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Modulation of oligodendrocyte precursor cells differentiation fate during CNS remyelination

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Restoring myelin production from within

Myelin sheaths provide insulation and structural support in neuronal axons. Understanding the molecular mechanisms of natural myelin production could help to design treatment regimes for disorders such as multiple sclerosis.

Health

Signal transmission in the central nervous system occurs down axons that are insulated by myelin coating. Genetic defects or pathological situations could lead to demyelination which leaves neuronal axons exposed and unable to guide the signal appropriately. Understanding the mechanisms that are naturally activated to trigger endogenous repair of myelin sheath formation could provide cues for the design of therapeutic interventions. The EU-funded ' Modulation of oligodendrocyte precursor cells differentiation fate during CNS remyelination' (MODOPCFATE) project will therefore investigate the differentiation pathway of oligodendrocyte precursor cells (OPCs). OPCs are cells that naturally restore demyelinated axons under normal circumstances. Scientists observed that microenvironmental signals in injured tissues activate OPCs to either differentiate classically into oligodendrocytes or alternatively into Schwann cells and astrocytes. This differentiation was highly location-dependent, implicating their role in OPC fate. To unveil the molecular determinants that drive OPC differentiation, researchers studied their interaction with other cells types such as microglia and astrocytes in the injured tissue. Microarray analysis of sections isolated from rat brains following injury identified genes that were differentially expressed in vascular and non-vascular regions of lesion areas. In particular, certain members of the Wnt and bone morphogenetic protein (BMP) signalling pathways were found to act as major regulators of OPC fate in the vascular areas. These findings led to the speculation that spatiotemporal differences in the expression of BMPs and their inhibitors drive OPC differentiation. For this purpose, researchers administered BMP antagonists into the lesions undergoing active remyelination. Results are expected to determine the extent to which restoration of myelin sheaths by oligodendrocytes could be modulated through such compounds. The processes of myelin restoration and OPC association with blood vessels are interconnected and do not occur in isolation. Yet there are endothelial-derived factors which prompt OPC proliferation and alternative differentiation. Targeting such molecular determinants could be exploited as a therapeutic intervention to trigger regenerative mechanisms for patients suffering from diseases like multiple sclerosis.

Keywords

Myelin, demyelination, multiple sclerosis, endogenous, oligodendrocyte precursor cells, differentiation, bone morphogenetic protein, signalling pathways, vascular

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