Von Willebrand Disease: From In Vivo to In Vitro Disease Models

Abstract

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.

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

“…Therefore, it is conceivable that the genetic manipulation of ECFCs could lead to even more effective therapeutic outcomes. Preliminary studies revealed that ECFCs can be engineered to deliver recombinant proteins to treat anemia [216], hemophilia A [217,218], or von Willebrand disease [219,220] or to secrete angiogenic inhibitors [221,222]. When ECFCs were engineered with non-viral plasmids encoding for human coagulation factor VIII (FVIII), they mainly engrafted within the bone marrow and spleen of NOD/SCID (non-obese diabetes/severe combined immunodeficiency) mice and retained both transgene expression and the endothelial phenotype; in addition, they persisted in secreting in circulation therapeutic levels of FVIII even at 5 months after transplantation [217].…”

Development and evaluation of a bovine lung-on-chip (bLOC) to study bovine respiratory diseases

“…The high quantities of mucin ( MUC5AC ) mRNA and protein expression were not surprising, given the sensitivity of secretory cells to shear stress, resulting in a cycle of excessive mucin production [ 31 ]. The increase in mRNA expression of the endothelial marker VWF (in contrast to the stable expression of CD34) was surprising, although this could reasonably be attributed to the response of endothelial cells to perfusion (again, shear stress) [ 32 ], or reflect the role of endothelial cell-secreted VWF in the repair of damage to the vascular endothelium [ 33 ].…”

Proteomic profiling of serum exosomes reveals acute phase response and promotion of inflammatory and platelet activation pathways in patients with heat stroke

“…It not only participates in coagulation but also helps recruit leukocytes [19] directly by binding to surface P-selectin glycoprotein ligand 1 to support their rolling and later, interaction with surface β2 integrin for promoting strong adhesion, or indirectly through the activated platelets. In presence of pathogens, vWF multimers can combine with neutrophil extracellular traps to form a network to aggregate leukocytes and platelets while promoting immunothrombosis [20]. High vWF antigen levels have been reported to exist in trauma and are associated with increased endothelial permeability, persistently lower platelet counts, microthrombi formation, and organ failure [21].…”