Global exosome transcriptome profiling reveals biomarkers for multiple sclerosis

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Multiple sclerosis (MS) is a complex disease with a varied clinical course and prognosis. The complexity of the diagnostic procedure makes it necessary to search for simpler methods that might permit for rapid and reliable diagnosis. Therefore, the need for an MS biomarker is a burning and still unresolved issue.1 In light of accumulating evidence for a potential role of exosomes in the regulation of the immune system, it is expected that studies on exosome content will be of help in the delineation of new diagnostic and prognostic biomarkers in MS. Exosomes are microvesicles of a size between 30 and 100nm, which serve as small membranous transport vesicles that are formed in the cytoplasm and released from the surface of almost all living cells.2 Exosomes are believed to provide a means of cell‐to‐cell communication by transporting their cargo and delivering it to target cells. Exosomes have been shown to be picked up by other cells and to transfer their contents intracellularly, which can profoundly influence the function of the recipient cell.2 Exosomes have been shown to contribute to a number of disease states, including cancer and neurodegenerative conditions.4 Recently, growing evidence has emerged on a role for exosomes in immune processes, including autoimmunity.3
One of the most promising exosomal biomarker materials involves small noncoding RNA.2 It is well established that numerous non–protein‐coding RNA molecules are involved in fundamental biological processes via regulation of gene expression and protein synthesis. In this regard, particularly well understood is the function of microRNAs (miRNAs). miRNAs are endogenous ∼22nt noncoding RNAs that post‐transcriptionally regulate gene expression and function.6 They provide a guide for proteins involved in the function of RNA‐induced silencing complexes that degrade complimentary target mRNAs or block their translation. In MS and its animal model, experimental autoimmune encephalomyelitis, several miRNAs have already been found to correlate with immune cell polarization and their effector functions.7 Thus, miRNAs provide a new direction in our understanding of immune regulation in MS. The role of extracellular miRNAs remains a fascinating new aspect of their biology, which is still poorly understood. Until recently, most studies focused on the analysis of free‐floating extracellular miRNAs in biological fluids. Measurement of miRNAs within exosomes likely provides a more reliable approach than the analysis of free‐floating miRNAs, because exosomes effectively separate and protect their content from the extracellular environment, allowing intact cargo to be safely transported.12 In addition, the exosome miRNA profile is prespecified and is not random.2 This refers to the finding that exosomes target selected cells and induce changes that are preprogrammed in the exosome host cells. Thus, analysis of exosomal miRNAs might provide important data on the regulation of immune reactions in MS.
In this study, using a next generation sequencing (NGS) method, we were able to characterize the total transcriptome profile of circulating exosomes. We have demonstrated large quantities of miRNAs within serum exosomes. In particular, we identified 4 exosomal miRNAs that were significantly downregulated in MS patients during both clinical and radiological flare of the disease.

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