Micro-RNA Подпись в CSF до и после автоматической гематопоэтической трансплантации стволовой клетки для многоразового склероза.
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Pavlovic Ivan, Axling Fredrik, Nazir Faisal Hayat, Müller Malin, Wiberg Anna, Burman Joachim
Аннотация
Оригинал публикации
Micro-RNA Signature in CSF Before and After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis.
BACKGROUND AND OBJECTIVES: MicroRNAs (miRNAs) are regulators of gene expression and have been reported to be dysregulated in people with multiple sclerosis (pwMS). Autologous hematopoietic stem cell transplantation (aHSCT) is an immune-ablative treatment intervention for pwMS. Currently, it is unknown if aHSCT affects expression levels of miRNAs in CSF. We explored the ability of circulating miRNA to discriminate between pwMS and healthy controls (HCs) and investigated whether these miRNAs were affected by treatment with aHSCT.
METHODS: Using quantitative reverse transcription PCR, 87 miRNAs were analyzed in CSF samples of a discovery cohort (baseline: 4 & HC: 4). The top 22 miRNAs discriminating between pwMS and HCs were then analyzed in 187 CSF samples of a validation cohort (pwMS: 50, HC: 32). Samples, failing quality control or being follow-ups to baseline samples with quality control issues, were excluded from further analyses. The remaining 133 samples (HC: 29, MS: baseline: 33, 1 year: 30, 2 years: 26, 3-5 years: 15) were analyzed for expression of the top 22 miRNAs.
RESULTS: Twelve miRNAs were dysregulated in pwMS compared with HC (q < 0.05). Associations with clinical and analytical parameters were observed in relation to all 12 miRNAs; however, a cluster of 4 miRNAs (miR-16-5p, miR-21-5p, miR-150-5p, and miR-146a-5p) with strong correlations (r > 0.60, p < 0.001) with multiple parameters was identified. Of the 12 miRNAs, 8 were differentially expressed in pwMS with gadolinium-enhancing lesions at baseline and 4 by prior disease-modifying treatment class (p < 0.05). These 4 miRNAs correlated strongly with each other, decreased after aHSCT, and remained low throughout the follow-up period (p < 0.05). Target and pathway analysis of these revealed association with biological processes affecting cytokine production, inflammatory response, and regulation of myelin maintenance.
DISCUSSION: miRNAs are dysregulated in CSF from pwMS and particularly in patients with less effective treatments and/or higher inflammatory disease activity. A 4-miRNA signature with elevated expression of miR-16-5p, miR-21-5p, miR-150-5p, and miR-146a-5p was recurring in multiple analyses. After intervention with aHSCT, the expression levels approached the levels of the HCs, suggesting a potent treatment effect.