Extracellular vesicles are membrane-bound particles released by cells that serve as crucial mediators of intercellular communication, carrying proteins, lipids, and nucleic acids. Their significance extends across a wide range of physiological processes, including immune responses, tissue repair, and development, and they are also implicated in various pathological conditions, such as cancer and neurodegenerative diseases.
But, how do extracellular vesicles influence cell signaling pathways, ultimately impacting both normal and disease states?
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What Are Extracellular Vesicles?
Extracellular vesicles encompass a heterogeneous group of membrane-bound particles, including exosomes, microvesicles, and apoptotic bodies, each with distinct biogenesis pathways.
Exosomes originate from multivesicular bodies (MVBs) that fuse with the plasma membrane, releasing vesicles containing selected cargo such as RNAs, proteins, and lipids. Microvesicles bud directly from the plasma membrane, carrying a different set of biomolecules. Apoptotic bodies, released during cell death, contain cellular debris, including fragments of the nucleus, cytoplasm, and organelles.
Extracellular vesicles are secreted through various mechanisms (e.g., exocytosis). They act as crucial mediators in cell-to-cell communication pathways by transferring their cargo to recipient cells and ultimately altering cellular signaling networks and functions.
Mechanisms of Action in Cell Communication
Extracellular vesicles play a crucial role in cell-to-cell communication and exhibit therapeutic potential. Specific cargo loading regulates cellular responses1.
They transfer molecules to recipient cells via direct fusion with the plasma membrane, receptor-mediated endocytosis, and phagocytosis, thus delivering their transported compounds (i.e., proteins, RNAs, lipids, etc.).
Extracellular vesicles play a pivotal role in modulating immune responses by presenting antigens, transferring signaling molecules, and influencing immune cell activation. For instance, they deliver microbial antigens to antigen-presenting cells (APCs), triggering immune responses and contributing to antimicrobial host defense2,3.
Thus, extracellular vesicles influence the activation, differentiation, and proliferation of immune cells, ultimately enhancing or suppressing immune responses2.
Extracellular vesicles can also interact with the extracellular matrix (ECM), contributing to its homeostasis in physiological contexts like angiogenesis and wound healing. ECM maintenance is crucial for various physiological processes and contributes to avoiding a wide range of disease states, such as those involved in fibrosis, cancer, and arthritis4.
Extracellular Vesicles - the cells' secret messengers - Scientific version
Role in Health and Disease
As described above, extracellular vesicles have been involved in the pathogenesis of various diseases, including chronic liver disease, cancer, and neurodegenerative diseases. For instance, extracellular vesicles are significantly elevated in chronic liver disease, carrying altered cargo that enhances inflammation, fibrosis, and angiogenesis, ultimately exacerbating disease progression5.
Moreover, in conditions like Alzheimer's and Parkinson's, extracellular vesicles transport misfolded proteins and altered genetic material, potentially spreading pathogenic proteins and serving as biomarkers for such diseases6.
Extracellular vesicles display great potential as therapeutic agents across various medical fields, including cancer, cardiovascular, and autoimmune diseases. In cardiovascular diseases, for instance, extracellular vesicles offer unique opportunities as therapeutic agents due to their stability and ability to carry bioactive molecules7.
Tumor-derived extracellular vesicles (TEVs), which can be defined as small particles released by cancer cells, play a significant role in intercellular communication within the tumor microenvironment.
TEVs carry a variety of bioactive molecules, including proteins, nucleic acids, and lipids, which can influence cancer progression and serve as potential biomarkers for diagnosis and treatment. They influence the tumor microenvironment through various mechanisms, including the transfer of oncogenic molecules that alter cellular behavior and promote tumor progression8,9.
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Challenges and Future Directions
Technical challenges in EV research include the complexity of isolating pure EV populations, accurately characterizing their molecular cargo and function as cellular systems, and standardizing experimental protocols associated with the study of their transported molecules.
Improving the isolation of extracellular vesicles is crucial for effective use in diagnostics and therapeutics. Traditional methods like ultracentrifugation have limitations, prompting the development of modern techniques that enhance purity and yield. Size Exclusion Chromatography (SEC) is highlighted for its ability to isolate extracellular vesicles with higher purity and yield compared to other methods.
