Main takes on exosome biogenesis
Regarding biogenesis of extracellular vesicles, three different pathways are described in the literature corresponding to the three original subtypes. The exocytosis of exosomes follows an endosomal pathway: lipids, proteins, and nucleic acids to be secreted are transported to a multivesicular body (MVB) into intraluminal vesicles (ILVs). MVBs will fuse with the plasma membrane, releasing ILVs as exosomes in the extracellular environment (Schorey et al, 2015). Microvesicles or ectosomes are directly shed from the plasma membrane. The molecular cargo follows a vertical trafficking to the plasma membrane, then by modification of membrane lipids, and budding of cytoplasmic protrusions, the vesicle is secreted (Tricarico, Clancy, and D’Souza-Schorey 2017). Finally, apoptotic bodies are secreted by cells in both pathological and physiological conditions when programmed cell death is engaged. Plasma membrane is blebbing, delivering a large vesicle into the extracellular matrix (Gustafson et al, 2017).
Once released into the extracellular environment, extracellular vesicles are transported to a target cell via body fluids. The target can be local (autocrine and paracrine effect) or far from the parent cell (endocrine effect) (Zhang et al. 2014). Even though the EV-cell interaction is still unclear and specific molecular drivers of EV-cell interaction are unknow, three general cell-EV uptake mechanisms are described in the literature. First, extracellular vesicles can have a contact with target cells by interaction of surface proteins from both extracellular vesicle and cell membranes. The second uptake mechanism is the internalization of the exosome into the cell by endocytosis (phagocytosis or micropinocytosis). The last mechanism is the fusion between exosome membrane and plasma or endosomal cell membrane (Russell et al. 2019).