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At the dawn of the Human Genome Project, scientists embarked on a quest to decode the key to all human diseases. We believed that by understanding our DNA, we could unlock the mysteries of health and illness. However, as the project progressed, we realised the secrets of many diseases lay not in our genes, but in the realm of epigenetics.
Epigenetics reveals that while every cell in our body contains the same genetic blueprint, they perform vastly different functions due to epigenetic regulation. One of the most intriguing elements of epigenetics is the role of small RNAs. These small RNAs are enriched in extracellular particles (EPs) released by cells.
Cells communicate by exchanging molecules. Some of the molecules as small RNAs are sensitive to environmental conditions and need to be wrapped in a protective packaging. EPs provide stable long-distance travel for molecules to reach other cells. Certain molecules require a liquid environment for transportation, necessitating a more specialized vehicle: extracellular vesicles (EVs).
VESICLE STRUCTURE
External protein markers provide information about donor and recipient cells, similarly like a labelling tag with a specific data about the sender and an address directing the package to the right addressee.
Vesicles have lipid bilayer that protects their bioactive cargo similarly as an envelope or packaging box and allows vesicle content to reach distant recipient cells without damage.
Biomolecules are carrier inside their membranous envelope. For example, stem cell exosomes carry more than 170 miRNA regulating over 10 key signalling pathways1, over a thousand of different proteins related to 10 distinct bioactivity clusters, and nearly 2000 lipid species from 22 lipid classes2.
PARTICLE BIOGENESIS AND CLASSES
Among these particles, a particular type stands out due to its unique formation within cells: exosomes. Exosomes are formed from intracellular membrane compartments during endosomal maturation process and released to extracellular space from the multivesicular body (MVE). Extracellular fluids and larger biomolecules enter cells usually by endocytosis resulting in early endosome. The endosome further matures by exchanging cargo with intracellular compartments such as Golgi complex (G), endoplasmic reticulum (ER), nucleus (N), mitochondria (Mito). At this stage, endosome might fuse with autophagosome or lysosome and have their cargo degraded, or form MVE that can dock at the plasma membrane and release vesicles into extracellular space as exosome.
Another large class of vesicles are ectosomes ranging in size from 30 nm to 10 μm. They bud directly from the plasma membrane into the extracellular space. Microvesicles, oncosomes, small ectosomes, arrestin domain-containing protein 1-mediated microvesicles (ARMMs) are all ectosomes but they differ in size, molecular composition, and mechanistic details of their release.
Increasingly appreciated are non-vesicular extracellular particles (NVEPs). NVEPs were demonstrated not only well-known entities, such as lipoprotein particles, nucleosomes, and vaults, but also recently discovered exomeres and supermeres.
The expanding world of EVs and NVEPs is largely due to improvements in techniques and methodology, as well as the growing awareness of their complexity and heterogeneity, which has spurred an active search for new particle subsets.
G – Golgi complex, ER – endoplasmic reticulum, Mito – mitochondria, N – nucleus, Lyso – lysosome, MVE – multivesicular body, EE – early endosome
EXTRACELLULAR PARTICLES ARE EPIGENETIC POWERHOUSES
After travelling large distances both EVs and NVEPs can be recognised and internalised by both neighbour and distant cells. Their reinternalised cargo is further processed similarly as de novo formed endosome.
Extracellular particles carry a treasure trove of small RNAs, making them significantly more potent than purified extracts or natural products. Extracellular particles stimulate regeneration and modulate immunity by affecting gene transcription, protein synthesis, and signalling pathways.
EPs also contain pre-assembled protein complexes, proteoglycans, and lipids that function like prefabricated building blocks. These components can be readily used in cellular molecular construction without the need for de novo synthesis, providing a tremendous energy advantage.
Find out more about extracellular particles in our animated explanation by clicking here.
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EXOLITUS, UAB
Kaunas, Lithuania Corp. ID 305464858
Kaunas, Lithuania Corp. ID 305464858
info@exolitus.com
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