Regulators of the megakaryocyte and platelet cytoskeleton
At sites of vascular injury, circulating blood platelets come into contact with exposed subendothelial components and form a plug to prevent excessive blood loss. 1011 platelets are produced daily in the human body to fulfill the normal hemostatic function. The individual’s platelet count is maintained in a range of approximately 150.000-400.000/μL, requiring a constant balance of platelet production and clearance.
Platelets are produced by megakaryocytes (MKs) in the bone marrow in a unique process in mammalian physiology. Mature MKs are localized in close proximity to sinusoidal blood vessels and convert their cytoplasmic, membranous network into long protrusions, called proplatelets, which extend into the lumen of bone marrow sinusoids. Finally, platelets are sequentially released from the ends of proplatelet tips by the shear forces present the blood stream. Conditions that cause insufficient platelet production or accelerated platelet clearance pose a risk for excessive bleeding. Unraveling the mechanisms involved in platelet formation could therefore provide new options for therapeutic interventions.
Platelet formation is a highly cytoskeletal mechanics driven process. Similarly, cytoskeletal rearrangements are a prerequisite for platelet activation, including the change from discoid to spheric shape, granule release and eventually adhesion and spreading on immobilized ligands. We investigate cytoskeletal dynamics during MK maturation, platelet biogenesis and platelet activation by using genetically modified mice. Our projects include on the one hand studies of mice with megakaryocyte/platelet-specific (Cre/loxP) loss of proteins of the Rho family of small GTPases, such as RhoA, RhoB and Cdc42 (in close collaboration with C. Brakebusch, BRIC, University of Copenhagen). In addition, the impact of actin-binding proteins, including Twinfilin 1/2a, Coactosin-like 1, Cyclase-associated protein 1/2 and Thymosin β4 in these processes is investigated.