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Myelin recovery in multiple sclerosis: the challenge of remyelination.

Podbielska M, Banik NL, Kurowska E, Hogan EL - Brain Sci (2013)

Bottom Line: The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective.This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination-with emphasis upon myelin composition/ architecture and oligodendrocyte maturation and differentiation.The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Institute of Molecular Medicine and Genetics, Georgia Regents University, 1120 15th Street, Augusta, GA 30912-2620, USA. kurowska@iitd.pan.wroc.pl.

ABSTRACT
Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+, NKT, CD4+CD25+ T regulatory cells) and B cells are involved in this disorder, thus new MS therapies seek damage prevention by resetting multiple components of the immune system. The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective. This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination-with emphasis upon myelin composition/ architecture and oligodendrocyte maturation and differentiation. The translational options target oligodendrocyte protection and myelin repair in animal models and assess their relevance in human. Remyelination may be enhanced by signals that promote myelin formation and repair. The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination.

No MeSH data available.


Related in: MedlinePlus

Features of the myelination process. (A) Sequential stages of oligodendrocyte maturation. Specific markers for differentiation status of the oligodendrocyte lineage. Differentiation into mature oligodendrocytes is associated with acquisition of myelin-related proteins. (B) Myelin sheath organization in the CNS. Myelinating glial cells, oligodendrocytes in the CNS form the myelin sheath by enwrapping axons. Myelinated axon regions are interrupted by non-myelinated regions (nodes of Ranvier). Myelinated axons have four distinct domains: node (N), paranode (PN), juxtaparanode (JXP) and internode (INT). Nodes of Ranvier are regions of concentrated sodium channels that form between two internodes. Adjacent to the nodes of Ranvier are the paranode and the juxtaparanode. All four domains have characteristic proteins (see upper inset). At the nodes of Ranvier, Neurofascin 186 (Nf-186) supports the clustering of Na+ channels. The nodal Na+ channels are separated from the juxtaparanodal K+ channels via the paranode, where Neurofascin 155 (Nf-155) binds tightly to the axonal complex of Contactin and Contactin-associated protein (Caspr). CNP, an abundant cytoplasmic myelin protein, is predominantly found at the paranode. At the juxtaparanode, clustered K+ channels are associated to Caspr-2 and Contactin-2.
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brainsci-03-01282-f002: Features of the myelination process. (A) Sequential stages of oligodendrocyte maturation. Specific markers for differentiation status of the oligodendrocyte lineage. Differentiation into mature oligodendrocytes is associated with acquisition of myelin-related proteins. (B) Myelin sheath organization in the CNS. Myelinating glial cells, oligodendrocytes in the CNS form the myelin sheath by enwrapping axons. Myelinated axon regions are interrupted by non-myelinated regions (nodes of Ranvier). Myelinated axons have four distinct domains: node (N), paranode (PN), juxtaparanode (JXP) and internode (INT). Nodes of Ranvier are regions of concentrated sodium channels that form between two internodes. Adjacent to the nodes of Ranvier are the paranode and the juxtaparanode. All four domains have characteristic proteins (see upper inset). At the nodes of Ranvier, Neurofascin 186 (Nf-186) supports the clustering of Na+ channels. The nodal Na+ channels are separated from the juxtaparanodal K+ channels via the paranode, where Neurofascin 155 (Nf-155) binds tightly to the axonal complex of Contactin and Contactin-associated protein (Caspr). CNP, an abundant cytoplasmic myelin protein, is predominantly found at the paranode. At the juxtaparanode, clustered K+ channels are associated to Caspr-2 and Contactin-2.