It can effectively separate extracellular vesicles from non-vesicular contaminants, making it a preferred choice for isolating small extracellular vesicles from complex fluids like plasma and tissues10,11.
Regarding future directions, bioengineering approaches are enabling the development of engineered extracellular vesicles with targeted delivery capabilities, enhancing their therapeutic potential.
This opens promising avenues for regenerative medicine, where extracellular vesicles can deliver bioactive compounds to damaged tissues, and drug delivery, where extracellular vesicles can serve as biocompatible and targeted carriers for therapeutic molecules, offering significant advantages over traditional drug delivery systems.
Conclusion
Extracellular vesicles play an essential role in intercellular communication by transferring molecular cargo and modulating recipient cell function, impacting both physiological and pathological processes.
Their promising applications in medicine and biotechnology span diagnostics, therapeutics, and regenerative medicine, offering non-invasive access to cellular information and the potential for targeted drug delivery.
Given their versatility and clinical relevance, continued research is crucial to fully understand EV biology, develop standardized protocols, and translate these findings into effective EV-based diagnostics and therapeutics, ultimately improving patient outcomes.
References
- Mir, B., & Goettsch, C. (2020). Extracellular Vesicles as Delivery Vehicles of Specific Cellular Cargo. Cells, 9. https://doi.org/10.3390/cells9071601.
- Kumari, P., Wright, S., & Rathinam, V. (2024). Role of Extracellular Vesicles in Immunity and Host Defense. Immunological Investigations, 53, 10 - 25. https://doi.org/10.1080/08820139.2024.2312896.
- Robbins, P., & Morelli, A. (2014). Regulation of immune responses by extracellular vesicles. Nature Reviews Immunology, 14, 195-208. https://doi.org/10.1038/nri3622.
- Lewin, Samuel, Stuart Hunt, and Daniel W. Lambert. "Extracellular vesicles and the extracellular matrix: a new paradigm or old news?." Biochemical Society Transactions 48.5 (2020): 2335-2345.
- Lee, C., Han, J., & Jung, Y. (2022). Pathological Contribution of Extracellular Vesicles and Their MicroRNAs to Progression of Chronic Liver Disease. Biology, 11. https://doi.org/10.3390/biology11050637.
- Hill, A. (2019). Extracellular Vesicles and Neurodegenerative Diseases. The Journal of Neuroscience, 39, 9269 - 9273. https://doi.org/10.1523/JNEUROSCI.0147-18.2019.
- Chong, S., Lee, C., Huang, C., Ou, Y., Charles, C., Richards, A., Neupane, Y., Pavón, M., Zharkova, O., Pastorin, G., & Wang, J. (2019). Extracellular Vesicles in Cardiovascular Diseases: Alternative Biomarker Sources, Therapeutic Agents, and Drug Delivery Carriers. International Journal of Molecular Sciences, 20. https://doi.org/10.3390/ijms20133272.
- Tai, Y., Chu, P., Lee, B., Chen, K., Yang, C., Kuo, W., & Shen, T. (2019). Basics and applications of tumor-derived extracellular vesicles. Journal of Biomedical Science, 26. https://doi.org/10.1186/s12929-019-0533-x.
- Arkhypov, I., Lasser, S., Petrova, V., Weber, R., Groth, C., Utikal, J., Altevogt, P., & Umansky, V. (2020). Myeloid Cell Modulation by Tumor-Derived Extracellular Vesicles. International Journal of Molecular Sciences, 21. https://doi.org/10.3390/ijms21176319.
- Bordas, M., Genard, G., Ohl, S., Nessling, M., Richter, K., Roider, T., Dietrich, S., Maass, K., & Seiffert, M. (2020). Optimized Protocol for Isolation of Small Extracellular Vesicles from Human and Murine Lymphoid Tissues. International Journal of Molecular Sciences, 21. https://doi.org/10.3390/ijms21155586.
- Brennan, K., Martin, K., Fitzgerald, S., O’Sullivan, J., Wu, Y., Blanco, A., Richardson, C., & Gee, M. (2020). A comparison of methods for the isolation and separation of extracellular vesicles from protein and lipid particles in human serum. Scientific Reports, 10. https://doi.org/10.1038/s41598-020-57497-7.
Further Reading