Extracellular vesicles and nanoparticles: emerging complexities

Abstract

The study of extracellular vesicles (EVs) and nanoparticles (NPs) is rapidly expanding because recent discoveries have revealed a much greater complexity and diversity than was appreciated only a few years ago. New types of EVs and NPs have recently been described. Proteins and nucleic acids previously thought to be packaged in exosomes appear to be more enriched in different types of EVs and in two recently identified amembranous NPs, exomeres and supermeres. Thus, our understanding of the cell biology and intercellular communication facilitated by the release of EVs and NPs is in a state of flux. In this review, we describe the different types of EVs and NPs, highlight recent advances, and present major outstanding questions.

Keywords: ectosomes; exomeres; exosomes; extracellular vesicles; microvesicles; supermeres.

Figure 1.. The world of extracellular vesicles and nanoparticles.

Most mammalian cells are between 10 to 100 μm in diameter and can release a diversity of heterogenous EVs and NVEPs ranging in size from about 5 nm up to more than 5 μm. The overlapping sizes of many EVs and NVEPs make it difficult to separate them completely. ACLY, ATP citrate lyase; ARMM, arrestin domain-containing protein 1-mediated microvesicle; ARRDC1, arrestin domain-containing protein 1; FASN, fatty acid synthase; HDL, high-density lipoprotein; HSPA13, heat shock protein family A (Hsp70) member 13; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; MVP, major vault protein; SMAP, supramolecular attack particle; TGFBI, transforming growth factor beta-induced; TSP1, thrombospondin 1; VLDL, very-low-density lipoprotein.

Figure 2.. Current understanding of the biogenesis pathways of EVs and select nanoparticles.

The ectosome class of EVs, ranging in size from 30 nm to 10 μm, are generated by direct outward budding of the cell plasma membrane into the extracellular space. Microvesicles, large oncosomes, small ectosomes and ARMMs are ectosomes but they differ in size, molecular composition, and mechanistic details of their release. Microvesicles, small ectosomes and ARMMs are secreted from both normal and cancer cells while large oncosomes are released from cells having undergone malignant transformation. Apoptotic bodies and vesicles range in size from 100 nm to 5 μm and are released when cells undergo apoptosis. Inward budding of the limiting membranes of late endosomes generates intraluminal vesicles (ILVs) causing formation of multivesicular endosomes (MVEs). The MVEs may traffic to lysosomes for degradation or to the cell surface for fusion with the plasma membrane whereupon the ILVs are released to the extracellular space as 30 – 120 nm exosomes. Alternatively, the MVE may fuse with an autophagosome to generate a hybrid organelle, termed the amphisome. Amphisomes may traffic to lysosomes for degradation or to the plasma membrane for release of its contents to the extracellular space. Migrasomes are 500 nm to 3 μm EVs that are released from the retraction fibers of migrating cells and are dependent on the formation of tetraspanin- and cholesterol-enriched microdomains. Exophers are large, 3.5 – 4 μm EVs that contain damaged mitochondria and protein aggregates that appear to be released under stress conditions to maintain tissue homeostasis. The exact release mechanism of exophers is currently unknown but may involve autophagic machinery. Exomeres and supermeres are amembranous 20 – 50 nm nanoparticles released from both normal and cancer cells, and they can be detected in the circulation. They are enriched for specific proteins and nucleic acids compared to EVs but the biogenesis of exomeres and supermeres is currently unknown.