Cells release membrane vesicles which mediate pathological progression and can be used as biomarkers to detect and monitor illness.

Cells release various types of membrane vesicles under physiological and pathological conditions. Although these vesicles vary widely in origin they share several common traits. They are all approximately spherical, contain soluble proteins in their lumen and are bounded by a lipid bilayer similar to other membranes in the cell. This lipid bilayer displays the luminal surface of the membrane from which the vesicle formed. For example, a vesicle formed from the plasma membrane will outwardly display the extracellular surface of the plasma membrane. This is in contrast to intracellular vesicles which enclose their luminal surface [1].

Exosomes are formed as part of the endosomal pathway within eukaryotic cells. Invagination of the plasma membrane forms early endosomes which mature into late endosomes. During the maturation process the limiting membrane of the early endosomes undergoes invagination forming small vesicles in the lumen of the endosome. In the classical endosomal pathway the late endosomes fuse with the lysosomes and the contained vesicles and proteins are degraded. However, in 1985, it was demonstrated that the late endosomes can also fuse with the plasma membrane which releases the contents of the late endosome into the extracellular space [2]. The released vesicles are termed exosomes [3].

Since first being observed, evidence has accumulated that exosomes are more than inert particles to be expelled from the body and have a variety of biological roles mediated by their proteome. In addition to release during reticulocyte maturation exosomes are also involved in morphogen signalling and a variety of immunological activities [4-6]. Argosomes, which appear identical to exosomes, have been described [7, 8] as a mechanism for the dispersal of morphogens, specifically Wingless in Drosophila, and the creation of the morphogen gradient. Exosomes have both immuno-stimulatory and immuno-inhibitory activities depending on the context. B cells which have been transformed with Epstein-Barr virus release exosomes which can activate CD4+ T cells. This activation is antigen specific [9]. Dendritic cells which have been pulsed with peptides from tumours release exosomes which support tumour rejection. Again, this activity is antigen specific [10, 11]. Exosomes released from melanoma [12], prostate [13] and mammary [14] tumour cells have been shown to mediate lymphocyte apoptosis and may be involved in tumour immune evasion. Intestinal epithelial cells release exosomes which may mediate antigen presentation in the mucosal and systemic immune system and be involved in tolerance [15]. During pregnancy exosomes of placental origin are present in the maternal circulation and may be involved in the deletion of reactive lymphocytes [16, 17]. Exosomes may also be involved in the progression of neurological disease. β-amyloid peptide which is involved in the pathogenesis of Alzheimer’s disease is released from cells in association with exosomes [18]. Prion infectivity is released from neuroblastoma cells in association with exosomes in vitro [19-21] and in vivo is present in exosomes purified from the cerebrospinal fluid of sheep [22].

Potential roles for exosomes have been described in a variety of different systems. Intensive study of exosomes, at least in the context of disease, has only really begun in the past decade and there are still many unknowns. I have been studying exosomes in two distinct systems; the kidneys and the central nervous system.

I have been using a cell model of the collecting duct in the kidney to study how changes in the cell alter the exosomes released.

In the central nervous system I’ve been using mass spectrometry [23] to study the proteome of exosomes as a potential source of biomarkers for disease.

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