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1.
The second post-natal week in rat is the period of the most intense oligodendrocyte development and myelination. This period coincides with peak iron import by oligodendrocytes. During that time oligodendrocyte progenitors (OPCs) are sensitive to agents that may disturb normal iron homeostasis and assimilation of iron into these cells. One mechanism by which iron homeostasis can be disrupted is by environmental exposure to other metals. Vanadium is a transition metal, and exposure to vanadium during early brain development produces hypomyelination with variety of related neuro-behavioral phenotypes. In the current study, we investigated mechanisms of hypomyelination induced by vanadium exposure in developing rat brain. We demonstrate that both in vivo and in vitro, OPCs are more sensitive to vanadium exposure than astrocytes or mature oligodendrocytes. Vanadium exposure in OPCs resulted in increased ROS generation and increased annexinV labeling suggestive of apoptosis. Because ferritin is a major iron delivery protein for oligodendrocytes, we exposed the cells to recombinant ferritin and iron both of which exacerbated vanadium cytotoxicity, while the iron chelator desferroxamine (DFO) prevented cytotoxic/apoptotic effects of vanadium. To illustrate relationship between ferritin and vanadium, we demonstrate that vanadium exacerbated DNA nicking produced by iron-rich spleen ferritin, but not iron-poor apoferritin, resulting in a single and double strand breaks in a DNA relaxation assay. We propose that developmental exposure to vanadium interferes with normal iron assimilation into oligodendrocytes resulting in oxidative stress and apoptosis. Therefore, depletion of OPCs due to vanadium exposure in early post-natal period may be an important mechanism of vanadium-induced hypomyelination.  相似文献   

2.
We previously demonstrated ferritin binding is specific to white matter in mouse and human brain tissue and is not found within Multiple Sclerotic plaques. These results suggest that ferritin receptors are selectively expressed on oligodendrocytes. The present studies were designed to test the hypothesis that oligodendrocyte progenitor cells selectively bind ferritin and internalize it by methods consistent with receptor-mediated endocytosis. Using a cell culture system enriched for oligodendrocyte progenitor cells, we determined, that oligodendrocyte progenitor cells bind ferritin in a saturable and competitive manner with a K(d) of 5 nM and a receptor density of 0.06 fmol bound/20,000 cells. FITC tagged ferritin is internalized by A2B5, O4 or CNPase expressing cells in the culture, but not by GFAP+ cells. The uptake of ferritin into the oligodendrocyte progenitors was inhibited by treating the cells with inhibitors of receptor mediated endocytosis (hypertonic medium, potassium deficient medium, ATP depletion, sulfhydryl reagents). In addition exogenous ferritin decreased iron responsive element/iron regulatory protein binding indicating that the iron within the internalized ferritin is released and contributes to the intracellular iron pool. Given the relatively high amount of iron that can be delivered via ferritin, and the selective distribution of ferritin receptors in the white matter tracts in vivo, we propose that ferritin is a major source of iron for oligodendrocytes.  相似文献   

3.
4.
Iron is an essential trophic factor that is required for oxygen consumption and ATP production. Thus it plays a key role in vital cell functions. Although the brain has a relatively high rate of oxygen consumption compared to other organs, oligodendrocytes are the principal cells in the CNS that stain for iron under normal conditions. The importance of iron in myelin production has been demonstrated by studies showing that decreased availability of iron in the diet is associated with hypomyelination. The timing of iron delivery to oligodendrocytes during development is also important because hypomyelination and the associated neurological sequelae persist long after the systemic iron deficiency has been corrected. Therefore, identifying the molecular roles of iron in oligodendrocyte development and myelin production, and the mechanisms and timing of iron acquisitions are important prerequisites to developing effective therapies for dysmyelinating disorders. It is the purpose of this review to give a comprehensive overview of the existing literature on role of iron in oligodendrocytes and the mechanisms of iron acquisition and intracellular handling.  相似文献   

