Oligodendrocytes and Progenitors Become Progressively Depleted within Chronically Demyelinated Lesions

Department of Pathology and the Center for Neurobiology and Behavior, Columbia University, New York, New York, USA.
American Journal Of Pathology (Impact Factor: 4.59). 06/2004; 164(5):1673-82. DOI: 10.1016/S0002-9440(10)63726-1
Source: PubMed


To understand mechanisms that may underlie the progression of a demyelinated lesion to a chronic state, we have used the cuprizone model of chronic demyelination. In this study, we investigated the fate of oligodendrocytes during the progression of a demyelinating lesion to a chronic state and determined whether transplanted adult oligodendrocyte progenitors could remyelinate the chronically demyelinated axons. Although there is rapid regeneration of the oligodendrocyte population following an acute lesion, most of these newly regenerated cells undergo apoptosis if mice remain on a cuprizone diet. Furthermore, the oligodendrocyte progenitors also become progressively depleted within the lesion, which appears to contribute to the chronic demyelination. Interestingly, even if the mice are returned to a normal diet following 12 weeks of exposure to cuprizone, remyelination and oligodendrocyte regeneration does not occur. However, if adult O4+ progenitors are transplanted into the chronically demyelinated lesion of mice treated with cuprizone for 12 weeks, mature oligodendrocyte regeneration and remyelination occurs after the mice are returned to a normal diet. Thus, the formation of chronically demyelinated lesions induced by cuprizone appears to be the result of oligodendrocyte depletion within the lesion and not due to the inability of the chronically demyelinated axons to be remyelinated.

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    • "It still remains to be shown whether replenishment of the NG2 cell population can be a cause for remyelination failure under certain conditions. While repeated acutely demyelinated lesions undergo successful remyelination (Penderis et al., 2003), other studies suggest that NG2 cells can become depleted after acute demyelination (Keirstead et al., 1998) and their repopulation may not occur fast enough to meet the demands of chronic ongoing demyelination (Mason et al., 2004). Recruitment of new NG2 cells could occur by proliferation of local NG2 cells and/or migration and differentiation of cells from the SVZ (Nait-Oumesmar et al., 1999; Picard-Riera et al., 2002; Etxeberria et al., 2010; Tepavcevic et al., 2011). "
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    ABSTRACT: NG2 cells, also referred to as oligodendrocyte precursor cells (OPCs) or polydendrocytes, represent a major resident glial cell population that is distinct from mature astrocytes, oligodendrocytes, microglia, and neural stem cells and exist throughout the gray and white matter of the developing and mature central nervous system (CNS). While their most established fate is the oligodendrocyte, they retain lineage plasticity in an age- and region-specific manner. During development, they contribute to 36% of protoplasmic astrocytes in the ventral forebrain. Despite intense investigation on the neuronal fate of NG2 cells, there is no definitive evidence that they contribute substantially to the neuronal population. NG2 cells have attributes that suggest that they have functions other than to generate oligodendrocytes, but their exact role in the neural network remains unknown. Under pathological states, NG2 cells not only contribute to myelin repair, but they become activated in response to a wide variety of insults and could play a primary role in pathogenesis.
    Frontiers in Neuroscience 06/2014; 8(8):133. DOI:10.3389/fnins.2014.00133 · 3.66 Impact Factor
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    • "Once demyelination is complete the amount of activated RCA-1 (RCA, Ricinus communis agglutinin-1)/Mac-3-positive microglia starts to decrease (Mason et al., 2004; Skripuletz et al., 2011b). In contrast, activated microglia persist at a low level in chronically demyelinated lesions in mice treated with cuprizone up to 12 weeks (Mason et al., 2004; Lindner et al., 2009). "
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    ABSTRACT: Although astrogliosis and microglia activation are characteristic features of multiple sclerosis (MS) and other central nervous system (CNS) lesions the exact functions of these events are not fully understood. Animal models help to understand the complex interplay between the different cell types of the CNS and uncover general mechanisms of damage and repair of myelin sheaths. The so called cuprizone model is a toxic model of demyelination in the CNS white and gray matter, which lacks an autoimmune component. Cuprizone induces apoptosis of mature oligodendrocytes that leads to a robust demyelination and profound activation of both astrocytes and microglia with regional heterogeneity between different white and gray matter regions. Although not suitable to study autoimmune mediated demyelination, this model is extremely helpful to elucidate basic cellular and molecular mechanisms during de- and particularly remyelination independently of interactions with peripheral immune cells. Phagocytosis and removal of damaged myelin seems to be one of the major roles of microglia in this model and it is well known that removal of myelin debris is a prerequisite of successful remyelination. Furthermore, microglia provide several signals that support remyelination. The role of astrocytes during de- and remyelination is not well defined. Both supportive and destructive functions have been suggested. Using the cuprizone model we could demonstrate that there is an important crosstalk between astrocytes and microglia. In this review we focus on the role of glial reactions and interaction in the cuprizone model. Advantages and limitations of as well as its potential therapeutic relevance for the human disease MS are critically discussed in comparison to other animal models.
    Frontiers in Cellular Neuroscience 03/2014; 8:73. DOI:10.3389/fncel.2014.00073 · 4.29 Impact Factor
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    • "GST-π is a myelin-and oligodendrocyte-associated enzyme used to identify mature (myelin-forming) oligodendrocytes in mice [18] . In sections labeled with the specific antibody to GST-π, cuprizone exposure for 7 days reduced the number of GST-π positive cells (Fig. 2A–D). "
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    ABSTRACT: Chronic long-term exposure to cuprizone causes severe brain demyelination in mice, which leads to changes in locomotion, working memory and anxiety. These findings suggest the importance of intact myelin for these behaviors. This study aimed to investigate the possible behavioral changes in mice with mild oligodendrocyte/myelin damage that parallels the white matter changes seen in the brains of patients with psychiatric disporders. We used the cuprizonetreated mouse model to test both tissue changes and behavioral functions (locomotor activity, anxiety status, and spatial working memory). The results showed that mice given cuprizone in their diet for 7 days had no significant myelin breakdown as evaluated by immunohistochemical staining for myelin basic protein, while the number of mature oligodendrocytes was reduced. The number and length of Caspr protein clusters, a structural marker of the node of Ranvier, did not change. The locomotor activity of the cuprizonetreated mice increased whereas their anxiety levels were lower than in normal controls; spatial working memory, however, did not change. These results, for the first time, link emotion-related behavior with mild white matter damage in cuprizone-treated mice.
    Neuroscience Bulletin 08/2013; 29(5). DOI:10.1007/s12264-013-1369-0 · 2.51 Impact Factor
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