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LMCB - MRC Laboratory for Molecular Cell Biology

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Daniel Cutler's picture
LMCB Group Leader, UCL Professor 
 
+44 (0)20 7679 7808
LMCB Room 2.12
 
Endothelial Cell Biology

Research Synopsis

Endothelial cells contain a storage organelle, Weibel-Palade Bodies (WPB), which contains key components of both inflammatory and haemostatic processes. As a rapid-response system, the WPB are of critical importance in initiating haemostatic and inflammatory responses within the rapidly-changing vascular environment. The major content protein of WPB is von Willebrands factor (VWF), an adhesive glycoprotein that plays a major role in primary haemostasis. This very large highly multimerised protein is stored within the WPB coiled up as proteinacious tubules. Mutations within VWF are the commonest cause of the inherited bleeding disorder Von Willebrands Disease. In addition to mutations causing a loss of platelet binding or other direct haemostatic problems, mutations in VWF can affect the formation of the protein tubules, leading to formation of damaged, poorly functional WPB. We are working with endothelial cells from patients with bleeding disorders to further understand these complex defects. Recent advances in microscopy and in bioinformatics have revealed that WPB size increases in half-micron steps. The subunits are brought together in the trans-Golgi where they assemble into the wide distribution of lengths that we find in human cells. By manipulating WPB length, we have shown that short WPB are much less efficient at supporting platelet recruitment, and thus initiating primary haemostasis. Our lab exploits our new understanding of the cellular controls on WPB formation to (1) understand how these act in concert to produce a functional output from the WPB, thus controlling the activated endothelial cell phenotype; (2) determine how changes to WPB produce different functional responses to endothelial antagonists; (3) identify and characterise new controls on endothelial phenotype.
Recently we have begun to explore the fact that the machinery involved in making WPB is also needed for making platelet granules, small organelles that are critical to the platelet function in haemostasis. We have applied super-resolution microscopy to platelet diagnosis, and are now also working with endothelial cells from patients with platelet function disorders.
 

 

Selected Publications

Lopes da Silva M & Cutler DF (2016). Von Willebrand Factor multimerization and the polarity of secretory pathways in endothelial cells. Blood.
Ferraro F, et al (2016). Weibel-Palade body size modulates the adhesive activity of its von Willebrand Factor cargo in cultured endothelial cells. SCIENTIFIC REPORTS, 6, ARTN 32473. doi:10.1038/srep32473
Westmoreland D, et al (2016). Super-resolution microscopy as a potential approach to diagnosis of platelet granule disorders. Journal of thrombosis and haemostasis : JTH, 14 (4), 839-849.
Ferraro F, et al (2014). A two-tier Golgi-based control of organelle size underpins the functional plasticity of endothelial cells. Dev Cell, 29 (3), 292-304. doi:10.1016/j.devcel.2014.03.021
Doyle EL, et al (2011). CD63 is an essential cofactor to leukocyte recruitment by endothelial P-selectin. Blood, 118 (15), 4265-4273. doi:10.1182/blood-2010-11-321489
Nightingale TD, et al (2011). Actomyosin II contractility expels von Willebrand factor from Weibel-Palade bodies during exocytosis. J Cell Biol, 194 (4), 613-629. doi:10.1083/jcb.201011119

Funders

Medical Research Council
British Heart Foundation

Research Themes

Polarity and cell shape, Cytoskeleton and cell cortex, Organelle biogenesis, Endothelial cells, Platelets, Haemostasis, Membrane trafficking, Inflammation

Technology

Light microscopy, Translational research, Bioinformatics, Super-resolution microscopy, Electron Microscopy

People

Kimberley Harrison-Lavoie (Research Assistant)
Mafalda Lopes da Silva (Postdoctoral Fellow)
Jessica McCormack (Postdoctoral Fellow)
Francesca Patella (Postdoctoral Fellow)

Collaborators

Louise Cramer (LMCB, UK)
Paul Gissen (LMCB, UK)
Robin Ketteler (LMCB, UK)
Janos Kriston-Vizi (LMCB, UK)
Karen Page (UCL, UK)
Anna Randi (Imperial College, UK)
Tom Nightingale (QMUL, UK)