Exosomal profiling should be used to monitor disease activity in MS patients: Commentary

One of the major challenges in multiple sclerosis (MS) research is developing simple and reliable fluid body biomarkers for disease diagnosis, prognosis, and treatment outcomes. ¹ Extracellular vesicles (EVs) produced in brain cross the blood–brain barrier and transfer parental cell lineage markers as well as transcripts/proteins/lipids that can inform about the status of brain tissue to peripheral body fluids. This finding has fueled several studies aiming at testing the potential of EVs as non-invasive MS biomarkers. Most studies focused on the transcriptome of small EVs (exosomes) circulating in the blood, an easily accessible body fluid. Changes in specific microRNAs were identified in MS patients versus healthy subjects but with low reproducibility among studies, ² thus questioning whether plasma EVs profiling may help monitoring disease activity in MS patients. Despite these discouraging data, Marcin P. Mycko is still positive about the ability of plasma EVs to capture disease activity in MS. He believes that standardization and automation of methods for EV isolation will reduce the technical differences which negatively impacted previous EV profiling studies. More importantly, he suggests focusing on EVs produced by the brain cell types most affected in MS, that is, oligodendrocytes, microglia, or astrocytes, instead of total blood EVs, in which brain-derived EVs are highly diluted by EVs produced in the periphery, reducing the likelihood of detecting alterations. ³ While this raises the question of what cell lineage markers can selectively extract brain cell–specific EVs, being enriched in EVs produced in brain but not in peripheral tissues, their cargo may actually reflect the status of parental cells during MS, ³ implementing the monitoring of patients in clinical practice. In line with higher prognostic potential of specific brain EV populations in MS, a recent study showed that the number of EVs derived from microglia/macrophages in the cerebrospinal fluid, a less accessible fluid but enriched in brain-derived EVs, can predict the disease course in MS. ⁴

The negative view of Matthieu Deltombe and Vincent van Pesch essentially relies on general technical issues related to the EVs field. The scientists claim the need of consensus on methods to be adopted for blood sample processing, EV extraction, and profiling to reduce the methodological heterogeneity that may underlie lack of reproducibility of EV profiling data in MS. This request is perfectly in line with the goal of the International Society for Extracellular Vesicles (ISEV) to improve reproducibility of research on EVs. To achieve this goal, a permanent ISEV subcommittee, the Rigor & Standardization Subcommittee, ⁵ has been created that includes regulatory agencies such as European Medicines Agency (EMA) and the Food and Drug Administration (FDA). Further considerations by Deltombe and van Pesch about cost-effectiveness, time consumption of EV analyses, and accessibility of methodologies to most clinical laboratories are all reasonable and shared by the MS community.

In summary, the big effort of ISEV to improve reproducibility of EV research and the evidence that EV profiling in other research fields have been registered in ClinicalTrials.gov. strongly suggest that technical issues could be solved and encourage further research toward blood EVs-related biomarkers in MS, not necessarily limited to miRNA profiling.