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With few exceptions, first generation stem cell therapies appear to produce their positive results, such as months-long suppression of chronic inflammation, via signaling generated by transplanted cells in the short time before they die. A sizable fraction of the signaling that passes between cells is carried within extracellular vesicles, small membrane-wrapped packages of molecules generated by one cell and taken up by another. There are many forms of extracellular vesicle, largely classified by size at the present time in absence of a better understanding of function. Research has shown that harvesting vesicles from stem cells in culture and then transplanting those vesicles can produce similar benefits to transplanting the cells themselves, while being a much easier proposition from the point of view of the cost and logistics of storage, delivery, and quality control.

Nonetheless, the use of extracellular vesicles in therapy retains many of the challenges of the use of cells in therapy. Standardization is very hard. Too little is known of how to constrain cells to produce specific vesicles and vesicle content. One still needs to source and manage the cells that generate the vesicles in the first place. Outcomes vary widely from patient to patient and clinic to clinic. This is why the pace of progress towards widespread use in the clinic outside the medical tourism field remains slow. Today's open access paper considers extracellular vesicle therapy specifically in the case of brain injury and neurodegenerative conditions, but the points made are broadly applicable to all forms of therapy that make use of vesicles harvested from cells.

Extracellular vesicle therapy in neurological disorders

Extracellular vesicles (EVs) are vital for cell-to-cell communication, transferring proteins, lipids, and nucleic acids in various physiological and pathological processes. They play crucial roles in immune modulation and tissue regeneration but are also involved in pathogenic conditions like inflammation and degenerative disorders. EVs have heterogeneous populations and cargo, with numerous subpopulations currently under investigations. EV therapy shows promise in stimulating tissue repair and serving as a drug delivery vehicle, offering advantages over cell therapy, such as ease of engineering and minimal risk of tumorigenesis.

Despite the rapid growth in the EV field, much remains to be studied. There are numerous EV classes and subclasses yet to be fully characterized. The heterogeneity within EV classes leads to variability in their effects. Studies isolating EVs from the same cell line report different cargo and mechanisms of action. The effects of EV subpopulations are also not fully understood, with research predominantly focused on exosomes. The roles of microvesicles (MVs) are still controversial, as they can be either therapeutic or pathogenic depending on their source. MVs and other large EVs may be worth exploring further since they can deliver more cargo.

Characterization and purification of EVs are crucial for clinical application. To control the effects of EVs, production methods need to be strictly replicable to avoid heterogeneity, with specific culture and modulation techniques. EVs are involved in multiple pathological processes, such as inflammation, tumorigenesis, and toxic protein spreading. Blocking these pathological EVs is challenging due to a lack of specificity, necessitating more precise techniques for targeting them. Multiple sources of EVs have been studied, but not thoroughly across all domains of treatment. Some cell sources may be better suited for certain roles; for example, stem cells for neuroregeneration, glia for immunomodulation, and endothelial cells for angiogenesis. The targeting ability of EVs is another area that has not been extensively explored. Optimal EV preconditioning, administration regimens, and safety profiles also require further investigation.

A better understanding of EV subtypes and their specific roles will mark a significant milestone in medicine, leading to safer, more effective and disease-tailored EV therapy for a variety of neurological disorders.