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ReMyelination

  1. ReMyelination is extensive in a subset of Multiple Sclerosis patients
    Brain 2006 Dec;129(Pt 12):3165-72

  2. Inflammation stimulates ReMyelination in areas of chronic DeMyelination
    Brain 2005 Mar;128(Pt 3):528-39

  3. Re-expression of PSA-NCAM by DeMyelinated Axons: an inhibitor of ReMyelination in Multiple Sclerosis?
    Brain 2002 Sep;125(Pt 9):1972-9

  4. Do Central Nervous System Axons ReMyelinate?
    Pathol Biol (Paris) 2000 Feb;48(1):70-9

  5. Oligodendrocyte Survival, loss and birth in Chronic MS lesions
    Brain 2000 Jan;123(Pt 1):105-115

  6. Novel microtubule-associated protein-2 expressed in Oligodendrocytes in Multiple Sclerosis lesions
    J NeuroChem 1999 Dec;73(6):2531-7

  7. Stem Cell transplantation in DysMyelinated shiverer mouse
    The National Academy of Sciences 0027-8424/99/967029-6 Vol. 96, Issue 12, 7029-7034, June 8, 1999

  8. NeuroTrophin-3 (NT-3) promotes growth of Axons in the Spinal Cord's dorsal columns
    Eur J NeuroSci 1999 Nov;11(11):3873-83

  9. Survival of chronically-injured Neurons can be prolonged with NeuroTrophic Factors
    NeuroScience 1999;94(3):929-36

  10. Bulk File Must Read
    Dr. Cedric S. Raine's Multiple Sclerosis investigations

  11. ReMyelination in Multiple Sclerosis
    Mult Scler 1997 Apr;3(2):133-6

  12. Conduction in central segmentally DeMyelinated Axons
    J NeuroSci 1997 Oct 1;17(19):7267-77

  13. Glial Growth Factor 2 (GGF2) enhances ReMyelination
    The National Academy of Sciences: Vol. 95, Issue 17, 10100-10105, August 18, 1998

  14. Advances in Glial Growth Factor 2 (GGF2) program for MS
    Cambridge NeuroScience, Inc.

  15. Microglia not Oligodendrocyte cells are eliminated by Apoptosis
    J Immunol 159: 5733-41 (1997)

  16. ReMyelination occurs in Nascent lesions
    Annals of Neurology 1993 Feb; 22(2): 137-51

  17. Bulk File
    Oligodendrocytes, Myelin, and Lesions in Multiple Sclerosis

  18. Oligodendrocytes proliferate & differentiate in early MS lesions
    Lab Invest 61:489-503 (1989)

  1. Chronic stage MS lesions retain Oligodendrocyte Precursor Cells
    J NeuroSci 1998 Jan 15;18(2):601-609

  2. Glial fibrillary Acidic Protein (GFAP) necessary for Myelination
    Am J Pathol 1998 Jan; 152(1):251-259

  3. Expression of a developmental Gene correlates with ReMyelination
    Ann Neurol 41: 797-805 (1997)

  4. PreMyelinating Oligodendrocytes in chronic lesions of Multiple Sclerosis
    N Engl J Med 2002 Jan 17;346(3):165-73

  5. The role of NCAM in ReMyelination
    Neurol Sci 2002 Mar;22(6):429-35

  6. ReMyelinated lesions in Multiple Sclerosis - Magnetic Resonance image appearance
    Arch Neurol 2003;60(8):1073-81

  7. Impaired Remyelination and depletion of Oligodendrocyte Progenitors does not occur following repeated episodes of focal Demyelination in the rat Central Nervous System
    Brain 2003 Jun;126(Pt 6):1382-91

  8. Endogenous Nkx2.2+/Olig2+ Oligodendrocyte Precursor Cells fail to ReMyelinate the DeMyelinated adult rat Spinal Cord in the absence of Astrocytes
    Exp Neurol 2005 Mar;192(1):11-24



