Global exosome transcriptome profiling reveals biomarkers for multiple sclerosis

• Published in: Annals of neurology Vol. 81; no. 5; pp. 703 - 717
• Main Authors: Selmaj, Igor, Cichalewska, Maria, Namiecinska, Magdalena, Galazka, Grazyna, Horzelski, Wojciech, Selmaj, Krzysztof W., Mycko, Marcin P.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.05.2017
• Subjects: Adult; Aromatic compounds; Biomarkers; Biomarkers - blood; Brain; Cell Culture Techniques; Cell cycle; Cell interactions; Control methods; Exosomes; Exosomes - genetics; Exosomes - metabolism; Female; Gadolinium; Gene expression; Gene Expression Profiling - methods; Gene sequencing; Humans; Immunoregulation; In vitro methods and tests; Leukocytes (mononuclear); Magnetic resonance imaging; Male; MicroRNAs - blood; Middle Aged; miRNA; Multiple sclerosis; Multiple Sclerosis, Relapsing-Remitting - blood; Neuroimaging; Patients; Peripheral blood mononuclear cells; Polymerase chain reaction; Remission; Ribonucleic acid; RNA; Sequence Analysis, RNA; Transcription
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.24931

Objective Accumulating evidence supports a role for exosomes in immune regulation. In this study, we investigated the total circulating exosome transcriptome in relapsing–remitting multiple sclerosis (RRMS) patients and healthy controls (HC). Methods Next generation sequencing (NGS) was used to define the global RNA profile of serum exosomes in 19 RRMS patients (9 in relapse, 10 in remission) and 10 HC. We analyzed 5 million reads and >50,000 transcripts per sample, including a detailed analysis of microRNAs (miRNAs) differentially expressed in RRMS. The discovery set data were validated by quantification using digital quantitative polymerase chain reaction with an independent cohort of 63 RRMS patients (33 in relapse, 30 in remission) and 32 HC. Results Exosomal RNA NGS revealed that of 15 different classes of transcripts detected, 4 circulating exosomal sequences within the miRNA category were differentially expressed in RRMS patients versus HC: hsa‐miR‐122‐5p, hsa‐miR‐196b‐5p, hsa‐miR‐301a‐3p, and hsa‐miR‐532‐5p. Serum exosomal expression of these miRNAs was significantly decreased during relapse in RRMS. These miRNAs were also decreased in patients with a gadolinium enhancement on brain magnetic resonance imaging. In vitro secretion of these miRNAs by peripheral blood mononuclear cells was also significantly impaired in RRMS. Interpretation These data show that circulating exosomes have a distinct RNA profile in RRMS. Because putative targets for these miRNAs include the signal transducer and activator of transcription 3 and the cell cycle regulator aryl hydrocarbon receptor, the data suggest a disturbed cell‐to‐cell communication in this disease. Thus, exosomal miRNAs might represent a useful biomarker to distinguish multiple sclerosis relapse. Ann Neurol 2017;81:703–717