Investigation of the functional and structural role of podosomes in megakaryocytes

Schachtner, Hannah (2013) Investigation of the functional and structural role of podosomes in megakaryocytes. PhD thesis, University of Glasgow.

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Abstract

Megakaryocytes (Mks) give rise to platelets via extension of proplatelet arms, which are released through the vascular sinusoids into the bloodstream. Mks and their precursors undergo varying interactions with the extracellular environment in the bone marrow during their maturation and positioning in the vascular niche. The dynamic remodeling of the actin cytoskeleton and the formation of cell -matrix contacts such as podosomes are fundamental for this process. However, the role and function of podosome structures in Mks are poorly understood. Podsomes are well characterized in different cell-types of the myeloid lineage such as macrophages and dendritic cells. Their formation is associated with a dynamic F-actin turnover, fascilitated cell migration and the degradation of extracellular matrix (ECM). The function of podosome organelles is multifaceted and is described in association with cell adhesion, motility, ECM lysis, invasion and mechanosensors. A fundamental analysis of podosomes was necessary to define a potential function for these structures in Mks. I determined an abundant formation of classical podosomes with an F-actin core and a Vinculin ring in primary murine Mks, which were adherent on different physiological relevant ECM substrates such as fibrinogen, collagen I and a native basement membrane. Lifetime analysis was performed and was demonstrated to be dependent on the substrate as well as on Myosin-II activity. Another key feature of podosomes, the degradation of ECM proteins, could be detected and was mediated in an MMP associated manner. Furthermore, I verified that podosomes are necessary to penetrate a native basement membrane, which is amongst others part of blood vessels. II In this thesis I therefore demonstrate multifaceted properties of Mk podosomes and direct a potential function of these structures in the process of Mk maturation and possibly in platelet formation

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: podosomes, cell adhesion, cell migration, megakaryocytes
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences > Beatson Institute of Cancer Research
Funder's Name: UNSPECIFIED
Supervisor's Name: Machesky, Dr. L.M.
Date of Award: 2013
Depositing User: Dr. HS Schachtner
Unique ID: glathesis:2013-4032
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 01 Mar 2013 10:59
Last Modified: 01 Mar 2013 11:06
URI: http://theses.gla.ac.uk/id/eprint/4032

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