      Internet Links
  1. The Myelin Project  The Myelin Project
  2. Axonal Protection In Multiple Sclerosis—a Particular Need During ReMyelination?
    by: Kenneth J. Smith
    Institute of Psychiatry, Department of Clinical NeuroSciencesy, King's College London 19 Newcomen Street, London, SE1 1UL, UK
    Brain 2006


  3. Human Trials Imminent For MS Volunteers
    The Canadian Myelin Research Initiative
    Research News: November 1999


  4. Stem Cells Come Of Age
    by: Tim Beardsley
    Scientific American, July 1999




#1

Chronic MS Lesions Retain
Oligodendrocyte Precursor Cells

Wolswijk G
J NeuroSci 1998 Jan 15;18(2):601-609
Netherlands Institute for Brain Research, Graduate School NeuroSciences Amsterdam, 105 AZ Amsterdam ZO, The Netherlands
UI# 98086312
Abstract

In the past decade, considerable progress has been made in the understanding of the biology of rodent Oligodendrocyte Precursor Cells and their role in the generation of Oligodendrocytes in the developing and adult rodent CNS.

Much less is known about human Oligodendrocyte lineage cells and about the reasons for the failure of the regeneration of the Oligodendrocyte population during chronic stages of Multiple Sclerosis (MS).

In particular, the fate of the Oligodendrocyte Precursor population in MS has remained elusive.

The present study examined the possibility that Oligodendrocyte regeneration ultimately fails because of the local destruction of both Oligodendrocytes and their Precursor cells.

Analysis of chronic stage MS tissue suggested that this is not the case, because all chronic MS lesions studied contained significant numbers of Oligodendrocyte Precursor Cells.

Identified as Process-bearing cells that bound the O4 AntiBody but not AntiBodies to GalC and GFAP.

The Oligodendrocyte Precursor Cells appeared, however, to be relatively quiescent.

Because, none expressed the Nuclear Proliferation Antigen recognized by the Ki-67 AntiBody, and because most lesions lacked Myelinating Oligodendrocytes in their centers.

Thus, it appears that the regeneration of the Oligodendrocyte population fails during chronic stages of MS.

Because, of the inability of Oligodendrocyte Precursor Cells to proliferate and differentiate rather than because of the local destruction of all Oligodendrocyte lineage cells.

The identification of ways of stimulating the endogenous Oligodendrocyte Precursor population to expand and generate ReMyelinating Cells may represent an alternative to transplantation of Oligodendrocyte Lineage Cells to promote Myelin repair in MS.



#2

Glial Fibrillary Acidic Protein
Necessary for Myelination

Liedtke W, Edelmann W, Chiu FC, Kucherlapati R, Raine CS
Am J Pathol 1998 Jan; 152(1):251-259
Albert Einstein College of Medicine, Dept of Pathology, Bronx, New York 10461, USA
UI# 98083005
Abstract

Insights into the role of the Astrocyte intermediate Filament protein, Glial Fibrillary Acidic Protein (GFAP), have only recently emerged.

With reports on subtle abnormalities in GFAP-deficient mice, including the documentation of defective long-term maintenance of Central Nervous System Myelination.

Here, we extend these observations by examining the Astroglial response in GFAP-/- mice with AutoImmune EncephaloMyelitis (EAE), a model for Multiple Sclerosis.

Clinically, the Monophasic Disease was more severe in GFAP-/- mice than in wild-type littermates despite increased ReMyelination in the former.

More in keeping with the clinical course was the observation of an infiltrative EAE lesion in GFAP-/- mice.

GFAP-/- Astrocytes had a reduced cyto-architectural stability as evidenced by less abundant and irregularly spaced HemiDesmosomes.

The blunt GFAP-/- Astrocyte Processes possessed intermediate filaments consisting mainly of Vimentin, though to a lesser degree than in the wild-type.

In contrast, in wild-type littermates, GFAP was most abundant and Nestin occurred at lower levels.

