Biologie Intégrée du Globule Rouge UMR_S1134, Inserm, Univ. Paris Diderot, Sorbonne Paris Cité, Univ. de la Réunion, Univ. des Antilles, INTS, 6 rue Alexandre Cabanel, 75015 Paris, France.
Lab Chip. 2018 Sep 26;18(19):2975-2984. doi: 10.1039/c8lc00637g.
The human red blood cell is a biconcave disc of 6-8 × 2 μm that is highly elastic. This capacity to deform enables it to stretch while circulating through narrow capillaries to ensure its main function of gas exchange. Red cell shape and deformability are altered in membrane disorders because of defects in skeletal or membrane proteins affecting protein-protein interactions. Red cell properties are also altered in other pathologies such as sickle cell disease. Sickle cell disease is a genetic hereditary disorder caused by a single point mutation in the β-globin gene generating sickle haemoglobin (HbS). Hypoxia drives HbS polymerisation that is responsible for red cell sickling and reduced deformability. The main clinical features of sickle cell disease are vaso-occlusive crises and haemolytic anaemia. Foetal haemoglobin (HbF) inhibits HbS polymerisation and positively impacts red cell survival in the circulation but the mechanism through which it exerts this action is not fully characterized. In this study, we designed a microfluidic biochip mimicking the dimensions of human capillaries to measure the impact of repeated mechanical stress on the survival of red cells at the single cell scale under controlled pressure. We show that mechanical stress is a critical parameter underlying intravascular haemolysis in sickle cell disease and that high intracellular levels of HbF protect against lysis. The biochip is a promising tool to address red cell deformability in pathological situations and to screen for molecules positively impacting this parameter in order to improve red cell survival in the circulation.
人类的红细胞是一种 6-8×2μm 的双凹圆盘，具有高度的弹性。这种变形能力使它能够在循环过程中通过狭窄的毛细血管伸展，以确保其主要的气体交换功能。由于影响蛋白质-蛋白质相互作用的骨架或膜蛋白缺陷，在膜疾病中红细胞的形状和变形能力会发生改变。在其他病理情况下，如镰状细胞病，红细胞的特性也会发生改变。镰状细胞病是一种由β-珠蛋白基因中的单点突变引起的遗传性遗传疾病，导致镰状血红蛋白（HbS）的产生。缺氧会导致 HbS 聚合，从而导致红细胞镰变和变形能力降低。镰状细胞病的主要临床特征是血管阻塞危象和溶血性贫血。胎儿血红蛋白（HbF）抑制 HbS 聚合，并对循环中红细胞的存活产生积极影响，但它发挥这种作用的机制尚未完全阐明。在这项研究中，我们设计了一种微流控生物芯片，模拟人类毛细血管的尺寸，以在受控压力下从单细胞水平测量重复机械应力对红细胞存活的影响。我们表明，机械应力是镰状细胞病血管内溶血的一个关键参数，而高细胞内 HbF 水平可防止溶血。该生物芯片是一种很有前途的工具，可以用于研究病理情况下的红细胞变形能力，并筛选出对该参数有积极影响的分子，以提高循环中红细胞的存活率。
