Article

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: 4.6). 06/2004; 164(5):1673-82. DOI: 10.1016/S0002-9440(10)63726-1
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
103 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dedicator of cytokinesis 3 (Dock3) belongs to an atypical family of the guanine nucleotide exchange factors. It is predominantly expressed in the neural tissues and causes cellular morphological changes by activating the small GTPase Rac1. We previously reported that Dock3 overexpression protects retinal ganglion cells from excitotoxic cell death. Oligodendrocytes are the myelinating cells of axons in the central nervous system and these cells are damaged in demyelinating disorders including multiple sclerosis (MS) and optic neuritis. In this study, we examined if Dock3 is expressed in oligodendrocytes and if increasing Dock3 signals can suppress demyelination in a cuprizone-induced demyelination model, an animal model of MS. We demonstrate that Dock3 is expressed in oligodendrocytes and Dock3 overexpression protects myelin in the corpus callosum following cuprizone treatment. Furthermore, we show that cuprizone demyelinates optic nerves and the extent of demyelination is ameliorated in mice overexpressing Dock3. Cuprizone treatment impairs visual function, which was demonstrated by multifocal electroretinograms, an established non-invasive method, and Dock3 overexpression prevented this effect. In mice overexpressing Dock3, Erk activation is increased, suggesting this may at least partly explain the observed protective effects. Our findings suggest that Dock3 may be a therapeutic target for demyelinating disorders including optic neuritis.Cell Death and Disease (2014) 5, e1395; doi:10.1038/cddis.2014.357; published online 28 August 2014.
    Cell Death & Disease 08/2014; 5:e1395. · 6.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Oligodendrocytes (OLGs) are generated late in development and myelination is thus a tardive event in the brain developmental process. It is however maintained whole life long at lower rate, and myelin sheath is crucial for proper signal transmission and neuronal survival. Unfortunately, OLGs present a high susceptibility to oxidative stress, thus demyelination often takes place secondary to diverse brain lesions or pathologies. OLGs can also be the target of immune attacks, leading to primary demyelination lesions. Following oligodendrocytic death, spontaneous remyelination may occur to a certain extent. In this review, we will mainly focus on the adult brain and on the two main sources of progenitor cells that contribute to oligodendrogenesis: parenchymal oligodendrocyte precursor cells (OPCs) and subventricular zone (SVZ)-derived progenitors. We will shortly come back on the main steps of oligodendrogenesis in the postnatal and adult brain, and summarize the key factors involved in the determination of oligodendrocytic fate. We will then shed light on the main causes of demyelination in the adult brain and present the animal models that have been developed to get insight on the demyelination/remyelination process. Finally, we will synthetize the results of studies searching for factors able to modulate spontaneous myelin repair.
    Frontiers in neuroscience. 01/2014; 8:145.
  • Source
    [Show abstract] [Hide abstract]
    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. 01/2014; 8:133.

Full-text

Download
2 Downloads
Available from