Taken together, the present study introduces the novel concepts that GFAP plays an important role in the control of clinical disease associated with formation of a clearly defined edge to the EAE lesion.

And, that GFAP is operative in the regulation of the intermediate Filament components in Reactive Fibrillary AstroGliosis.



#3

Expression of Early Gene
Correlates with ReMyelination

Capello E; Voskuhl RR; McFarland HF; Raine CS
Ann Neurol 41: 797-805 (1997)
Albert Einstein College of Medicine, Dept of Pathology, Bronx, NY 10461, USA
UI # 97332879
Abstract

Central Nervous System tissue from Multiple Sclerosis and non-Multiple Sclerosis subjects was studied for the expression of Exon 2 Myelin Basic Protein Gene products.

At the Protein and message levels by ImmunoCytocHemistry and In Situ Hybridization, respectively.

The Exon 2-encoded pProtein sequence is normally expressed during the development of (CNS) Myelination.

Within the 21.5- and 20.2-kd Isoforms of Myelin Basic Protein and is downregulated in the adult Central Nervous System where the 18.5- and 17.2-kd Isoforms predominate, the latter devoid of Exon 2 owing to alternative splicing.

Exon 2 Myelin Basic Protein Gene products were readily demonstrable in Multiple Sclerosis samples, the highest levels correlating with ReMyelination in chronic Lesions.

While normal adult Central Nervous System and Non-Multiple Sclerosis material showed very low levels and fetal human Central Nervous System tissue (a positive control) showed high levels.

We conclude that recapitulation of OntoGenetic events during Myelin repair accounts for the increased expression of the Exon 2-encoded Protein sequence in the adult Central Nervous System during Multiple Sclerosis.

An event that might underly the previously observed T-Cell activation to this protein sequence during relapses.



#4

PreMyelinating Oligodendrocytes in Chronic Lesions Of Multiple Sclerosis

Chang A, Tourtellotte WW, Rudick R, Trapp BD
N Engl J Med 2002 Jan 17;346(3):165-73
Lerner Research Institute, Cleveland Clinic Foundation, Department of NeuroSciences, Cleveland, OH 44195, USA
PMID# 11796850
Abstract

Background
Multiple Sclerosis is an Inflammatory Disease of the Central Nervous System that destroys Myelin, Oligodendrocytes, and Axons.

Since most of the lesions of Multiple Sclerosis are not ReMyelinated, enhancement of ReMyelination is a possible therapeutic strategy that could perhaps be achieved with the transplantation of Oligodendrocyte-Producing Cells into the lesions.

We investigated the frequency distribution and configuration of Oligodendrocytes in chronic lesions of Multiple Sclerosis to determine whether these factors limit ReMyelination.

Methods
Forty-eight chronic lesions obtained at autopsy from 10 patients with Multiple Sclerosis were examined ImmunoCytoChemically for Oligodendrocytes and Oligodendrocyte Progenitor Cells.

Using confocal microscopy, we examined the three-dimensional relations between Axons and the Processes of PreMyelinating Oligodendrocytes.

Results
Thirty-four of the 48 chronic lesions of Multiple Sclerosis contained Oligodendrocytes with multiple extended Processes that associated with DeMyelinated Axons but failed to Myelinate them.

These Axons were Dystrophic and contained multiple swellings. In some regions, the densities of PreMyelinating Oligodendrocytes (25 per square millimeter of tissue) were similar to those in the developing rodent Brain (23 per square millimeter).

In the patients with disease of long duration (more than 20 years), there were fewer lesions with PreMyelinating Oligodendrocytes (P<0.001).

Conclusions
PreMyelinating Oligodendrocytes are present in chronic lesions of Multiple Sclerosis, so ReMyelination is not limited by an absence of Oligodendrocyte Progenitors or their failure to generate Oligodendrocytes.

Our findings suggest that in the chronic lesions of Multiple Sclerosis, the Axons are not receptive for ReMyelination.

