The Power of Extracellular Vesicles

Our bodies are divided into tiny, powerful units called cells. All cells share common characteristics vital to their functions such as membrane-bound organelles and mitochondria. To meet the daily requirements of the body, cells specialize and express specific receptors to develop characteristics necessary for the task at hand. 

Cells within the body operate comparable to a well-managed restaurant, where each cell has a designated role crucial to the entity’s success. Similar to a restaurant; where notes and verbal orders are exchanged in a kitchen, cells produce signals by the release of molecules. These molecules are vital for coordinating cellular functions, from healing damage to digesting a meal. Every individual possesses trillions of cells, thus effective communication is necessary for our body to continue to operate to its expected level on a day-to-day basis.

How Do Cells Communicate with Each Other?

Cells communicate using various methods to ensure the body can execute its functions in an efficient and timely manner. 

The Endocrine System sends intercellular signals using hormones. Hormones are molecules released into the bloodstream and travel through the entire body delivering messages. If a cell possesses the right receptor, hormones act as keys to stimulate a response. Once these “keys” bind to a cell’s receptor they initiate a chain of events within the cell. For example, after a meal, our pancreas senses the rise in blood sugar (glucose) and releases the hormone insulin into the bloodstream. Insulin will bind to its specific receptor, allowing cells such as muscle and fat to absorb sugar from the blood to convert it into energy.

The Paracrine System sends intercellular signals to adjacent cells like chefs working side by side in the kitchen, where one chef will quickly hand instructions or ingredients off to another. Paracrine signaling provides immediate and more targeted intercellular communication. For example, after the body sustains an injury like a cut, the cells adjacent to the injury release paracrine signals to nearby blood vessels, causing them to constrict and reduce the bleeding. 

The Autocrine System utilizes the cell's ability to receive the same signal it releases; similar to a chef tasting their cooking and adjusting the recipe while the dish is in the pan. This system allows for the cell to self-regulate. Immune cells utilize the Autocrine System when they recognize an infection and release signals to stimulate their division and proliferation, helping to increase the number of cells combating the infection.  

The Juxtacrine System initiates intercellular communication through direct contact creating an immediate response. The Juxtacrine system uses cellular contact between one cell’s ligand and another. Cardiac cells use the Juxtacrine System for communication to coordinate heartbeats in a timely and reliable manner.  

The body has many different forms of communication, with each having its own set of challenges. In relation to their size, cellular messengers travel great distances, leaving them vulnerable to degradation or destruction leading to a failure to deliver the message. Enzymes circulating the human body like proteases and phosphatases are designed to protect the body from potentially harmful molecules but they can also break down and degrade these messages hindering cellular communication. To combat this issue, our bodies package important molecules into “lipid-bound” vesicles called extracellular vesicles (EVs). EVs are released for endocrine, paracrine, or autocrine communication to protect them from degradation or modification on their journey across the body. 

Extracellular Vesicles: Cellular Messengers and Treasures for Health

EVs are tiny entities carrying a vast array of biomolecules including proteins, carbohydrates, fatty acids, and nucleic acids. The scientific community previously believed them to be cellular waste causing them to have been overlooked for decades. As research progressed, a paradigm shift has occurred; and we have come to understand their crucial role in protecting and shuttling messages among cells.

EVs function as biological 'envelopes'. They carry and preserve the integrity of intercellular cell-state-specific messages across biological systems. The ‘cargo’ within each EV is a direct reflection of the cell’s status when the EVs are released. EVs can serve as a distress signal or a sign of well-being within the cell. This cellular mechanism allows for detailed  intra- and intercellular communication, vital for the body's sustainability and adaptability.

The three main types of EVs are exosomes, ectosomes, and apoptotic bodies; each varying in origin, pathway, content, and function. Exosomes are the smallest of the three, typically ranging from 30 to 100 nanometers in diameter. They are formed within the endosomal network of the cell. Ectosomes are larger, typically about 100 to 1,000 nanometers across, and they bud directly from the plasma membrane. Both exosomes and ectosomes facilitate intercellular signaling through cell-state-specific messages. These messages alert nearby and distant cells of ongoing trauma. In contrast, apoptotic bodies are the largest, varying from 1 to 5 micrometers, and as the name suggests, they arise from cells undergoing apoptosis, or programmed cell death. Their primary role is to prevent potentially harmful or unnecessary substances from contacting other cells by securely encapsulating these materials.

