Rethinking extracellular vesicles: more than just molecular messengers

Extracellular vesicles (EVs) have become a focal point of research in recent years, captivating scientists with their role in communication between cells and organisms. While their importance in disease processes and therapeutic applications is widely acknowledged, questions persist about their primary function. A new perspective by researchers at Harvard University challenges conventional thinking about EVs, suggesting that they serve as essential elements providing membrane area for long-distance, contact-dependent cellular communication based on protein-protein interaction.

Traditionally, EVs have been viewed as carriers of genetic information, but their potential for facilitating cellular communication through membrane interactions has been largely overlooked. The study introduces the concept that the significant membrane area provided by EVs enables membrane contact-dependent interactions, facilitating the lateral diffusion and sorting of membrane ligands such as proteins, polysaccharides, or lipids. This promotes avidity-driven effects and the assembly of co-stimulatory architectures at the EV-cell interface.

The four pillars of intercellular communication along the two axes of long/short distance and contact independent/dependent signalling.

One intriguing aspect of this perspective is the concept of vesicle-induced receptor sequestration (VIRS), wherein EVs confine and concentrate receptors at the EV contact site, leading to a dense local concentration of receptors into signalosomes. This process can dramatically enhance the signaling strength of EV-presented ligands compared to their soluble counterparts, by 10-1000-fold.

The implications of this perspective are significant, not only for advancing our understanding of EV biology but also for EV-based applications and therapeutics. By shifting the focus from the content of EVs to their unique biophysical properties as presentation platforms for long-distance, contact-dependent signaling, researchers may uncover new avenues for harnessing the potential of EVs in various fields.

Moreover, considering the role of EVs in immune evasion mechanisms employed by virus-transformed or cancer cells adds another layer of complexity to their functional significance. Understanding how these cells exploit EV-mediated signaling mechanisms could lead to the development of innovative strategies to counteract immune evasion and combat diseases more effectively.

Jahnke K, Staufer O. (2024) Membranes on the move: The functional role of the extracellular vesicle membrane for contact-dependent cellular signalling. J Extracell Vesicles 13(4):e12436. [article]

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