Exosomes Research

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What are exosomes?

Once thought to be carriers of unwanted cytosolic waste, extracellular vesicles (EVs) are now understood to be important mediators of intercellular communication under both physiological and pathological conditions. To emphasize the importance of EVs as intercellular messengers, it is worth noting that they have been observed in every Kingdom of life, from the smallest bacteria to every cell in the human body. Exosomes are the smallest EVs and are of particular interest in the tumor microenvironment (TME), where they have been shown to directly mediate angiogenesis, tumor metastasis, and immunosuppression.

EVs can be categorized into three main groups based on size, biogenesis, and function:


Exosomes
(small EVs)

Microvesicles (medium/large EVs)

Apoptotic bodies
(large EVs)

Size 30-150 nm 100-1000 nm Up to 5000 nm
Biogenesis Endosomal Budding Apoptosis
Function Intercellular communication (varied) Intercellular communication (varied) Contain intracellular contents from apoptotic cells

Request a copy of our Apoptosis, Necroptosis, and Autophagy Poster


In place of specific nomenclature relating to biogenesis (e.g. exosome, microvesicle, apoptotic body), the International Society of Extracellular Vesicles (ISEV) recommends referring to EVs based on the following:


Physical Characteristics

Biochemical Composition

Origins

Description Size (small, medium/large) Density (low, medium, high) Specific protein, lipid, or genomic content Cell type, treatment conditions
Examples Small EVs (sEVs): <200 nm Medium/large EVs (m/lEVs): >200 nm CD81+, CD9+, Annexin V+, EpCAM+, EGFR+, miRNAs Neuronal, epithelial, tumor-derived, hypoxic

For example, if isolating EVs from hypoxia-treated neurons using differential centrifugation and ultrafiltration, they would be “small hypoxic neuronal EVs.” The most stringent way to verify the endosomal nature of exosomes is visually by electron microscopy.


Exosome Biogenesis: How are they made?



Exosomes are formed in the endosomal maturation pathway. Briefly, inward budding of endosomes into multivesicular bodies (MVBs) results in the formation of intraluminal vesicles (ILVs). MVBs are destined for one of two fates: degradation or release. MVBs destined for degradation will either (A) fuse directly with the lysosome or (B) fuse with an autophagosome during the process of autophagy. This "amphisome" (MVB plus autophagosome) finally fuses with the lysosome. Alternatively, MVBs destined for release, traffic to the plasma membrane. Upon fusion with the plasma membrane, ILVs are secreted as exosomes via exocytosis.” The rate at which exosomes are secreted varies depending on the cellular source, but certain pathologies, like cancer or hypoxia, can increase the rate of EV release.

MVs, in contrast, are vesicles formed directly from the outward protrusions of the plasma membrane and involve cytoskeletal and membrane rearrangement. Both exosomes and MVs are actively secreted from live cells. Apoptotic bodies are unique EVs as they are only formed during programmed cell death, or apoptosis, and are rapidly phagocytosed by patrolling macrophages.


Exosome Function: What do they do?

EVs are secreted with a diverse array of cargo necessary for intercellular communication, both locally and in distant tissues. This cargo includes genetic information such as messenger RNA (mRNA), microRNA (miRNA), non-coding RNA (ncRNA), as well as lipids and many classes of proteins. Novus Biologicals has an extensive offering of antibodies to “essential” exosome markers, as well as tissue and tumor-specific exosome markers validated for a range of applications including Simple Western and Flow Cytometry.

Exosomes and MVs are actively released from many cell types including reticulocytes, lymphocytes, dendritic cells, fibroblasts, endothelial cells, and stem cells as part of a range of dynamic intercellular signaling processes.


Roles of Extracellular Vesicles



The Future of Exosomes

The number of applications for exosomes is constantly increasing. In addition to their role as biomarkers for cancers and other diseases, their vesicular nature and wide range of functions make them attractive candidates for therapeutic delivery, regenerative medicine, and vaccine adjuvants.


Biomarkers

Therapeutic Delivery

Regenerative Medicine

Vaccine Adjuvants

Proteins and genetic markers found in exosomes can serve as indicators of disease prognosis and progression.

  • Cancer
  • Cardiovascular Disease
  • Diabetes Meletus
  • Rheumatoid Arthritis
  • Alzheimer's
  • Parkinson's

Vesicles carrying small molecules can avoid some of the pitfalls associated with therapeutic-delivery.

  • Stable over long-distances
  • Carriers of vaccine antigens (mRNA, DNA)
  • Transport of water-soluble molecules
  • Potential to cross membranes (Blood-Brain-Barrier)

Mesenchymal stem/stromal cell (MSC)-derived exosomes have potential to promote tissue repair and regeneration through angiogenesis and cell propagation in preclinical models of:

  • Liver Disease
  • Cardiac Disease
  • Neuronal Disease
  • Cartilage Repair
  • Lung Fibrosis

Dendritic cell (DC) derived exosomes can carry peptide-loaded MHC II molecules and activation markers

  • Smaller and less immunogenic than DC-based vaccine strategies

EVs from pro-inflammatory macrophages can potentiate inflammation

References:

Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018;7:. https://doi.org/10.1080/20013078.2018.1535750.


Kowal J, Arras G, Colombo M, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A. 2016;113(8):E968-E977. https://doi.org/10.1073/pnas.1521230113

Woith E, Fuhrmann G, Melzig MF. Extracellular Vesicles-Connecting Kingdoms. Int J Mol Sci. 2019;20(22):5695. Published 2019 Nov 14. https://doi.org/10.3390/ijms20225695


Van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 2018:213–28. https://doi.org/10.1038/nrm.2017.125.


Jadli, A.S., Ballasy, N., Edalat, P. et al. Inside(sight) of tiny communicator: exosome biogenesis, secretion, and uptake. Mol Cell Biochem 467, 77–94 (2020). https://doi.org/10.1007/s11010-020-03703-z


Bebelman MP, Smit MJ, Pegtel DM, Baglio SR. Biogenesis and function of extracellular vesicles in cancer. Pharmacol Ther 2018:1–11. https://doi.org/10.1016/j.pharmthera.2018.02.013.


Nikfarjam S, Rezaie J, Zolbanin NM, Jafari R. Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine. J Transl Med 2020:449. https://doi.org/10.1186/s12967-020-02622-3.