Due to their function of delivering messages among cells or safeguarding them, EVs are a gold mine for biomarkers in various fields. EVs have revolutionized diagnostic testing through the monitoring of biomarkers to aid in the early detection of diseases. These biomarkers can be linked to various diseases including cancer, neurological disorders, and cardiovascular conditions. The specificity and resilience of EVs make their clinical use invaluable in advancing our understanding and detection of complex diseases.

Building from their role as natural biomarkers, EVs present a novel avenue in therapeutic innovation. A prime example is XoFlo, an advanced therapeutic derived from the EVs of mesenchymal stem cells, which are known for their regenerative properties. These cells are meticulously harvested from the bone marrow of exceptionally fit donors, such as triathletes, ensuring robust and potent products. XoFlo has been recognized for its potential in treating severe COVID-19, offering hope for harnessing the body's intrinsic healing mechanisms to combat complex diseases.

Drawing upon the innate wisdom of our cellular communication systems and the pioneering potential of EVs, the future of medicine is poised for groundbreaking advancements in diagnosis and therapy. As we continue to unlock the secrets held within these tiny messengers, we are stepping into a new era of personalized and precision medicine that could reshape healthcare as we know it.

Written by Hash Brown Taha

Edited by Emmett Covello 

References

1.  Lightner AL, Sengupta V, Qian S, et al. Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicle Infusion for the Treatment of Respiratory Failure From COVID-19: A Randomized, Placebo-Controlled Dosing Clinical Trial. Chest. Dec 2023;164(6):1444-1453. doi:10.1016/j.chest.2023.06.024
2. Taha HB, Bogoniewski A. Analysis of biomarkers in speculative CNS-enriched extracellular vesicles for parkinsonian disorders: A comprehensive systematic review and diagnostic meta-analysis. Journal of Neurology. 2023;doi:https://doi.org/10.1007/s00415-023-12093-3
3. Taha HB, Bogoniewski A. Extracellular vesicles from bodily fluids for the accurate diagnosis of Parkinson's disease and related disorders: A systematic review and diagnostic meta-analysis. Journal of Extracellular Biology. 2023;2(11):e121. doi:https://doi.org/10.1002/jex2.121
4. Roudi S, Rädler JA, El Andaloussi S. Therapeutic potential of extracellular vesicles in neurodegenerative disorders. Review. Handbook of clinical neurology. 2023;193:243-266. doi:10.1016/B978-0-323-85555-6.00017-5
5. Gurung S, Perocheau D, Touramanidou L, Baruteau J. The exosome journey: from biogenesis to uptake and intracellular signaling. Cell Commun Signal. Apr 23 2021;19(1):47. doi:10.1186/s12964-021-00730-1
6. Dixson AC, Dawson TR, Di Vizio D, Weaver AM. Context-specific regulation of extracellular vesicle biogenesis and cargo selection. Nat Rev Mol Cell Biol. Feb 10 2023;doi:10.1038/s41580-023-00576-0
7. Hoshino A, Kim HS, Bojmar L, et al. Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers. Cell. Aug 20 2020;182(4):1044-1061 e18. doi:10.1016/j.cell.2020.07.009
8. Cheng L, Hill AF. Therapeutically harnessing extracellular vesicles. Nat Rev Drug Discov. May 2022;21(5):379-399. doi:10.1038/s41573-022-00410-w
9. Khadka A, Spiers JG, Cheng L, Hill AF. Extracellular vesicles with diagnostic and therapeutic potential for prion diseases. Cell Tissue Res. Apr 2023;392(1):247-267. doi:10.1007/s00441-022-03621-0
10. Hill AF. Extracellular vesicles and neurodegenerative diseases. Review. Journal of Neuroscience. 2019;39(47):9269-9273. doi:10.1523/JNEUROSCI.0147-18.2019
11. Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, Bremer N. Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19. Stem Cells Dev. Jun 15 2020;29(12):747-754. doi:10.1089/scd.2020.0080