Myelin Impairs CNS Remyelination by Inhibiting Oligodendrocyte Precursor Cell Differentiation

Kotter, Mark R.; Li, Wenwu; Zhao, Chao; Franklin, Robin J.M.

doi:10.1523/jneurosci.2615-05.2006

Cited by 675 publications

(602 citation statements)

References 30 publications

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“…Using heterochronic parabiosis (Villeda et al 2011) in a toxin-induced focal demyelination model of mouse spinal cord, Ruckh et al demonstrated improvements in the remyelination of aged brains mediated by endogenous OPCs whose differentiation capacity was restored by exposing them to a youthful systemic environment. Considering previous hypotheses about the role of the innate immune system in remyelination (Kotter et al 2006), these results support the idea that young macrophages recruited during remyelination facilitate OPC differentiation by removing inhibitory myelin debris (Ruckh et al 2012).…”

Section: Remyelination and Agingsupporting

confidence: 88%

Nutritional factors and aging in demyelinating diseases

Adamo

2013

Genes Nutr

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Demyelination is a pathological process characterized by the loss of myelin around axons. In the central nervous system, oligodendroglial damage and demyelination are common pathological features characterizing white matter and neurodegenerative disorders. Remyelination is a regenerative process by which myelin sheaths are restored to demyelinated axons, resolving functional deficits. This process is often deficient in demyelinating diseases such as multiple sclerosis (MS), and the reasons for the failure of repair mechanisms remain unclear. The characterization of these mechanisms and the factors involved in the proliferation, recruitment, and differentiation of oligodendroglial progenitor cells is key in designing strategies to improve remyelination in demyelinating disorders. First, a very dynamic combination of different molecules such as growth factors, cytokines, chemokines, and different signaling pathways is tightly regulated during the remyelination process. Second, factors unrelated to this pathology, i.e., age and genetic background, may impact disease progression either positively or negatively, and in particular, age-related remyelination failure has been proven to involve oligodendroglial cells aging and their intrinsic capacities among other factors. Third, nutrients may either help or hinder disease progression. Experimental evidence supports the anti-inflammatory role of omega-6 and omega-3 polyunsaturated fatty acids through the competitive inhibition of arachidonic acid, whose metabolites participate in inflammation, and the reduction in T cell proliferation. In turn, vitamin D intake and synthesis have been associated with lower MS incidence levels, while vitamin D-gene interactions might be involved in the pathogenesis of MS. Finally, dietary polyphenols have been reported to mitigate demyelination by modulating the immune response.

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Section: Remyelination and Agingsupporting

confidence: 88%

Nutritional factors and aging in demyelinating diseases

Adamo

2013

Genes Nutr

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“…[72][73][74] Furthermore, myelin debris itself inhibits remyelination via inhibition of OPC differentiation. 74,75 The results show that the increase in oligodendrogenesis is linked to increased proliferation of the NG2 ϩ OPC population and to morphologic changes specific to the T PLP mice. Although proliferation is a characteristic feature of OPC activation, 14,16,76 these cells also respond by changing their structure and level of expression of NG2.…”