5.
Iron is an essential trophic element that is required for cell viability and differentiation, especially in oligodendrocytes, which consume relatively high rates of energy to produce myelin. Multiple iron metabolism proteins are expressed in the brain including transferrin receptor and ferritin-H. However, it is still unknown whether they are developmentally regulated in oligodendrocyte lineage cells for myelination. Here, using an in vitro cultured differentiation model of oligodendrocytes, we found that both transferrin receptor and ferritin-H are significantly upregulated during oligodendrocyte maturation, implying the essential role of iron in the development of oligodendrocytes. Additional different doses of Fe3+ in the cultured medium did not affect oligodendrocyte precursor cell maturation or ferritin-H expression but decreased the expression of the transferrin receptor. These results indicate that upregulation of both transferrin receptor and ferritin-H contributes to maturation and myelination of oligodendrocyte precursor cells.  相似文献   

6.
CNS myelination defects occur in mice deficient in receptor-like protein tyrosine phosphatase alpha (PTPα). Here, we investigated the role of PTPα in oligodendrocyte differentiation and myelination using cells and tissues from wild-type (WT) and PTPα knockout (KO) mice. PTPα promoted the timely differentiation of neural stem cell-derived oligodendrocyte progenitor cells (OPCs). Compared to WT OPCs, KO OPC cultures had more NG2+ progenitors, fewer myelin basic protein (MBP)+ oligodendrocytes, and reduced morphological complexity. In longer co-cultures with WT neurons, more KO than WT OPCs remained NG2+ and while equivalent MBP+ populations of WT and KO cells formed, the reduced area occupied by the MBP+ KO cells suggested that their morphological maturation was impeded. These defects were associated with reduced myelin formation in KO OPC/WT neuron co-cultures. Myelin formation was also impaired when WT OPCs were co-cultured with KO neurons, revealing a novel role for neuronal PTPα in myelination. Canonical Wnt/β-catenin signaling is an important regulator of OPC differentiation and myelination. Wnt signaling activity was not dysregulated in OPCs lacking PTPα, but suppression of Wnt signaling by the small molecule XAV939 remediated defects in KO oligodendrocyte differentiation and enhanced myelin formation by KO oligodendrocytes. However, the myelin segments that formed were significantly shorter than those produced by WT oligodendrocytes, raising the possibility of a role for glial PTPα in myelin extension distinct from its pro-differentiating actions. Altogether, this study reveals PTPα as a molecular coordinator of oligodendroglial and neuronal signals that controls multiple aspects of oligodendrocyte development and myelination.  相似文献   

7.
Demyelinating diseases are characterized by an extensive loss of oligodendrocytes and myelin sheaths from axolemma. These neurological disorders are a common cause of disability in young adults, but so far, there is no effective treatment against them. It has been suggested that neural stem cells (NSCs) may play an important role in brain repair therapies. NSCs in the adult subventricular zone (SVZ), also known as Type-B cells, are multipotential cells that can self-renew and give rise to neurons and glia. Recent findings have shown that cells derived from SVZ Type-B cells actively respond to epidermal-growth-factor (EGF) stimulation becoming highly migratory and proliferative. Interestingly, a subpopulation of these EGF-activated cells expresses markers of oligodendrocyte precursor cells (OPCs). When EGF administration is removed, SVZ-derived OPCs differentiate into myelinating and pre-myelinating oligodendrocytes in the white matter tracts of corpus callosum, fimbria fornix and striatum. In the presence of a demyelinating lesion, OPCs derived from EGF-stimulated SVZ progenitors contribute to myelin repair. Given their high migratory potential and their ability to differentiate into myelin-forming cells, SVZ NSCs represent an important endogenous source of OPCs for preserving the oligodendrocyte population in the white matter and for the repair of demyelinating injuries.  相似文献   

