Fig. 3

Biogenesis of exosomes, and cellular uptake and journey of internalized and endogenously produced exosomes. a Biogenesis of exosomes. Extracellular constituents along with cell surface proteins enter cells through endocytosis of plasma membrane segments. This resulting plasma membrane bud leads to the formation of Early sorting endosomes (ESEs) or fuses with ESEs pre-formed by the constituents of the endoplasmic reticulum (ER), trans-Golgi network (TGN), and mitochondria. ESEs give rise to Late sorting endosomes (LSEs). Invagination in the LSE results in the Multivesicular bodys (MVBs) generation containing Intraluminal vesicles (ILVs) as future exosomes. MVBs can ultimately undergo degradation in the lysosomes with the degradation products recycled by the cells. MVBs can also be transported to the plasma membrane and dock on the luminal side of the plasma membrane. Exocytosis follows and results in the release of the exosomes. b Cellular uptake and journey of internalized and endogenously produced exosomes. In the recipient cell (which can be the exosome-producing cell itself), exogenous exosomes may be internalized by multiple pathways and can undergo various fates. Depending on the cell type, extracellular exosomes can dock either at the plasma membrane to release their intraluminal contents into the cytoplasm of recipient cell by fusion. They can remain bound to the surface (for example, to integrins) and initiate intracellular signalling pathways (for example, antigen presentation). Extracellular exosomes may also be internalized by various types of endocytosis: phagocytosis, micropinocytosis, clathrin-dependent endocytosis, lipid raft dependent endocytosis, and caveolae endocytosis. Internalization will target exogenous extracellular exosomes into the canonical endosomal pathway, whereby they reach MVBs, in which the internalized exosomes are likely to mix with endogenous ILVs. Exosome biogenesis and cellular uptake pathways intersection results in a composition of net production of mixed endogenous and exogenous exosomes population.