A recent study has identified a key molecular mechanism involved in how cells communicate through extracellular vesicles (EVs), which are small particles that can transport proteins, lipids, and nucleic acids between cells. The research, published in the Journal of Extracellular Vesicles, highlights the role of the Commander protein complex in coordinating both the entry and internal routing of these vesicles within recipient cells.
The study was led by Professor Albert Lu from the Faculty of Medicine and Health Sciences at UB and CELLEX Biomedical Research Centre (IDIBAPS-UB), along with María Yáñez-Mó from the Severo Ochoa Centre for Molecular Biology (CSIC-UAM). Carles Enrich, also from IDIBAPS-UB, participated in the project.
Professor Lu explained, "understanding how receptor cells capture and process extracellular vesicles is essential to understanding how our body communicates at the molecular level." He added, "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."
To investigate how EVs are taken up by cells, researchers used CRISPR-Cas9 technology for large-scale genomic screening. By systematically deactivating each human gene in different groups of genetically modified cells, they exposed these groups to fluorescently labeled EVs. Using flow cytometry and fluorescence-activated cell sorting (FACS), they measured and separated cells based on their ability to absorb EVs. Mass sequencing then identified which genes were deactivated in each group.
Findings indicate that the Commander endosomal recycling complex acts as a general regulator for vesicle uptake across various human cell lines. This suggests that "the mechanism is conserved and potentially universal, although its activity could vary depending on the cell type or physiological context," according to Lu.
This research has implications for therapy development because EVs’ ability to cross membranes allows them to serve as natural carriers for drugs or other therapeutic molecules. As Lu noted, "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."
Ongoing work aims to clarify further details about how the Commander complex influences vesicle uptake and intracellular processing across different tissues. Researchers also want to determine if disruptions in this pathway may affect cellular communication in diseases 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," concluded Lu.