Mentions: The central elements of the CNS—myelinating oligodendrocytes and astrocytes as well as neurons—are terminally differentiated cells with a limited capacity to respond to injury. They depend for renewal on the availability of their precursors—the oligodendrocyte progenitor cells (OPCs) and neuronal progenitor cells (NPCs), that undergo proliferation, migration and differentiation into defined progeny [21]. Generation of OPCs in the spinal cord occurs in two phases [22]. The first is ventral, with OPCs observed initially within the ventricular zone of the motor neuron progenitor (pMN) domain of neuroepithelium in early embryonic life [23,24]. Conversely, the second phase occurs in the dorsal spinal cord and hindbrain/telencephalon of the brain in late embryonic development and early post-natal life [25,26,27,28] and depends on inhibition of bone morphogenetic proteins (BMPs) [29]. The proliferating cells migrate into the developing white matter [30,31,32], exit the cell cycle, undergo differentiation into mature oligodendrocytes, and begin to express a subset of myelin-associated proteins [33,34]. Subsequent sequential stages of maturation to myelinating oligodendrocytes are identified by cell type-specific markers (Figure 2A). OPCs are highly proliferative, motile, bipolar cells expressing high levels of the GT3 ganglioside, A2B5, platelet-derived growth factor α receptor (PDGFαR), and the neuron-glial antigen 2 (NG2), a transmembrane chondroitin sulfate proteoglycan (CSPG). It is important to recognize differences between developmental myelination and myelin repair in the adult CNS. In the adult brain and spinal cord, OPCs are ubiquitous and represent a large percentage of the total cell population, as much as 9% of cells in white matter and 3% in gray matter [35,36]. Although both processes share many similarities, and the study of developmental myelination contributes to our understanding of myelin regeneration, there are also divergences for the role of transcription and growth factors. Adult OPCs are distinct from perinatal ones [37,38].


Myelin recovery in multiple sclerosis: the challenge of remyelination.

Podbielska M, Banik NL, Kurowska E, Hogan EL - Brain Sci (2013)

Features of the myelination process. (A) Sequential stages of oligodendrocyte maturation. Specific markers for differentiation status of the oligodendrocyte lineage. Differentiation into mature oligodendrocytes is associated with acquisition of myelin-related proteins. (B) Myelin sheath organization in the CNS. Myelinating glial cells, oligodendrocytes in the CNS form the myelin sheath by enwrapping axons. Myelinated axon regions are interrupted by non-myelinated regions (nodes of Ranvier). Myelinated axons have four distinct domains: node (N), paranode (PN), juxtaparanode (JXP) and internode (INT). Nodes of Ranvier are regions of concentrated sodium channels that form between two internodes. Adjacent to the nodes of Ranvier are the paranode and the juxtaparanode. All four domains have characteristic proteins (see upper inset). At the nodes of Ranvier, Neurofascin 186 (Nf-186) supports the clustering of Na+ channels. The nodal Na+ channels are separated from the juxtaparanodal K+ channels via the paranode, where Neurofascin 155 (Nf-155) binds tightly to the axonal complex of Contactin and Contactin-associated protein (Caspr). CNP, an abundant cytoplasmic myelin protein, is predominantly found at the paranode. At the juxtaparanode, clustered K+ channels are associated to Caspr-2 and Contactin-2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4061877&req=5