Understanding the cellular interactions between PreMyelinating Oligodendrocytes, Axons, and the MicroEnvironment of lesions of Multiple Sclerosis may lead to effective strategies for enhancing ReMyelination.



#5

The Role Of NCAM In ReMyelination

Massaro AR
Neurol Sci 2002 Mar;22(6):429-35
Institute of Neurology, UCSC Medical School, Largo Gemelli 8, I-00168 Rome, Italy
PMID# 11976973
Abstract

The Neural Cell Adhesion Molecule (NCAM) is expressed by Myelinating Precursor Cells in Neonatal mouse Spinal Cord and by ReMyelinating Cells after chemically induced DeMyelination in adult mouse.

It shows tempting suggestions about its possible involvement in the reparative mechanisms and the ReMyelination processes that take place in Multiple Sclerosis (MS).

In fact, its levels progressively increase in the CerebroSpinal Fluid (CSF) of acute MS patients subjected to Steroid treatment, paralleling the progressive clinical improvement after the attack.

Such an increase is not found in acute MS patients not treated with Steroids nor in non-acute patients subjected to the same Steroid treatment.



#6

ReMyelinated Lesions In Multiple Sclerosis -
Magnetic Resonance Image Appearance

Barkhof F, Bruck W, De Groot CJ, Bergers E, Hulshof S, Geurts J, Polman CH, van der Valk P
Arch Neurol 2003;60(8):1073-81
Dutch MR-MS Center, and Vrije Universiteit Medical Center, Department of Radiology, PO Box 7057, 1007 MB Amsterdam, the Netherlands
PMID# 12925362
Abstract

Background
Various types of pathologic mechanisms in Multiple Sclerosis (MS) can alter Magnetic Resonance Imaging (MRI) signals, and the appearance of ReMyelinated lesions on MRI is largely unknown.

Objective, Design & Setting
To describe the MRI appearance of ReMyelinated lesions in MS. Comparison of postmortem MRI findings with HistoPathologic findings. Brain donations from a general community.

Patients
Magnetic Resonance images from 36 rapid autopsies yielded 161 areas that could be matched with Histologic characteristics.

Including 149 focal T2-weighted abnormalities, with a range of signal intensities on T1-weighted images. In a subset of 49 lesions, Magnetization Transfer Ratios could be determined.

Main Outcome Measures
An observer blinded to the MRI findings assessed the presence of ReMyelination using Light Microscopic Criteria; in 25 areas, in situ hybridization was used to assess the presence of Oligodendrocytes expressing ProteoLipid Protein Messenger RNA.

    Results
  1. ReMyelinated areas were found in 67 lesions (42%)
  2. Partial ReMyelination was present in 30 lesions (19%)
  3. Whereas 37 lesions (23%) were fully ReMyelinated

ReMyelinated lesions contained enhanced numbers of Oligodendrocytes containing ProteoLipid Protein Messenger RNA. All areas with ReMyelination shown HistoPathologically were HyperIntense on T2-weighted images.

Strong HypoIntensity on T1-weighted images was significantly associated (chi2 = 29.8, P < .001) with DeMyelinated and partially ReMyelinated lesions compared with fully ReMyelinated lesions.

The Magnetization Transfer Ratio of ReMyelinated lesions (mean [SD], 27.6% [41%]) differed (F = 46.3, P< .001) from both Normal-Appearing White Matter (35.2% [32%]) and DeMyelinated lesions (22.3% [48%]).

Conclusions
ReMyelinated lesions return an abnormal signal on T2-weighted images. Both T1-weighted images and Magnetization Transfer Ratios may have (limited) additional value in separating lesions with and without ReMyelination.



