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Ansa-Addo, Ephraim A. (2010) Plasma membrane-derived vesicles: composition and function. Doctoral thesis, London Metropolitan University.
Plasma membrane-derived vesicles (PMVs) are small, intact, membrane vesicles, which are released by most cells upon activation with various extracellular stimuli. This study identified that procedures used in the isolation of PMVs could be further improved by first sonicating (sonicating water-bath) samples prior to isolation of PMVs. Following water-sonication, centrifugation of cell-debris-free supernatants at 25,000 g for 2 h, yielded mostly PMVs with minimal contamination with exosomes.Agents (Histamine, PMA, ATRA) currently used in differentiation therapy for the treatment of acute myelocytic leukaemia (AML), are reported here to induce the release of PMVs from various cells and to halt the overproliferation of THP-1 promonocytes in vitro. Further investigations with the TGF-p receptor antagonist, SB-431542, showed that this inhibition was due to TGF-ß1 present on PMVs, which initiates TGF-ß signalling.
This thesis also identified a novel host cell entry strategy involving PMVs, employed by T. cruzi during infection. T. cruzi metacyclic trypomastigotes trigger the release of PMVs through integrins, lipid raft microdomains and Cat' channels such as stretchactivated channels (SAC) from several cell types. Released PMVs bound to the surface of T. cruzi and abolished its complement-mediated lysis by inhibiting activation of the C3 convertase. These PMVs also carried TGF-ß, which enhanced mammalian cell invasion by T. cruzi metacyclics. Furthermore, T. cruzi-elicited release of PMVs, results in damage to the host plasma membrane. Parasites take advantage of the resulting membrane breach to enter cells before lysosomal membrane repair. Together, these results postulate important functions for PMVs in both mammalian cells and pathogens.
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