Study sheds light on how extracellular vesicles mediate intercellular communication

A new study describes a key molecular mechanism that explains how cells exchange information through extracellular vesicles (EVs), small particles with great therapeutic potential. The results, published in the Journal of Extracellular Vesicles, reveal that the Commander protein complex, previously known for its role in membrane recycling, also coordinates the entry and internal destination of vesicles within the cell. This finding sheds light on the process of intercellular communication, which is fundamental to the development of new therapies and diagnostic tools.

The study was led by Professor Albert Lu, from the Faculty of Medicine and Health Sciences of the UB and the CELLEX Biomedical Research Centre (IDIBAPS-UB), and María Yáñez-Mó, from the Severo Ochoa Centre for Molecular Biology (CSIC-UAM). Carles Enrich, professor at the same faculty (IDIBAPS-UB), also participated. 

According to Albert Lu, "understanding how receptor cells capture and process extracellular vesicles is essential to understanding how our body communicates at the molecular level." "Furthermore - he continues - this knowledge is key to harnessing the therapeutic and diagnostic potential of these vesicles, since their effectiveness depends on being able to direct them and have them captured by the appropriate target cells."

An innovative methodology based on the CRISPR technique

Extracellular vesicles (EVs) are nanoparticles secreted by all cells that act as biological messengers: they transport proteins, lipids and nucleic acids. To identify the molecular mechanisms that direct their uptake and internalization in the cell, researchers have used an innovative methodological approach consisting of applying massive genomic screening based on CRISPR-Cas9 technology.

This tool allows researchers to deactivate each of the more than 20,000 human genes one by one, to analyse their role in the process. In this case, the researchers genetically modified the cells so that each group had a different gene deactivated. The cells were then exposed to EVs labelled with a fluorescent dye and, using flow cytometry, the cells that captured more or fewer vesicles were measured. Fluorescence-activated cell sorting (FACS) was then used to separate the cells with higher or lower uptake capacity. The deactivated genes in each group were subsequently identified using mass sequencing.

This systematic and unbiased approach allows us to discover new regulators without relying on prior hypotheses, unlike traditional techniques that focus on specific candidates."

Professor Albert Lu, Faculty of Medicine and Health Sciences of the UB and the CELLEX Biomedical Research Centre (IDIBAPS-UB)

The results indicate that the Commander endosomal recycling complex, formed by various proteins, acts as a fundamental and general regulator of vesicle uptake. The fact that the study was conducted on different human cell lines suggests that "the mechanism is conserved and potentially universal, although its activity could vary depending on the cell type or physiological context," adds the researcher.

Potential for new regenerative, oncological or anti-inflammatory therapies

Understanding this process has important therapeutic implications, since the ability of these vesicles to cross membranes and reach specific tissues makes them potential natural vehicles for transporting drugs or therapeutic molecules. "Understanding how their entry, intracellular trafficking and delivery of their molecular cargo are regulated opens the door to designing EVs with controlled directionality, improving their efficacy in regenerative, oncological or anti-inflammatory therapies," Lu points out.

Researchers are currently working to gain a more detailed understanding of the role of the Commander complex in controlling the uptake and intracellular fate of these vesicles, as well as to determine whether this mechanism is maintained in other types of cells or tissues. They also wish to explore whether alterations in the complex could be involved in alterations in cell communication in pathological contexts, such as cancer or neurodegenerative disorders. "In the long term, the goal is to be able to manipulate this pathway to modulate communication between cells and improve the use of EVs as therapeutic and diagnostic tools," concludes the researcher.