#7

Impaired Remyelination And Depletion Of Oligodendrocyte Progenitors Does Not Occur Following Repeated Episodes Of Focal Demyelination In The Rat Central Nervous System

Penderis J, Shields SA, Franklin RJ
Brain 2003 Jun;126(Pt 6):1382-91
University of Cambridge, Cambridge Centre for Brain Repair and Department of Clinical Veterinary Medicine, Madingley Road, Cambridge, UK
PMID# 12764059
Abstract

It has been hypothesized that the progressive failure of ReMyelination in chronic Multiple Sclerosis is, in part, the consequence of repeated episodes of DeMyelination at the same site, eventually depleting Oligodendrocyte Progenitor Cells (OPCs) and exhausting the ReMyelinating capacity.

We investigated the effect of previous focal, Ethidium Bromide-induced DeMyelination of BrainStem White Matter (with intervening recovery) on the efficiency of the ReMyelination process during second and third subsequent episodes of DeMyelination, and the OPC response during a second episode of DeMyelination.

Previous focal DeMyelinating lesions followed by recovery did not result in any retardation of the ReMyelination process, nor did they alter the proportion of Schwann Cell versus Oligodendrocyte ReMyelination.

The OPC response during ReMyelination was quantified by in situ hybridization using a probe to Platelet-Derived Growth Factor-alpha Receptor (PDGF alpha R), an OPC-expressed mRNA.

Following recovery from focal, toxin-induced CNS DeMyelination, the OPC density returned to levels equivalent to those in normal White Matter.

Further more, there was no depletion of OPCs following repeated episodes of focal, toxin-induced CNS DeMyelination at the same site.

These results indicate that repeated CNS DeMyelination, which has the opportunity to repair in the intervening period, is not characterized by impaired ReMyelination or depletion of OPCs.depletion of OPCs.



#8

Endogenous Nkx2.2+/Olig2+ Oligodendrocyte Precursor Cells fail to Remyelinate the Demyelinated adult rat Spinal Cord in the absence of Astrocytes

Talbott JF, Loy DN, Liu Y, Qiu MS, Bunge MB, Rao MS, Whittemore SR
Exp Neurol 2005 Mar;192(1):11-24
University of Louisville, The MD/PhD Program, Louisville, KY 40292, USA
PMID# 15698615
Abstract

Chronic DeMyelination is a pathophysiologic component of compressive Spinal Cord Injury (SCI) and a characteristic finding in Demyelinating Diseases including Multiple Sclerosis (MS).

A better characterization of endogenous cells responsible for successful ReMyelination is essential for designing therapeutic strategies aimed at restoring functional Myelin.

The present study examined the SpatioTemporal response of endogenous Oligodendrocyte Precursor Cells (OPCs) following Ethidium Bromide (EB)-induced DeMyelination of the adult rat Spinal Cord.

Beginning at 2 days post-EB injection (dpi), a robust mobilization of highly proliferative NG2+ cells within the lesion was observed, none of which expressed the Oligodendrocyte lineage-associated transcription factor Nkx2.2.

At 7 dpi, a significant up-regulation of Nkx2.2 by OPCs within the lesion was observed, 90% of which coexpressed NG2 and virtually all of which coexpressed the bHLH transcription factor Olig2.

Despite successful recruitment of Nkx2.2+/Olig2+ OPCs within the lesion, DeMyelinated Axons were not ReMyelinated by these OPCs in regions lacking Astrocytes.

Rather, Schwann Cell ReMyelination predominated throughout the central core of the lesion, particularly around blood vessels.

Oligodendrocyte ReMyelination was observed in the Astrogliotic perimeter, suggesting a necessary role for Astrocytes in Oligodendrocyte maturation.

In addition, re-expression of the Radial Glial Antigen, RC-1, by reactive Astrocytes and Ependymal Cells was observed following injury.

However, these cells did not express the Neural Stem Cell (NSC)-associated transcription factors Sox1 or Sox2, suggesting that the endogenous response is primarily mediated by Glial progenitors.

In vivo electrophysiology demonstrated a limited and unsustained functional recovery concurrent with endogenous ReMyelination following EB-induced lesions.



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