Mechanics of diseased red blood cells in human spleen and consequences for hereditary blood disorders.
Mechanics of diseased red blood cells in human spleen and consequences for hereditary blood disorders.
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DOI：
10.1073/pnas.1806501115
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发表时间：
2018-09-18
影响因子：
11.1
通讯作者：
Suresh S
中科院分区：
文献类型：
--
作者：
Li H;Lu L;Li X;Buffet PA;Dao M;Karniadakis GE;Suresh S
内皮间缝隙（IES）是人类脾脏中最靠西的循环通路，在此过滤老化和患病的红细胞（RBC）。我们使用一个双组分红细胞模型来探测健康和患病红细胞穿越IES的动力学。我们的模拟结果表明，脾脏不仅能感知和清除形状和变形性异常的红细胞，还能改变含有遗传性血液疾病引起的蛋白质缺陷的红细胞的几何形状。这里提出的框架是足够普遍的扩展到阐明脾脏在其他血液疾病的病理生理作用。在红细胞（RBC）疾病中，脾脏通过清除受损的RBC而导致贫血，但其独特的机械挑战RBC的能力也存在诱导其他致病作用的风险。我们分析了遗传性球形红细胞增多症（HS）和遗传性椭圆形红细胞增多症（HE）中的红细胞，这是导致红细胞膜蛋白缺陷的两种典型血液疾病。我们使用一个双组分蛋白质规模的红细胞模型来模拟人脾脏中内皮间缝隙（IES）的穿越，这是对健康和患病红细胞的严格生物力学挑战，无法在体内直接观察到。在HS中，我们的研究结果证实，红细胞失去表面，由于脂双层和细胞骨架之间的凝聚力减弱，并揭示表面损失可能会导致红细胞的囊泡，因为它穿过IES。在HE中，穿过IES诱导RBC持续伸长，在严重疾病中弹性受损和破碎。因此，我们的模拟表明，在遗传性红细胞疾病中，脾脏不仅过滤掉病理性红细胞，而且直接导致红细胞改变。这些结果提供了一个机制的理由，不同的临床结果记录后，HS患者血影蛋白缺陷和抗凝血蛋白缺陷的红细胞脾切除术，并提供了深入了解人类脾脏在红细胞疾病的致病作用。
The interendothelial slit (IES) is the narrowest circulatory pathway in the human spleen where aged and diseased red blood cells (RBCs) are filtered. We use a two-component RBC model to probe the dynamics of healthy and diseased RBCs traversing IES. Our simulations reveal that the spleen not only senses and clears RBCs with abnormal shapes and deformability but also alters the geometries of RBCs that contain protein defects arising from hereditary blood disorders. The framework presented here is sufficiently general to be extended to elucidate the pathophysiological roles of the spleen in other blood diseases. In red blood cell (RBC) diseases, the spleen contributes to anemia by clearing the damaged RBCs, but its unique ability to mechanically challenge RBCs also poses the risk of inducing other pathogenic effects. We have analyzed RBCs in hereditary spherocytosis (HS) and hereditary elliptocytosis (HE), two typical examples of blood disorders that result in membrane protein defects in RBCs. We use a two-component protein-scale RBC model to simulate the traversal of the interendothelial slit (IES) in the human spleen, a stringent biomechanical challenge on healthy and diseased RBCs that cannot be directly observed in vivo. In HS, our results confirm that the RBC loses surface due to weakened cohesion between the lipid bilayer and the cytoskeleton and reveal that surface loss may result from vesiculation of the RBC as it crosses IES. In HE, traversing IES induces sustained elongation of the RBC with impaired elasticity and fragmentation in severe disease. Our simulations thus suggest that in inherited RBC disorders, the spleen not only filters out pathological RBCs but also directly contributes to RBC alterations. These results provide a mechanistic rationale for different clinical outcomes documented following splenectomy in HS patients with spectrin-deficient and ankyrin-deficient RBCs and offer insights into the pathogenic role of human spleen in RBC diseases.
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