不易变形的红细胞亚群在生物力学上诱发镰状细胞病的内皮炎症。

IF 21 1区 医学 Q1 HEMATOLOGY Blood Pub Date : 2024-11-07 DOI:10.1182/blood.2024024608
Christina Caruso, Xiaopo Cheng, Marina E Michaud, Hannah M Szafraniec, Beena E Thomas, Meredith E Fay, Robert G Mannino, Xiao Zhang, Yumiko Sakurai, Wei Li, David R Myers, Clinton H Joiner, David K Wood, Manoj Bhasin, Michael D Graham, Wilbur A Lam
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引用次数: 0

摘要

镰状细胞病(SCD)的典型特征是红细胞(RBC)变形能力降低,导致微血管阻塞和炎症。虽然已知镰状红细胞的生物物理特性会影响 SCD 的血管病变,但红细胞变形能力差对内皮功能障碍的影响还有待充分探讨。利用相互关联的体外和硅学方法,我们提出了一种 SCD 血管病变的新模式,即变形性差的镰状红细胞通过机械传导直接导致内皮功能障碍,内皮细胞能感知异常物理力并对其做出病理生理反应,而与微血管阻塞、粘附或溶血无关。我们证明,将镰状红细胞或药物脱水的健康红细胞灌注到小静脉大小的 "内皮化 "微流体中会导致与内皮细胞的病理性物理相互作用,从而直接诱发炎症通路。我们结合计算模拟和大静脉尺寸的内皮化微流体,观察到灌注不同变形能力的异质镰状红细胞亚群以及与正常红细胞混合的脱水正常红细胞悬浮液会导致变形能力较弱的红细胞亚群向血管壁异常边缘化,造成局部剪应力增加。血管壁应力的增加取决于亚群异质性和氧张力的程度,并通过机械传导途径导致炎症性内皮基因表达。我们的多层面方法证明,变形能力降低的镰状红细胞的存在直接导致病理物理(即直接碰撞和/或压缩力)和剪切力介导的与内皮细胞的相互作用,并诱发炎症反应,从而阐明了 SCD 中血管功能障碍的普遍性。
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Less-deformable erythrocyte subpopulations biomechanically induce endothelial inflammation in sickle cell disease.

Abstract: Sickle cell disease (SCD) is canonically characterized by reduced red blood cell (RBC) deformability, leading to microvascular obstruction and inflammation. Although the biophysical properties of sickle RBCs are known to influence SCD vasculopathy, the contribution of poor RBC deformability to endothelial dysfunction has yet to be fully explored. Leveraging interrelated in vitro and in silico approaches, we introduce a new paradigm of SCD vasculopathy in which poorly deformable sickle RBCs directly cause endothelial dysfunction via mechanotransduction, during which endothelial cells sense and pathophysiologically respond to aberrant physical forces independently of microvascular obstruction, adhesion, or hemolysis. We demonstrate that perfusion of sickle RBCs or pharmacologically-dehydrated healthy RBCs into small venule-sized "endothelialized" microfluidics leads to pathologic physical interactions with endothelial cells that directly induce inflammatory pathways. Using a combination of computational simulations and large venule-sized endothelialized microfluidics, we observed that perfusion of heterogeneous sickle RBC subpopulations with varying deformability, as well as suspensions of dehydrated normal RBCs admixed with normal RBCs, leads to aberrant margination of the less-deformable RBC subpopulations toward the vessel walls, causing localized, increased shear stress. Increased wall stress is dependent on the degree of subpopulation heterogeneity and oxygen tension and leads to inflammatory endothelial gene expression via mechanotransductive pathways. Our multifaceted approach demonstrates that the presence of sickle RBCs with reduced deformability leads directly to pathological physical (ie, direct collisions and/or compressive forces) and shear-mediated interactions with endothelial cells and induces an inflammatory response, thereby elucidating the ubiquity of vascular dysfunction in SCD.

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来源期刊
Blood
Blood 医学-血液学
CiteScore
23.60
自引率
3.90%
发文量
955
审稿时长
1 months
期刊介绍: Blood, the official journal of the American Society of Hematology, published online and in print, provides an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. Primary research articles will be published under the following scientific categories: Clinical Trials and Observations; Gene Therapy; Hematopoiesis and Stem Cells; Immunobiology and Immunotherapy scope; Myeloid Neoplasia; Lymphoid Neoplasia; Phagocytes, Granulocytes and Myelopoiesis; Platelets and Thrombopoiesis; Red Cells, Iron and Erythropoiesis; Thrombosis and Hemostasis; Transfusion Medicine; Transplantation; and Vascular Biology. Papers can be listed under more than one category as appropriate.
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