Extracellular vesicle biogenesis

How are extracellular vesicles formed?

By Maarten Danial, PhD

A way to distinguish between the subtypes of extracellular vesicles (EVs) is through the mechanism of biogenesis. Exosomes find their origins as endosomes, where the membrane folds (invaginates) and takes up cytoplasmic contents in the process of forming intraluminal bodies.[1] These early endosomes mature into multivesicular bodies (MVBs) where their contents are processed. As an example, the post-translational modifications (PTMs) found on proteins can be removed or simplified as the processing takes place. Further maturation of the MVBs will lead to a subpopulation fusing with the cell surface membrane, taking membrane proteins in the process and releasing the intraluminal bodies as exosomes into the extracellular space.[2]

Microvesicles are extracellular vesicles formed by the budding of the cell surface membrane and are typically larger in size (100 to 1000 nm) than exosomes.[3] The budding process starts off with a redistribution of the cell membrane, which coincides with the actomyosin contractile machinery. Studies have shown that there is a depletion of cholesterol in the plasma membrane in nascent microvesicles.[4] Although it is not well understood, microvesicles often contain cytoskeletal proteins such as actin and tubulin.[5] Other active cytoplasmic proteins may be incorporated into the microvesicles depending on the type of target cell.

Apoptotic bodies represent the largest class of extracellular vesicle with sizes ranging from 1 to 5 μm in diameter. They are produced by blebbing of the cell membrane during cell death through the formation of protrusions known as apoptopodia.[6] In the process of forming, the apoptopodia enclose cellular contents including cell organelles, nuclear DNA, fragmented nucleic acids, and cytoplasmic proteins. As a result, the composition of apoptotic bodies does not differ greatly from the cell lysate.

How are extracellular vesicles formed

References

[1] T. Wollert & J. H. Hurley Nature (2010), 464, 864–869.
[2] R. M. Johnstone et al. J. Biol. Chem (1987). 262, 9412–9420.
[3] M. Mathieu, L. Martin-Jaular, G. Lavieu, C. Théry Nat. Cell Biol.(2019), 21, 9–17.
[4] I. del Conde, C. N. Shrimpton, P. Thiagarajan, J. A. Lopez Blood (2005), 106, 1604 – 1611.
[5] G. Van Niel, et al. Nat. Rev. Mol. Cell Biol. (2018), 19, 213–228.
[6] I. K. Poon, et al. Nature (2014) 507, 329–334.

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