8.
Myelin loss is frequently observed in human Alzheimer's disease (AD) and may constitute to AD‐related cognitive decline. A potential source to repair myelin defects are the oligodendrocyte progenitor cells (OPCs) present in an adult brain. However, until now, little is known about the reaction of these cells toward amyloid plaque deposition neither in human AD patients nor in the appropriate mouse models. Therefore, we analyzed cells of the oligodendrocyte lineage in a mouse model with chronic plaque deposition (APPPS1 mice) and samples from human patients. In APPPS1 mice defects in myelin integrity and myelin amount were prevalent at 6 months of age but normalized to control levels in 9‐month‐old mice. Concomitantly, we observed an increase in the proliferation and differentiation of OPCs in the APPPS1 mice at this specific time window (6–8 months) implying that improvements in myelin aberrations may result from repair mechanisms mediated by OPCs. However, while we observed a higher number of cells of the oligodendrocyte lineage (Olig2+ cells) in APPPS1 mice, OLIG2+ cells were decreased in number in postmortem human AD cortex. Our data demonstrate that oligodendrocyte progenitors specifically react to amyloid plaque deposition in an AD‐related mouse model as well as in human AD pathology, although with distinct outcomes. Strikingly, possible repair mechanisms from newly generated oligodendrocytes are evident in APPPS1 mice, whereas a similar reaction of oligodendrocyte progenitors seems to be strongly limited in final stages of human AD pathology. © 2012 Wiley Periodicals, Inc.  相似文献   

9.
Progenitor proliferation and differentiation are necessary for oligodendrocyte replacement. Previously, we showed that intraspinal activation of microglia and macrophages with the TLR4 agonist lipopolysaccharide (LPS) induced robust oligodendrocyte genesis. In this study we investigated whether this process involves iron since LPS can alter macrophage regulation of iron and its storage protein ferritin, and oligodendrocytes require iron for proper development and myelination. Further, activated macrophages can sequester and release iron and ferritin. We first examined whether iron or ferritin was present following LPS microinjection. Using Perl's stain, we noted a slight increase in iron at 1d, and peak iron levels 3d post-injection coincident with maximal macrophage activation. Ferritin+ cells were prevalent by 3d and included macrophages and NG2 cells (putative oligodendrocyte progenitors). At 7d, ferritin was mainly expressed by new oligodendrocytes prevalent throughout the lesions. Because of the timing and distribution of iron and ferritin after LPS, we next used an iron chelator to test whether free iron was necessary for maximal LPS-induced oligodendrocyte genesis. Chelating iron by Deferasirox (Exjade®) after LPS microinjection significantly reduced the number of proliferating NG2 cells and new oligodendrocytes. Of the remaining oligodendrocytes, there was a 2-fold decrease in those expressing ferritin, revealing that the number of oligodendrocytes with high iron stores was reduced. Collectively, these results establish that iron accumulates after intraspinal TLR4 activation and is required for maximal TLR4-induced oligodendrogenesis. Since TLR4 agonists are abundant in CNS injury/disease sites, these results suggest that iron may be essential for macrophage/oligodendrocyte communication and adult glial replacement.  相似文献   

10.
Bu J  Banki A  Wu Q  Nishiyama A 《Glia》2004,48(1):51-63
Glial cells that express the NG2 proteoglycan (NG2(+) cells) are considered to be oligodendrocyte progenitors (OPCs) in the central nervous system (CNS), based on their ability to give rise to mature oligodendrocytes in vitro. To understand how dysmyelinated conditions influence OPC proliferation and differentiation, we studied proliferation and differentiation of NG2(+) OPCs in vivo in the shiverer mutant (shi), which do not form compact myelin due to a deletion in the myelin basic protein gene. Acute bromodeoxyuridine (BrdU) labeling studies revealed a 4- to 6-fold increase in NG2(+) cell proliferation in shi spinal cord between postnatal day18 (P18) and P60, and most BrdU(+) cells were NG2(+) after P18. The increased proliferation was accompanied by a 2-fold increase in the number of OPCs and oligodendrocytes. Survival studies following a single injection of BrdU at P18 revealed a decline in the number of BrdU(+)/NG2(+) cells with a concomitant increase in the number of BrdU(+) oligodendrocytes over time, suggesting that the proliferated NG2(+) cells had differentiated into oligodendrocytes. BrdU(+) oligodendrocytes were generated over a longer period of time in shi spinal cord and persisted longer in shi than in wild type spinal cord. These findings suggest that new oligodendrocytes continue to be generated in the dysmyelinated shi spinal cord by enhanced proliferation and differentiation of NG2(+) oligodendrocyte progenitor cells.  相似文献   

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