疾病，其中红细胞（RBC）表现出不均匀的形态变化和变形能力降低。我们采用了一个动力学模型的细胞形态镰状化，调用来自患者的具体数据的参数。该模型用于研究单个镰状细胞在毛细血管样微环境中的动力学，以解决与SCD相关的各种机制。我们发现，所有的红细胞，缺氧的影响和缺氧的影响，定期通过微门在氧合状态下。然而，受缺氧影响的细胞经历镰状化，这显著改变了细胞动力学。特别是，致密和刚性的镰状红细胞被阻塞，从而堵塞血液流动，而密度较小和可变形的红细胞能够通过选择蛇形路径绕过它们前面的死（捕获）细胞。我们已经进行了详细的计算模拟，以改变细胞行为，以响应形态学变化和膜硬化。我们的模型表明，SCD表现出很大的异质性，即使在一个特定的密度分级亚群。这些发现为单个镰状细胞在短暂缺氧条件下如何通过毛细血管提供了独特的见解，并为设计有效的SCD治疗干预提供了新的可能性。镰状细胞病是一种遗传性血液病，可导致血管闭塞性疼痛危象。在这里，我们通过由同伴微流体实验告知的患者特异性预测计算模拟来研究受控缺氧条件下的个体镰状细胞行为。我们确定了不同的动态行为之间的个别镰状红细胞和正常的微流体流动，并分析缺氧引起的改变，在生理条件下的单个细胞的行为和单细胞毛细血管阻塞。
Sickle cell disease (SCD) is a highly complex genetic blood disorder in which red blood cells (RBC) exhibit heterogeneous morphology changes and decreased deformability. We employ a kinetic model for cell morphological sickling that invokes parameters derived from patient-specific data. This model is used to investigate the dynamics of individual sickle cells in a capillary-like microenvironment in order to address various mechanisms associated with SCD. We show that all RBCs, both hypoxia-unaffected and hypoxia-affected ones, regularly pass through microgates under oxygenated state. However, the hypoxia-affected cells undergo sickling which significantly alters cell dynamics. In particular, the dense and rigid sickle RBCs are obstructed thereby clogging blood flow while the less dense and deformable ones are capable of circumnavigating dead (trapped) cells ahead of them by choosing a serpentine path. Informed by recent experiments involving microfluidics that provide in vitro quantitative information on cell dynamics under transient hypoxia conditions, we have performed detailed computational simulations of alterations to cell behavior in response to morphological changes and membrane stiffening. Our model reveals that SCD exhibits substantial heterogeneity even within a particular density-fractionated subpopulation. These findings provide unique insights into how individual sickle cells move through capillaries under transient hypoxic conditions, and offer novel possibilities for designing effective therapeutic interventions for SCD. Sickle cell disease is a genetic blood disease that causes vaso-occlusive pain crises. Here, we investigate the individual sickle cell behavior under controlled hypoxic conditions through patient-specific predictive computational simulations that are informed by companion microfluidic experiments. We identify the different dynamic behavior between individual sickle RBCs and normal ones in microfluidic flow, and analyze the hypoxia-induced alteration in individual cell behavior and single-cell capillary obstruction under physiological conditions.