Erythrocyte microRNAs show biomarker potential and implicate multiple sclerosis susceptibility genes

Abstract

Background Multiple sclerosis is a demyelinating autoimmune disease, for which there is no blood‐borne biomarker. Erythrocytes may provide a source of such biomarkers as they contain microRNAs. MicroRNAs regulate protein translation through complementary binding to messenger RNA. As erythrocytes are transcriptionally inactive, their microRNA profiles may be less susceptible to variation. The aim of this study was to assess the biomarker potential of erythrocyte microRNAs for multiple sclerosis and assess the potential contribution of erythrocyte‐derived extracellular vesicle microRNAs to pathology. Methods Erythrocytes were isolated from whole blood by density gradient centrifugation. Erythrocyte microRNAs of a discovery cohort (23 multiple sclerosis patients and 22 healthy controls) were sequenced. Increased expression of miR‐183 cluster microRNAs (hsa‐miR‐96‐5p, hsa‐miR‐182‐5p and hsa‐miR‐183‐5p) was validated in an independent cohort of 42 patients and 45 healthy and pathological (migraine) controls. Erythrocyte‐derived extracellular vesicles were created ex vivo and their microRNAs were sequenced. Targets of microRNAs were predicted using miRDIP. Results Hsa‐miR‐182‐5p and hsa‐miR‐183‐5p were able to discriminate relapsing multiple sclerosis patients from migraine patients and/or healthy controls with 89‐94% accuracy and around 90% specificity. Hsa‐miR‐182‐5p and hsa‐miR‐183‐5p expression correlated with measures of physical disability and hsa‐miR‐96‐5p expression correlated with measures of cognitive disability in multiple sclerosis. Erythrocytes were found to selectively package microRNAs into extracellular vesicles and 34 microRNAs were found to be differentially packaged between healthy controls and multiple sclerosis patients. Several gene targets of differentially expressed and packaged erythrocyte microRNAs overlapped with multiple sclerosis susceptibility genes. Gene enrichment analysis indicated involvement in nervous system development and histone H3‐K27 demethylation. Conclusions Erythrocyte miR‐183 cluster members may be developed into specific multiple sclerosis biomarkers that could assist with diagnosis and disability monitoring. Erythrocyte and their extracellular microRNAs were shown to target multiple sclerosis susceptibility genes and may be contributing to the pathophysiology via previously identified routes.

Extracellular Vesicles in Multiple Sclerosis: Role in the Pathogenesis and Potential Usefulness as Biomarkers and Therapeutic Tools

“…They, lacking a nucleus, show a stable content of miRNAs. The availability of such peripheral source of EVs makes them a very interesting specimen in the study of EV-derived miRNAs in MS. A very recent study investigated, for the first time, the involvement of erythrocyte-derived EV miRNAs in MS [ 64 ]. Erythrocyte-derived EVs were purified ex vivo from isolated erythrocytes.…”

“…This study highlighted that erythrocyte-derived EVs were selectively packaged and contained a majority of highly expressed miRNAs in red cells. In particular, hsa-miR-451a which is transferred from erythrocytes to endothelial cells by EVs, contributed to the loss of the integrity barrier in cerebral malaria, but it was also increased in MS patients’ plasma [ 64 ]. Actually, erythrocytes may have a role in MS due to their impaired antioxidant capacity and hemorheological changes that may contribute to BBB damage [ 64 ].…”

“…In particular, hsa-miR-451a which is transferred from erythrocytes to endothelial cells by EVs, contributed to the loss of the integrity barrier in cerebral malaria, but it was also increased in MS patients’ plasma [ 64 ]. Actually, erythrocytes may have a role in MS due to their impaired antioxidant capacity and hemorheological changes that may contribute to BBB damage [ 64 ]. This peculiarity links cerebral malaria to MS.…”

Biomarkers for respiratory diseases: Present applications and future discoveries

“…Although each cell contains almost the same gene sequence, the gene expression varies according to different tissues, developmental stages and environmental stimuli. DNA methylation, histone modification and noncoding RNAs are three main manifestations of the epigenome 67,68 . For example, several studies revealed that DNA methylation is involved in several steps of lung cancer pathogenesis, such as cell differentiation and epithelial‐mesenchymal transition.…”

Electrical and viscoelastic parameters of erythrocytes as predictors of exacerbation in inflammatory bowel diseases

“…Предложенный подход -использовать параметры эритроцитов для прогнозирования течения заболевания -не нов. Исследование показателей красной крови как биомаркеров и предикторов активно проводится при целом ряде патологий: в кардиологической практике показатель распределения эритроцитов по объему (RDW) рассматривается как долговременный прогностический фактор течения острого инфаркта миокарда [33], величина омега-3 индекса мембран эритроцитов дает стратификацию риска развития внезапной коронарной смерти [34], острого инфаркта миокарда [35,36]; в неврологии микро-РНК эри-троцитов рассматриваются как потенциальный биомаркер течения рассеянного склероза [37]; проведен анализ уровня RDW для прогноза течения колоректального рака [38]. Настоящая работа, находясь в тренде подобных исследований, демонстрирует возможности электрических и вязкоупругих параметров эритроцитов, измеренных методом диэлектрофореза, отличающегося минимальной пробоподготовкой, высокой скоростью выполнения, малой затратностью и трудоемкостью, высокой информативностью и наглядностью [9].…”