Signaling pathways in exosomes biogenesis, secretion and fate

Abstract

Exosomes are small extracellular vesicles (30-100 nm) derived from the endosomal system, which have raised considerable interest in the last decade. Several studies have shown that they mediate cell-to-cell communication in a variety of biological processes. Thus, in addition to cell-to-cell direct interaction or secretion of active molecules, they are now considered another class of signal mediators. Exosomes can be secreted by several cell types and retrieved in many body fluids, such as blood, urine, saliva and cerebrospinal fluid. In addition to proteins and lipids, they also contain nucleic acids, namely mRNA and miRNA. These features have prompted extensive research to exploit them as a source of biomarkers for several pathologies, such as cancer and neurodegenerative disorders. In this context, exosomes also appear attractive as gene delivery vehicles. Furthermore, exosome immunomodulatory and regenerative properties are also encouraging their application for further therapeutic purposes. Nevertheless, several issues remain to be addressed: exosome biogenesis and secretion mechanisms have not been clearly understood, and physiological functions, as well as pathological roles, are far from being satisfactorily elucidated.

Figure 1

The biogenesis of exosomes and their interaction with target cells. Exosomes originate from multivesicular bodies (MVBs), late endosome-derived cell compartments, which bud off parts of their limiting membrane into their lumen, forming intraluminal vesicles. MVBs can either fuse with the lysosome for degradation or with the plasma membrane to release exosomes into the extracellular space. Exosomes mediate cell-to-cell communication through different mechanisms of interaction with target cells. (A) Exosomes activate intracellular signaling by ligand-receptor interaction, without internalization. (B) Extracellular proteases cleave exosomal membrane proteins, releasing soluble ligands that bind to target receptors on the cell surface. (C) Target cells take up exosomes by membrane fusion, so exosomes release their content into the cytoplasm. (D) Target cells internalize exosomes by endocytic mechanisms (phagocytosis, macropinocytosis or receptor-mediated endocytosis).