Cilia proteins are biomarkers of altered flow in the vasculature.
Cilia proteins are biomarkers of altered flow in the vasculature.
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DOI：
10.1172/jci.insight.151813
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发表时间：
2022-03-22
期刊：
影响因子：
8
通讯作者：
Ramchandran R
中科院分区：
文献类型：
--
作者：
Gupta A;Thirugnanam K;Thamilarasan M;Mohieldin AM;Zedan HT;Prabhudesai S;Griffin MR;Spearman AD;Pan A;Palecek SP;Yalcin HC;Nauli SM;Rarick KR;Zennadi R;Ramchandran R
纤毛是一种基于微管的细胞器，从内皮细胞 (EC) 的顶端腔表面伸出，被广泛认为是低流量传感器。先前的报告表明，在高剪切应力下，EC 表面的纤毛会丢失，而最近的证据表明，脱纤毛（从细胞表面物理去除纤毛）是哺乳动物细胞中纤毛丢失的主要机制。因此，我们假设剪切应力变化促进的 EC 纤毛会表现为循环中纤毛相关蛋白丰度的增加。为了检验这一假设，我们进行了剪切应力实验，模拟人类原代细胞和斑马鱼模型系统中从低剪切应力到高剪切应力的流动条件。在原代细胞中，我们发现，在诱导剪切应力时，确实在体外流出物中观察到纤毛碎片，并且流出物含有通常在内皮细胞和上皮细胞中表达的纤毛蛋白。在斑马鱼中，在剪切应力诱导后，观察到表达纤毛的 EC 减少。为了测试这些发现的转化相关性，我们使用镰状细胞病患者的血液样本研究了我们的假设，发现纤毛蛋白的血浆水平与健康对照相比有所升高。此外，镰状红细胞在粘附到脑内皮细胞后，其表面显示出高水平的纤毛蛋白（ARL13b）。与镰状红细胞相互作用后，脑内皮细胞表现出高活性氧（ROS）水平。脑内皮细胞中ROS水平的减弱降低了红细胞上纤毛蛋白的水平，并挽救了脑内皮细胞中纤毛蛋白的水平。总的来说，这些数据表明，在各种改变的流动条件下，循环中的纤毛和纤毛蛋白是可检测到的，这可以作为受损内皮的替代生物标志物。
Cilia, microtubule-based organelles that project from the apical luminal surface of endothelial cells (ECs), are widely regarded as low-flow sensors. Previous reports suggest that upon high shear stress, cilia on the EC surface are lost, and more recent evidence suggests that deciliation—the physical removal of cilia from the cell surface—is a predominant mechanism for cilia loss in mammalian cells. Thus, we hypothesized that EC deciliation facilitated by changes in shear stress would manifest in increased abundance of cilia-related proteins in circulation. To test this hypothesis, we performed shear stress experiments that mimicked flow conditions from low to high shear stress in human primary cells and a zebrafish model system. In the primary cells, we showed that upon shear stress induction, indeed, ciliary fragments were observed in the effluent in vitro, and effluents contained ciliary proteins normally expressed in both endothelial and epithelial cells. In zebrafish, upon shear stress induction, fewer cilia-expressing ECs were observed. To test the translational relevance of these findings, we investigated our hypothesis using patient blood samples from sickle cell disease and found that plasma levels of ciliary proteins were elevated compared with healthy controls. Further, sickled red blood cells demonstrated high levels of ciliary protein (ARL13b) on their surface after adhesion to brain ECs. Brain ECs postinteraction with sickle RBCs showed high reactive oxygen species (ROS) levels. Attenuating ROS levels in brain ECs decreased cilia protein levels on RBCs and rescued ciliary protein levels in brain ECs. Collectively, these data suggest that cilia and ciliary proteins in circulation are detectable under various altered-flow conditions, which could serve as a surrogate biomarker of the damaged endothelium.
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