Endogenous Cell Repair of Chronic Demyelination

Armstrong, Regina C.; Le, Tai; Flint, Nicole C.; Vana, Adam C.; Zhou, Yuan

doi:10.1097/01.jnen.0000205142.08716.7e

Cited by 118 publications

(160 citation statements)

References 49 publications

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“…This may underlie the proregenerative effect of transplanted NPCs on cuprizoneexposed aged mice. Notably, FGF2 has been shown to inhibit OPC differentiation (McKinnon et al, 1990;Murtie et al, 2005;Armstrong et al, 2006). However, in addition to their mitogenic effect, NPCs enhanced maturation of oligodendrocytes in vitro and facilitated remyelination in vivo.…”

Section: Discussionmentioning

confidence: 99%

Transplanted Neural Precursors Enhance Host Brain-Derived Myelin Regeneration

Einstein¹,

Friedman-Levi²,

Grigoriadis³

et al. 2009

J. Neurosci.

112

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In multiple sclerosis lesions resident oligodendrocyte progenitor cells (OPCs) are present, but fail to remyelinate. In the current study we examined whether neural precursor cell (NPC) transplantation can facilitate host brain-derived remyelination. We used the chronic cuprizone-induced demyelination model in aged mice, in which slow remyelination follows cuprizone removal. NPCs were transplanted to the lateral ventricles (intracerebroventricular) of cuprizone-induced demyelinated brains. In this experimental setup, transplanted cells remained mostly in the periventricular area in an undifferentiated state. The extent of demyelination, remyelination, and proliferation of host brain regenerative cell population were examined at 1 week posttransplantation in the splenium of the corpus callosum, which was devoid of any transplanted cells. Transplantation of NPCs, but not of control, human embryonic kidney cells, significantly enhanced remyelination compared with sham-operated mice. Remyelination was performed exclusively by host brain OPCs. The proregenerative effect of transplanted NPCs was related to an increase in the proliferation of host brain OPCs. To examine the mechanism that underlies the proregenerative effect of NPCs in vitro, we used an NPC-OPC coculture system. These experiments indicated that NPCs induced the proliferation of OPCs and facilitated their differentiation into mature oligodendrocytes. The mitogenic effect of NPCs was mediated by platelet-derived growth factor-AA and fibroblast growth factor-2. In conclusion, NPC transplantation enhances hostderived myelin regeneration following chronic demyelination. This trophic effect may stimulate resident OPCs to overcome the remyelination failure in multiple sclerosis.

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Section: Discussionmentioning

confidence: 99%

Transplanted Neural Precursors Enhance Host Brain-Derived Myelin Regeneration

Einstein¹,

Friedman-Levi²,

Grigoriadis³

et al. 2009

J. Neurosci.

112

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“…9 After removal of the toxin spontaneous remyelination occurs. 10 Even though cortical demyelination has recently been described, 11 there was no detailed description and cortical remyelination has not yet been investigated. Here, we describe that cortical de-and remyelination are a prominent feature in this model and characterize the pathological process in detail.…”

mentioning

confidence: 99%

Cortical Demyelination Is Prominent in the Murine Cuprizone Model and Is Strain-Dependent

Skripuletz

Lindner

Kotsiari

et al. 2008

The American Journal of Pathology

240

193

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The cuprizone model of toxic demyelination in the central nervous system is commonly used to investigate the pathobiology of remyelination in the corpus callosum. However, in human demyelinating diseases such as multiple sclerosis, recent evidence indicates a considerable amount of cortical demyelination in addition to white matter damage. Therefore, we have investigated cortical demyelination in the murine cuprizone model. To induce demyelination, C57BL/6 mice were challenged with 0.2% cuprizone feeding for 6 weeks followed by a recovery phase of 6 weeks with a cuprizone-free diet. In addition to the expected demyelination in the corpus callosum, the cortex of C57BL/6 mice was completely demyelinated after 6 weeks of cuprizone feeding. After withdrawal of cuprizone the cortex showed complete remyelination similar to that in the corpus callosum. When C57BL/6 mice were fed cuprizone for a prolonged period of 12 weeks, cortical remyelination was significantly delayed. Because interstrain differences have been described, we also investigated the effects of cuprizone on cortical demyelination in BALB/cJ mice. In these mice, cortical demyelination was only partial. Moreover, cortical microglia accumulation was markedly increased in BALB/cJ mice, whereas microglia were absent in the cortex of C57BL/6 mice. In summary, our results show that cuprizone feeding is an excellent model in which to study cortical demyelination and remyelination, including contributing genetic factors represented by strain differences. (Am J Pathol

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“…Furthermore, pharmacological inhibition of notch signaling may enhance remyelination [9]. Our analysis of FGF2 null mice indicated improved remyelination associated with removal of FGF2 inhibition of OP differentiation, while we did not find evidence of an FGF2 effect on OP proliferation in vivo [2,3,15].…”

Section: Discussionmentioning

confidence: 36%

“…FGF2 expression increases postnatally in the CNS and can inhibit OP differentiation through activation of FGFR1 [14,25]. Similarly, Notch1 and FGFR1 expression is increased in demyelinated lesions along with Jagged1 and FGF2 [2,8,13,15]. Notch1 and Jagged1 expression in multiple sclerosis lesions correlated with areas of poor remyelination consistent with inhibition of OP cells into remyelinating oligodendrocytes [8].…”

Section: Discussionmentioning

confidence: 89%

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Interaction of fibroblast growth factor 2 (FGF2) and notch signaling components in inhibition of oligodendrocyte progenitor (OP) differentiation

Zhou

Armstrong

2007

Neuroscience Letters

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Oligodendrocyte progenitor (OP) cell differentiation is a critical process of developmental myelination, tumor formation, and remyelination in the CNS. Activation of the fibroblast growth factor 2 (FGF2) or notch pathway can inhibit differentiation of OP cells. The current study examines the interaction of FGF2 and notch signaling components in regulating OP differentiation. Cultured neonatal rat brain OP cells were used for transfection-based promoter assays and for infection with retroviruses expressing a GFP reporter to monitor OP differentiation into oligodendrocytes or astrocytes. FGF2 treatment resulted in a 4-fold increase of transcriptional activity from the promoter region of Hes5, a notch pathway target gene. FGF2 inhibition of OP differentiation into oligodendrocytes was perturbed by retroviral expression of a dominant negative construct for mastermind-like 1, which is an important co-activator of transcription for notch target genes. OP differentiation into oligodendrocytes was reduced by co-culture with fibroblasts expressing Jagged1, a ligand for notch receptors. This Jagged1 inhibition of OP differentiation was not altered by retroviral expression of a dominant negative FGF receptor construct. Constitutive activation of notch signaling, by retroviral expression of the Notch1 intracellular domain, greatly reduced OP differentiation into either oligodendrocytes or astrocytes and did not require FGF2 signaling. These findings indicate that inhibition of OP differentiation through the Notch1 pathway was not influenced by FGF2 signaling. However, FGF2 signaling may interact with down stream components of the notch signaling pathway, including mastermind-like1 and Hes5, to inhibit OP differentiation into oligodendrocytes.

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Endogenous Cell Repair of Chronic Demyelination

Cited by 118 publications

References 49 publications

Transplanted Neural Precursors Enhance Host Brain-Derived Myelin Regeneration

Transplanted Neural Precursors Enhance Host Brain-Derived Myelin Regeneration

Cortical Demyelination Is Prominent in the Murine Cuprizone Model and Is Strain-Dependent

Interaction of fibroblast growth factor 2 (FGF2) and notch signaling components in inhibition of oligodendrocyte progenitor (OP) differentiation

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