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
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.
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
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.
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.
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).
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.
The Role Of NCAM In ReMyelination
Neurol Sci 2002 Mar;22(6):429-35
Institute of Neurology, UCSC Medical School, Largo Gemelli 8, I-00168 Rome, Italy
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.
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
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.
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.
- ReMyelinated areas were found in 67 lesions (42%)
- Partial ReMyelination was present in 30 lesions (19%)
- 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%]).
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.
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
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.
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
Chronic DeMyelination is a pathophysiologic component of compressive Spinal Cord Injury (SCI) and a characteristic finding in Demyelinating Diseases including Multiple Sclerosis (MS).
Exp Neurol 2005 Mar;192(1):11-24
University of Louisville, The MD/PhD Program, Louisville, KY 40292, USA
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.