ABSTRACT
Exosomes as secreted vesicles were first reported in 1983 by Johnstone et al. While studying maturing reticulocytes (immature erythrocytes) by electron microscopy (EM), small 100 nm vesicles were observed on the outside of the cells. Immature erythrocytes are the precursors of red blood cells and contain cytoplasmic ribosomes and remnants of organelles such as mitochondria, the endoplasmic reticulum (ER), the Golgi apparatus, and an intact endosomal system.1 During their differentiation into mature erythrocytes, the ribosomes and other organelles are lost and several plasma membrane proteins are cleared, resulting in a decrease in size and loss of some specific
plasma membrane activities. The secretion of these vesicles termed “exosomes” was conceived as an unconventional mechanism to eliminate unwanted materials like proteins and lipids that facilitated maturation and loss in size. While the maturing reticulocytes clearly seem to benefit from exosome secretion, the exact role and fate of the expelled exosomes remained unknown.2-4 Similarly, the nonnucleated platelets (thrombocytes) also secrete large amounts of extracellular vesicles (EVs), including exosomes,5 as do their immature progenitors, the megakaryocytes.6 In the last decade it has become clear that most, if not all, cell types have the ability to secrete exosome-like vesicles in vitro,7 and widespread dispersal of exosomes in vivo has been established.8 Importantly, more recent, detailed molecular and cell biological studies yielded important new clues into the molecular mechanism(s) behind their biogenesis, sorting, secretion,8-14 and the finding that exosomes can transfer active signaling molecules to recipient cells.15,16 The interest became even higher as exosomes from mammalian cells also seem to influence cellcell communication rather unexpectedly through their ability to carry and transfer functional genetic material.17-22 These findings are supported by findings that human (tumor) viruses exploit this pathway for their benefit21-23 and that micro-ribonucleic acids (miRNAs) can cross a functional immunological synapse in vitro24 and possibly in vivo,25,26 but for the most part, physiological evidence for the role of exosome secretion in vivo has not been established. An exception to this rule are immune cell-derived exosomes that have recognized physiological properties in mice and humans.8 This may be partly for historic reasons since functional exosomes were shown to be secreted by immune cells first, but also due to the detailed understanding of the molecular mechanisms behind antigen processing, loading, and sorting in the endocytic pathway.
