General Introduction and Objectives 11 1 Since then, EVs have been identified as a heterogeneous group of lipid bilayered membrane structures (30-8000 nm in diameter 6), and are classified into three major subtypes based on their mode of biogenesis (Figure 1). In addition to their mode of release, EV size is often used for characterization: exosomes are regarded as the smallest type of EVs (30 – 100 nm in diameter), microvesicles range from 100 to 1000 nm in diameter, and apoptotic bodies may reach sizes up to several micrometers 7. However, there is some controversy on nomenclature and sizes as different types of EVs overlap in their size distribution 8, 9. Therefore, the term ‘Extracellular Vesicle’, as used in this thesis, is used as a generic term for all secreted vesicles. EVs carry proteins on their surface and a variety of macromolecules as cargo (e.g., lipids, proteins, enzymes, nucleic acids, protein-coding mRNAs and regulatory microRNAs 10, 11), which are thought to reflect the status of their cell of origin. Upon contact with or internalization by recipient cells, EVs have the ability to transfer information from one cell to another, thus modulating recipient cell behavior 12. Therefore, EVs have been recognized as mediators of intercellular communication during both normal physiological as well as in pathological processes 10, 13. As EVs are excreted by virtually all cell types in the human body, they can be found in all body fluids, such as the blood 6, saliva 14 and urine 15, 16. Figure 1 - Exosomes, Microvesicles, and Apoptotic bodies. Exosomes (left) are released into the extracellular domain through fusion of multivesicular bodies (MVB) with the cell membrane. Microvesicles (middle) are formed through outward budding of the cell membrane, and apoptotic bodies (right) are fragments of cells which have undergone apoptosis. Adapted from Karpmann, et al. 17.
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