Wang Yanru, Hofmann Linda, Huber Diana, Lochbaum Robin, Ludwig Sonja, Brunner Cornelia, Hoffmann Thomas K, Lehner René, Theodoraki Marie-Nicole
Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, 89075 Ulm, Baden-Wuerttemberg, Germany.
Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Baden-Wuerttemberg, Germany.
J Clin Med. 2024 Sep 13;13(18):5430. doi: 10.3390/jcm13185430.
: Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic disorder leading to frequent bleeding in several organs. As HHT diagnosis is demanding and depends on clinical criteria, liquid biopsy would be beneficial. Exosomes from biofluids are nano-sized vesicles for intercellular communication. Their cargo and characteristics represent biomarkers for many diseases. Here, exosomes of HHT patients were examined regarding their biosignature. : Exosomes were isolated from the plasma of 20 HHT patients and 17 healthy donors (HDs). The total exosomal protein was quantified, and specific proteins were analyzed using Western blot and antibody arrays. Human umbilical vein endothelial cells (HUVECs) co-incubated with exosomes were functionally examined via immunofluorescence, proliferation, and scratch assay. : The levels of the angiogenesis-regulating protein Thrombospondin-1 were significantly higher in HHT compared to HD exosomes. Among HHT, but not HD exosomes, a negative correlation between total exosomal protein and soluble Endoglin (sENG) levels was found. Other exosomal proteins (ALK1, ALK5) and the particle concentration significantly correlated with disease severity parameters (total consultations/interventions, epistaxis severity score) in HHT patients. Functionally, HUVECs were able to internalize both HD and HHT exosomes, inducing a similar change in the F-Actin structure and a reduction in migration and proliferation. : This study provided first insights into the protein cargo and function of HHT-derived exosomes. The data indicate changes in sENG secretion via exosomes and reveal exosomal Thrombospondin-1 as a potential biomarker for HHT. Several exosomal characteristics were pointed out as potential liquid biomarkers for disease severity, revealing a possible new way of diagnosis and prognosis of HHT.
遗传性出血性毛细血管扩张症（HHT）是一种导致多个器官频繁出血的遗传性疾病。由于HHT的诊断要求较高且依赖临床标准，液体活检将大有裨益。生物流体中的外泌体是用于细胞间通讯的纳米级囊泡。它们的货物和特征代表了许多疾病的生物标志物。在此，对HHT患者的外泌体进行了生物标志物研究。
从20名HHT患者和17名健康供体（HD）的血浆中分离出外泌体。对总外泌体蛋白进行定量，并使用蛋白质印迹法和抗体阵列分析特定蛋白。通过免疫荧光、增殖和划痕试验对与外泌体共同孵育的人脐静脉内皮细胞（HUVEC）进行功能检测。
与HD外泌体相比，HHT中外血管生成调节蛋白血小板反应蛋白-1的水平显著更高。在HHT外泌体中，但在HD外泌体中未发现，总外泌体蛋白与可溶性内皮糖蛋白（sENG）水平之间呈负相关。其他外泌体蛋白（ALK1、ALK5）和颗粒浓度与HHT患者的疾病严重程度参数（总会诊/干预次数、鼻出血严重程度评分）显著相关。在功能上，HUVEC能够内化HD和HHT外泌体，诱导F-肌动蛋白结构发生类似变化，并减少迁移和增殖。
本研究首次深入了解了HHT来源外泌体的蛋白质货物和功能。数据表明通过外泌体分泌的sENG发生了变化，并揭示外泌体血小板反应蛋白-1是HHT的潜在生物标志物。指出了几种外泌体特征作为疾病严重程度的潜在液体生物标志物，揭示了一种可能的HHT诊断和预后新方法。