Section: Discussionmentioning

confidence: 93%

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Nielsen

Toft-Hansen

Lambertsen

et al. 2011

The American Journal of Pathology

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In multiple sclerosis (MS), myelin-specific T cells are normally associated with destruction of myelin and axonal damage. However, in acute MS plaque, remyelination occurs concurrent with T-cell infiltration, which raises the question of whether T cells might stimulate myelin repair. We investigated the effect of myelin-specific T cells on oligodendrocyte formation at sites of axonal damage in the mouse hippocampal dentate gyrus. Infiltrating T cells specific for myelin proteolipid protein stimulated proliferation of chondroitin sulfate NG2-expressing oligodendrocyte precursor cells early after induction via axonal transection, resulting in a 25% increase in the numbers of oligodendrocytes. In contrast, T cells specific for ovalbumin did not stimulate the formation of new oligodendrocytes. In addition, infiltration of myelinspecific T cells enhanced the sprouting response of calretinergic associational/commissural fibers within the dentate gyrus. These results have implications for the perception of MS pathogenesis because they show that infiltrating myelin-specific T cells can stimulate oligodendrogenesis in the adult central nervous system. T cell infiltration, demyelination, and axonal damage are central pathologic features of multiple sclerosis (MS). Whereas the primary immune attack on oligodendrocytes and myelin is effected by T cells, 1,2 remyelination occurs in acute plaques, also in the presence of T cells. 3,4 Remyelination depends on chondroitin sulfate NG2-expressing adult oligodendrocyte precursor cells (OPCs). 5,6 OPCs retain the capacity to proliferate and differentiate into myelinating oligodendrocytes in response to toxic or inflammatory demyelination 7-9 and other forms of central nervous system (CNS) injury such as ischemia, 10 spinal cord injury, 11,12 axonal lesions, 13,14 and inflammation. 15 During differentiation, OPCs downregulate NG2 as cells acquire markers of mature oligodendrocytes such as 2=,3=-cyclic nucleotide 3=-phosphodiesterase (CNP). 16 The axonal damage that occurs within and distal to the acute MS lesion can be modeled in the hippocampal dentate gyrus by transection of the perforant pathway (PP), resulting in degeneration of the PP axons and their myelin sheaths in the outer part of the molecular layer. [17][18][19] PP lesions also induce proliferation of OPCs, which results in formation of new oligodendrocytes. 14 These newly formed oligodendrocytes are presumed to myelinate the axonal sprouts that extend from other afferent fiber systems in the dentate gyrus 20,21 such as the associational/commissural afferents from the calretinergic hilar mossy cells. 20,22,23 Indeed, in stratum radiatum of the hippocampal CA3 region, lesion-induced axonal sprouting is associated with formation of more oligodendrocytes and more myelin. 24 Because remyelination ultimately fails in MS, 25 it is assumed that autoimmune demyelination reduces the capacity for myelin repair. 26,27 We investigated the effect of myelin-specific T cells on the formation of oligodendrocytes in the dentate gyrus of ...

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“…One possibility is that the emergence of the remyelination-supportive microglia phenotype is causally linked to one of the prototypical microglia effector functions, namely phagocytosis. Undoubtedly, clearance of tissue debris is indispensable for regeneration to occur (Kotter et al, 2006). Nonetheless, it has been shown that phagocytosis of apoptotic cells and myelin debris renders microglia/ macrophages supportive of regenerative processes (Bechmann et al, 2001;Boven et al, 2006;Savill et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Identification of a microglia phenotype supportive of remyelination

Olah

Amor

Brouwer

et al. 2011

Glia

319

270

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In multiple sclerosis, endogenous oligodendrocyte precursor cells (OPCs) attempt to remyelinate areas of myelin damage. During disease progression, however, these attempts fail. It has been suggested that modulating the inflammatory environment of the lesion might provide a promising therapeutic approach to promote endogenous remyelination. Microglia are known to play a central role in neuroinflammatory processes. To investigate the microglia phenotype that supports remyelination, we performed genome-wide gene expression analysis of microglia from the corpus callosum during demyelination and remyelination in the mouse cuprizone model, in which remyelination spontaneously occurs after an episode of toxin-induced primary demyelination. We provide evidence for the existence of a microglia phenotype that supports remyelination already at the onset of demyelination and persists throughout the remyelination process. Our data show that microglia are involved in the phagocytosis of myelin debris and apoptotic cells during demyelination. Furthermore, they express a cytokine and chemokine repertoire enabling them to activate and recruit endogenous OPCs to the lesion site and deliver trophic support during remyelination. This study not only provides a detailed transcriptomic analysis of the remyelinationsupportive microglia phenotype but also reinforces the notion that the primary function of microglia is the maintenance of tissue homeostasis and the support of regeneration already at the earliest stages in the development of demyelinating lesions. V

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Myelin Impairs CNS Remyelination by Inhibiting Oligodendrocyte Precursor Cell Differentiation

Cited by 675 publications

References 30 publications

Nutritional factors and aging in demyelinating diseases

Nutritional factors and aging in demyelinating diseases

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Identification of a microglia phenotype supportive of remyelination

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