Circulating Endothelial Cells and Microvesicles as Biomarkers for Gene Therapy in Sickle Cell Disease

镰状细胞病（SCD）是世界范围内最常见的血红蛋白病， β-珠蛋白基因突变导致的SCD患者血红蛋白S的聚合有显著性差异， 病理生理后果-溶血、炎症、氧化应激、高凝状态和疼痛 血管闭塞危象，促进内皮和血管功能障碍。 SCD脉管系统反映了内皮/血管功能障碍， 促凝血表型（1），增加循环内皮细胞（CEC）和微泡的数量 (MVs) . CEC和内皮源性MV（EMV）的数量和激活状态增加， 可溶性粘附分子和凝血标志物的表达增加。此外，由于CEC 和EMV组成的变化反映了他们的内皮细胞起源的激活状态，他们正在出现 作为内皮功能障碍的指标（2-5）。先前的研究发现，血浆CEC、MV、可溶性 粘附分子和凝血因子在健康受试者中以低水平存在，但在健康受试者中升高。 各种全身性炎症性疾病，包括SCD（2，3，6-9）。因此，CEC和EMV是理想的 炎症性疾病的诊断和预后的生物标志物，使它们在诊断方面具有巨大的潜力 SCD严重度。标准化和验证CEC和EMV作为疾病修饰的生物标志物符合 治愈镰状细胞病倡议的目标，提供一个明确的科学方法来跟踪 治疗性基因SCD治疗后的血管内皮。

Sickle cell disease (SCD) is the most common hemoglobinopathy worldwide, resulting from a mutation in the β-globin gene. The polymerization of hemoglobin S in SCD has significant pathophysiological consequences -- hemolysis, inflammation, oxidative stress, hypercoagulability and painful vaso-occlusive crises that promote endothelial and vascular dysfunction. The SCD vasculature reflects the endothelial/vascular dysfunction with an active, pro-inflammatory, procoagulant phenotype (1), increasing the number of circulating endothelial cells (CECs) and microvesicles (MVs) . Increased number and activation status of CECs and endothelial-derived MVs (EMVs) is accompanied by heightened expression of soluble adhesion molecules and coagulation markers. Additionally, since CECs and EMVs compositional change reflects the activation state of their endothelial cell origin, they are emerging as indicators of endothelial dysfunction (2-5). Previous studies have found that plasma CECs, MVs, soluble adhesion molecules, and coagulation factors are present at low levels in healthy subjects, but are elevated in a variety of systemic inflammatory diseases, including SCD (2, 3, 6-9). Therefore, CECs and EMVs are ideal biomarkers for diagnosis and prognosis of inflammatory disorders, giving them huge potential in diagnosing SCD severity. Standardizing and validating CECs and EMVs as biomarkers of disease modification aligns with the goals of the Cure Sickle Cell Initiative, providing a defined scientific methodology to track changes in the vascular endothelium following curative gene SCD therapy.