Abstract
Demyelination is a nervous system disease in which the myelin sheaths of neurons are damaged due to inflammatory reactions, inherited abnormalities or trauma. This damage impairs the conduction of signals in the affected nerves, which in turn causes deficiencies in sensation, movement and cognition. Oligodendrocyte precursor cells (OPCs) are able to induce remyelination. However, the remyelination is suboptimal due to the limited migration of OPCs. In the present study, neonatal OPCs were isolated from rats for the investigation of the role of C-X-C motif chemokine ligand 12 (CXCL12), an important chemokine, in mediating the migration ability of OPCs. The present results demonstrated that CXCL12 stimulation markedly promoted the migration of OPCs and activated the dual specificity mitogen-activated protein kinase kinase 1 (MEK)/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/RAC-α serine/threonine-protein kinase (AKT) pathways. Knockdown of C-X-C motif chemokine receptor 4 (CXCR4; a receptor of CXCL12) reversed the CXCL12-induced migration of OPCs and blocked the MEK/ERK and PI3K/AKT pathways. In addition, specific inhibitors of the MEK/ERK and PI3K/AKT pathways significantly reduced the migration of OPCs. Based on these findings, it was concluded that CXCL12 may induce the migration of OPCs through the CXCR4-activated MEK/ERK and PI3K/AKT pathways. The results of the present study support the manipulation of CXCL12-mediated OPC migration to improve remyelination.
Highlights
Myelin is a fatty white substance that surrounds the axons of neurons
The immunostaining assay confirmed that the isolated oligodendrocyte precursor cells (OPCs) expressed neural/glial antigen 2 (NG2) and platelet‐derived growth factor (PDGF) receptor‐α (PDGFR‐α), OPC‐specific markers (Fig. 1A and B), they were negative for O4 and myelin basic protein (MBP), as markers of mature oligodendrocytes
The results of the present study demonstrated that C‐X‐C motif chemokine ligand 12 (CXCL12) induced the migration of OPCs via the C‐X‐C motif chemokine receptor 4 (CXCR4)‐activated mitogen‐activated protein kinase kinase 1 (MEK)/extracellular signal‐regulated kinase (ERK) and phosphoinositide 3‐kinase (PI3K)/AKT pathways
Summary
In the central nervous system (CNS), oligodendrocytes supply the myelin, which provides metabolic support to the axon and allows for the rapid transmission of action potentials along the axon [1]. The current treatment strategy for demyelination is based on remyelination, a process that may restore metabolic support to the axon to limit axonal degeneration and restore the nodes that are required to facilitate conduction and, function [2]. In the CNS, endogenous oligodendrocyte precursor cells (OPCs) contribute toward the replacement of oligodendrocytes required for remyelination following demyelination [6]. OPCs are able to proliferate and differentiate into mature oligodendrocytes to repair injured myelin following demyelination. Numerous studies have aimed to promote the maturation, proliferation and differentiation of OPCs in order to improve remyelination [7,8,9,10]. Efforts have been made to enhance oligodendrocyte replacement through cell transplantation by the authors of the present study and others [11,12,13,14]
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