Thesis defense Maaike Schillemans: Weibel-Palade body logistics

PhD thesis defense Maaike Schillemans

On 20 June 2019 (14:00 hrs) Maaike Schillemans will defend her PhD thesis 'Weibel-Palade body logistics: express delivery in the vasculature' at the University of Amsterdam. During her PhD Maaike studied how endothelial cells store and secrete Von Willebrand factor (VWF) from specialized storage organelles, the so-called Weibel-Palade bodies (WPBs).

To minimize blood loss and prevent or overcome infections in the event of vascular trauma the endothelial cells of the blood vessel wall pre-package a cocktail of hemostatic, inflammatory and angiogenic mediators in their WPBs. WPBs can be immediately released following blood vessel injury and promote adhesion of platelets and recruitment of leukocytes to sites of vascular damage.

Balanced release of WPB cargo such as VWF is pivotal: low VWF levels can lead to bleeding while elevated VWF is associated with high risk of thrombosis. How endothelial cells control biogenesis and exocytosis of WPBs is poorly understood. In this thesis, Maaike Schillemans has studied how SNARE proteins, molecular machines that catalyze the fusion of membranes, control exocytosis of WPBs and how defects in these pathways can lead to disease.

Blood outgrowth endothelial cells

To study WPB exocytosis in its native environment, Maaike and her team made use of blood outgrowth endothelial cells (BOECs), bona fide endothelial cells which can be readily isolated from peripheral blood of donors or patients. Using BOECs from patients with extremely rare diseases such as Microvillous Inclusion Disease (MVID) and Hermansky-Pudlak Syndrome type 2 (HPS2), she was able to show the important roles that the SNARE proteins syntaxin-3 and VAMP8 play in exocytosis of WPBs. Furthermore, this thesis also describes a novel, efficient method to genetically engineer human endothelial cells using CRISPR genome editing of cord blood-derived BOECs.

Weibel-Palade body interactomics

Although genetic and functional studies have already found some regulators of WPB exocytosis, the exact composition of the molecular machinery is far from clear. In collaboration with the Mass spectrometry facilities at Sanquin, Maaike performed unbiased proteomic screens for interactors of syntaxin-3 and STXBP5 to identify new components of the protein complexes that control WPB exocytosis. This has resulted in a rough map of endothelial SNARE interaction networks that may control WPB exocytosis and which may contain potential candidate targets that control plasma VWF levels in health and disease.

Promotor: Prof JJ Voorberg PhD
Copromotor: R Bierings PhD

Venue: Agnietenkapel, University of Amsterdam