brainsci-03-01282-f002: Features of the myelination process. (A) Sequential stages of oligodendrocyte maturation. Specific markers for differentiation status of the oligodendrocyte lineage. Differentiation into mature oligodendrocytes is associated with acquisition of myelin-related proteins. (B) Myelin sheath organization in the CNS. Myelinating glial cells, oligodendrocytes in the CNS form the myelin sheath by enwrapping axons. Myelinated axon regions are interrupted by non-myelinated regions (nodes of Ranvier). Myelinated axons have four distinct domains: node (N), paranode (PN), juxtaparanode (JXP) and internode (INT). Nodes of Ranvier are regions of concentrated sodium channels that form between two internodes. Adjacent to the nodes of Ranvier are the paranode and the juxtaparanode. All four domains have characteristic proteins (see upper inset). At the nodes of Ranvier, Neurofascin 186 (Nf-186) supports the clustering of Na+ channels. The nodal Na+ channels are separated from the juxtaparanodal K+ channels via the paranode, where Neurofascin 155 (Nf-155) binds tightly to the axonal complex of Contactin and Contactin-associated protein (Caspr). CNP, an abundant cytoplasmic myelin protein, is predominantly found at the paranode. At the juxtaparanode, clustered K+ channels are associated to Caspr-2 and Contactin-2.
Mentions: The central elements of the CNS—myelinating oligodendrocytes and astrocytes as well as neurons—are terminally differentiated cells with a limited capacity to respond to injury. They depend for renewal on the availability of their precursors—the oligodendrocyte progenitor cells (OPCs) and neuronal progenitor cells (NPCs), that undergo proliferation, migration and differentiation into defined progeny [21]. Generation of OPCs in the spinal cord occurs in two phases [22]. The first is ventral, with OPCs observed initially within the ventricular zone of the motor neuron progenitor (pMN) domain of neuroepithelium in early embryonic life [23,24]. Conversely, the second phase occurs in the dorsal spinal cord and hindbrain/telencephalon of the brain in late embryonic development and early post-natal life [25,26,27,28] and depends on inhibition of bone morphogenetic proteins (BMPs) [29]. The proliferating cells migrate into the developing white matter [30,31,32], exit the cell cycle, undergo differentiation into mature oligodendrocytes, and begin to express a subset of myelin-associated proteins [33,34]. Subsequent sequential stages of maturation to myelinating oligodendrocytes are identified by cell type-specific markers (Figure 2A). OPCs are highly proliferative, motile, bipolar cells expressing high levels of the GT3 ganglioside, A2B5, platelet-derived growth factor α receptor (PDGFαR), and the neuron-glial antigen 2 (NG2), a transmembrane chondroitin sulfate proteoglycan (CSPG). It is important to recognize differences between developmental myelination and myelin repair in the adult CNS. In the adult brain and spinal cord, OPCs are ubiquitous and represent a large percentage of the total cell population, as much as 9% of cells in white matter and 3% in gray matter [35,36]. Although both processes share many similarities, and the study of developmental myelination contributes to our understanding of myelin regeneration, there are also divergences for the role of transcription and growth factors. Adult OPCs are distinct from perinatal ones [37,38].

Bottom Line: The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective.This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination-with emphasis upon myelin composition/ architecture and oligodendrocyte maturation and differentiation.The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Institute of Molecular Medicine and Genetics, Georgia Regents University, 1120 15th Street, Augusta, GA 30912-2620, USA. kurowska@iitd.pan.wroc.pl.

ABSTRACT
Multiple sclerosis (MS) is the most common demyelinating and an autoimmune disease of the central nervous system characterized by immune-mediated myelin and axonal damage, and chronic axonal loss attributable to the absence of myelin sheaths. T cell subsets (Th1, Th2, Th17, CD8+, NKT, CD4+CD25+ T regulatory cells) and B cells are involved in this disorder, thus new MS therapies seek damage prevention by resetting multiple components of the immune system. The currently approved therapies are immunoregulatory and reduce the number and rate of lesion formation but are only partially effective. This review summarizes current understanding of the processes at issue: myelination, demyelination and remyelination-with emphasis upon myelin composition/ architecture and oligodendrocyte maturation and differentiation. The translational options target oligodendrocyte protection and myelin repair in animal models and assess their relevance in human. Remyelination may be enhanced by signals that promote myelin formation and repair. The crucial question of why remyelination fails is approached is several ways by examining the role in remyelination of available MS medications and avenues being actively pursued to promote remyelination including: (i) cytokine-based immune-intervention (targeting calpain inhibition), (ii) antigen-based immunomodulation (targeting glycolipid-reactive iNKT cells and sphingoid mediated inflammation) and (iii) recombinant monoclonal antibodies-induced remyelination.

No MeSH data available.


Related in: MedlinePlus