Abstract
The critical aspect in multiple sclerosis (MS) progression involves insufficient regeneration of CNS resulting from deficient myelin synthesis by newly generated oligodendrocytes (OLs). Although many studies have focused on the role of autoreactive lymphocytes in the inflammatory-induced axonal loss, the problem of insufficient remyelination and disease progression is still unsolved. To determine the effect of myelin-specific lymphocytes on OL function in MS patients and in a mouse model of MS, we cultured myelin induced MS CD49d+CD154+ circulating lymphocytes as well as Experimental Autoimmune Encephalomyelitis (EAE) mouse brain-derived T and memory B cells with maturing oligodendrocyte precursor cells (OPCs). We found that myelin-specific CD49d+CD154+ lymphocytes affected OPC maturation toward formation of immune reactive OLs. Newly generated OLs were characterized by imbalanced myelin basic protein (MBP) and proteolipid protein (PLP) production as well as proinflammatory chemokine/cytokine synthesis. The analysis of cellular pathways responsible for OL reprogramming revealed that CD49d+CD154+ lymphocytes affected miRNA synthesis by dysregulation of polymerase II activity. miR-665 and ELL3 turned out to be the main targets of MS myelin-specific lymphocytes. Neutralization of high intracellular miR-665 concentration restored miRNA and MBP/PLP synthesis. Together, these data point to new targets for therapeutic intervention promoting CNS remyelination.
Highlights
Dysfunction of oligodendrocytes (OLs), the cells responsible for neuron myelin sheath formation, is suggested as one of the most important factors underlying the incomplete remyelination in multipleCells 2019, 8, 1508; doi:10.3390/cells8121508 www.mdpi.com/journal/cellsCells 2019, 8, 1508 sclerosis (MS) pathology
We previously showed that interaction of RR-multiple sclerosis (MS) CD49d+ CD154+ lymphocytes with maturating human oligodendrocyte precursor cells resulted in increased production of proinflammatory cytokines/chemokines [10]
In the coculture of human oligodendrocyte precursor cells (hOPCs) with relapsing-remitting MS (RR-MS) CD49d+ CD154+ lymphocytes, significantly higher concentrations of insulin-like growth factor-1 (IGF-1), platelet derived growth factor subunit A (PDGF-A), and PDGF-R-α were detected in comparison to coculture with healthy control (HC) CD49d+ CD154+ lymphocytes, as seen in proteins opposite to HC produced brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and PDGF-A
Summary
Dysfunction of oligodendrocytes (OLs), the cells responsible for neuron myelin sheath formation, is suggested as one of the most important factors underlying the incomplete remyelination in multipleCells 2019, 8, 1508; doi:10.3390/cells8121508 www.mdpi.com/journal/cellsCells 2019, 8, 1508 sclerosis (MS) pathology. Dysfunction of oligodendrocytes (OLs), the cells responsible for neuron myelin sheath formation, is suggested as one of the most important factors underlying the incomplete remyelination in multiple. Relapse mainly involves the brain areas previously affected by the disease that leads to gradual accumulation of irreversible impairment due to extended local demyelination [2]. The crucial cause of slowly progressing, irreversible disease-related disability is a renewal of only fragmentary tissue [3]. Some studies highlighted the participation of oligodendrocytes (OLs) as the principle cells responsible for neuron myelin sheath formation, their critical role in incomplete remyelination in MS pathology is still not clarified [3,4]. The structure of new myelin sheaths formed in remyelinating lesions is thinner than during development [7].
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