de Boer Suzan, Eikenboom Jeroen
Department of Internal medicine, division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Hemasphere. 2019 Sep 27;3(5):e297. doi: 10.1097/HS9.0000000000000297. eCollection 2019 Oct.
Von Willebrand factor (VWF) plays an essential role in primary hemostasis and is exclusively synthesized and stored in endothelial cells and megakaryocytes. Upon vascular injury, VWF is released into the circulation where this multimeric protein is required for platelet adhesion. Defects of VWF lead to the most common inherited bleeding disorder von Willebrand disease (VWD). Three different types of VWD exist, presenting with varying degrees of bleeding tendencies. The pathophysiology of VWD can be investigated by examining the synthesis, storage and secretion in VWF producing cells. These cells can either be primary VWF producing cells or transfected heterologous cell models. For many years transfected heterologous cells have been used successfully to elucidate many aspects of VWF synthesis. However, those cells do not fully reflect the characteristics of primary cells. Obtaining primary endothelial cells or megakaryocytes with a VWD phenotype, requires invasive procedures, such as vessel collection or a bone marrow biopsy. A more recent and promising development is the isolation of endothelial colony forming cells (ECFCs) from peripheral blood as a true-to-nature cell model. Alternatively, various animal models are available but limiting, therefore, new approaches are needed to study VWD and other bleeding disorders. A potential versatile source of endothelial cells and megakaryocytes could be induced pluripotent stem cells (iPSCs). This review gives an overview of models that are available to study VWD and VWF and will discuss novel approaches that can be considered to improve the understanding of the structural and functional mechanisms underlying this disease.
血管性血友病因子（VWF）在初级止血过程中发挥着至关重要的作用，并且仅在内皮细胞和巨核细胞中合成与储存。血管受损时，VWF会释放到循环系统中，这种多聚体蛋白是血小板黏附所必需的。VWF缺陷会导致最常见的遗传性出血性疾病——血管性血友病（VWD）。VWD存在三种不同类型，出血倾向程度各异。可通过检测VWF产生细胞中的合成、储存和分泌情况来研究VWD的病理生理学。这些细胞既可以是原发性VWF产生细胞，也可以是转染的异源细胞模型。多年来，转染的异源细胞已成功用于阐明VWF合成的诸多方面。然而，这些细胞并不能完全反映原代细胞的特性。要获得具有VWD表型的原代内皮细胞或巨核细胞，需要进行侵入性操作，如血管采集或骨髓活检。最近一个有前景的进展是从外周血中分离出内皮集落形成细胞（ECFCs）作为一种天然的细胞模型。另外，有多种动物模型可用，但存在局限性，因此，需要新的方法来研究VWD和其他出血性疾病。诱导多能干细胞（iPSC）可能是内皮细胞和巨核细胞的一个潜在通用来源。本综述概述了可用于研究VWD和VWF的模型，并将讨论一些新方法，这些方法可被视为有助于增进对该疾病潜在结构和功能机制的理解。
