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, 585 (23), 3730-7

Mediators of Oligodendrocyte Differentiation During Remyelination


Mediators of Oligodendrocyte Differentiation During Remyelination

Jigisha R Patel et al. FEBS Lett.


Myelin, a dielectric sheath that wraps large axons in the central and peripheral nervous systems, is essential for proper conductance of axon potentials. In multiple sclerosis (MS), autoimmune-mediated damage to myelin within the central nervous system (CNS) leads to progressive disability primarily due to limited endogenous repair of demyelination with associated axonal pathology. While treatments are available to limit demyelination, no treatments are available to promote myelin repair. Studies examining the molecular mechanisms that promote remyelination are therefore essential for identifying therapeutic targets to promote myelin repair and thereby limit disability in MS. Here, we present our current understanding of the critical extracellular and intracellular pathways that regulate the remyelinating capabilities of oligodendrocyte precursor cells (OPCs) within the adult CNS.


Figure 1
Figure 1. Putative Remyelination Mechanisms
Depicted are roles for cytokines, chemokines, growth factors, transcription factors and other signaling proteins in remyelination of demyelinated lesions in MS. During demyelination, oligodendrocytes undergo apopotosis, leaving debris, which may contribute to the activation of microglia and astrocytes, which then express cytokines (TNF-α, IL-1β) [–16]. Cytokines alter expression of chemokines (CXCL1, CXCL2, CXCL12) and growth factors (IGF-1, PDGF, FGF, EGF), whose activation or inhibition of various aspects of remyelination are depicted via color-coding of arrows and signs of blockade, respectively, for each biologic process (migration, proliferation, OPC survival and differentiation). For certain molecules, such as CXCL1/2, opposing effects on OPCs have been observed, depending on the animal model used. Growth factors differentially impact on cell survival and proliferation while chemokines contribute to migration and differentiation, depending on OPC position. TLR2 activation inhibits OPC differentiation [79]. Notch-1 also blocks OPC differentiation to promote migration. Molecules that regulate OPC maturation are depicted in the context of intracellular signaling during differentiation. Included are chemokine (CXCR4/7, CXCR2) and growth factor (IGF-1R, EGFR) receptors, miRNAs, Lingo-1 and several transcription factors (Nkx2.2, Olig1/2, Mash1, Tcf4, SOX10) which may negatively or positively impact on the expression of myelin proteins including proteolipid protein (PLP), myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG).

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