Premyelinating Oligodendrocytes in Chronic Lesions of Multiple Sclerosis

Chang, Ansi; Tourtellotte, Wallace W.; Rudick, Richard A.; Trapp, Bruce D.

doi:10.1056/nejmoa010994

Cited by 901 publications

(727 citation statements)

References 38 publications

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“…An age‐dependent decrease in remyelination efficiency, possibly resulting from oligodendrocyte progenitor cells migrating and differentiating less efficiently with age in chronic lesions, has been previously highlighted 38, 39, 40. However, the relationship between the efficiency of remyelination, age, and disease duration is still controversial, and our results contribute to an ongoing debate regarding the key question of whether the remyelination potential remains constant throughout life or is modified by aging and disease stage 37, 41.…”

Section: Discussionsupporting

confidence: 60%

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis

Bodini

Veronese

García-Lorenzo

et al. 2016

Annals of Neurology

207

110

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BackgroundQuantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating therapies. Selectively binding myelin in the central nervous system white matter, Pittsburgh compound B ([11C]PiB) can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS.MethodsPatients with active relapsing‐remitting MS (n = 20) and healthy controls (n = 8) were included in a longitudinal trial combining PET with [11C]PiB and magnetic resonance imaging. Voxel‐wise maps of [11C]PiB distribution volume ratio, reflecting myelin content, were derived. Three dynamic indices were calculated for each patient: the global index of myelin content change; the index of demyelination; and the index of remyelination.ResultsAt baseline, there was a progressive reduction in [11C]PiB binding from the normal‐appearing white matter to MS lesions, reflecting a decline in myelin content. White matter lesions were characterized by a centripetal decrease in the tracer binding at the voxel level. During follow‐up, high between‐patient variability was found for all indices of myelin content change. Dynamic remyelination was inversely correlated with clinical disability (p = 0.006 and beta‐coefficient = –0.67 with the Expanded Disability Status Scale; p = 0.003 and beta‐coefficient = –0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index.Interpretation[11C]PiB PET allows quantification of myelin dynamics in MS and enables stratification of patients depending on their individual remyelination potential, which significantly correlates with clinical disability. This technique should be considered to assess novel promyelinating drugs. Ann Neurol 2016;79:726–738

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Section: Discussionsupporting

confidence: 60%

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis

Bodini

Veronese

García-Lorenzo

et al. 2016

Annals of Neurology

207

110

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“…Phenotypic profiles of such cells include: O4 ϩ GalC Ϫ NG2 Ϫ , 13 PDGF-R␣ ϩ GalC Ϫ , 14,15 PDGF-R␣ ϩ , NG2 ϩ , 16 and PLP ϩ pre-OLGs. 17 These cells do not however appear to be overrepresented nor are they consistently proliferating in the lesions. In late chronic MS lesions, where remyelination is less widespread than in early lesions, the number of both progenitors and mature OLGs is decreased compared to early active lesions.…”

mentioning

confidence: 89%

Distinctive Properties of Human Adult Brain-Derived Myelin Progenitor Cells

Ruffini

Arbour

Blain

et al. 2004

The American Journal of Pathology

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We used expression of the ganglioside A2B5 to isolate putative myelin progenitor cells from adult human central nervous system parenchyma and compared their phenotypic (expression of myelin lineage molecules) and functional (survival, proliferation) properties with mature oligodendrocytes (OLGs) derived from the same adult material and with A2B5 ؉ cells isolated from human fetal brain. A2B5 ؉ cells represented 3 to 5% of the total cell suspension derived from adult specimens. Results of protein (immunostaining) and RNA (polymerase chain reaction) analyses indicated that the adult A2B5 ؉ cells were more committed to the OLG lineage than their fetal counterparts while continuing to retain properties of progenitor cells compared to the postmitotic mature OLGs. Although the adult A2B5 ؉ cells retained the capacity to divide, albeit at a reduced rate compared to fetal A2B5 ؉ cells, they showed reduced survival and process outgrowth compared not only to fetal cells but also to mature OLGs. Our results confirm the presence of progenitor cells committed to the OLG lineage in the adult human central nervous system but raise the issues regarding the intrinsic capacity of these cells to contribute to the process of remyelination that may be necessary during demyelinating diseases. Recovery from relapses in multiple sclerosis (MS) is attributed at least in part to the extent of remyelination observed in early MS lesions. 16 and PLP ϩ pre-OLGs. 17 These cells do not however appear to be overrepresented nor are they consistently proliferating in the lesions. In late chronic MS lesions, where remyelination is less widespread than in early lesions, the number of both progenitors and mature OLGs is decreased compared to early active lesions.Roy and colleagues, 18 reported that progenitor cells (ganglioside A2B5-positive) comprised 3 to 5% of the total cell population derived from human adult temporal lobe resections and could undergo a limited number of cell divisions in vitro. OLGs could be derived only from the A2B5 ϩ population, although this population could also give rise to neurons and astrocytes. 20 -22 The purpose of our current study was to compare phenotypic (myelin lineage gene expression) and functional (in vitro survival, cell cycling, and process formation) properties of the adult A2B5 ϩ cells with those of mature OLGs isolated from the same tissue samples. We further compared the properties of adult A2B5 ϩ cells with their fetal counterparts providing insight for the observation that, when compared to fetal A2B5 ϩ cells, transplanted adult A2B5 ϩ cells produce fewer surviving cells but among those a higher proportion contribute to myelination of the dismyelinated mouse mutants, shiverer mice. 19 -21 Our results demonstrate that the adult A2B5 ϩ cells retain properties of progenitor cells when compared to postmitotic mature human OLGs and are more committed to the OLG lineage than their fetal counterparts. Adult A2B5 ϩ cells,

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“…Some studies showed a depletion of progenitor cells after focal demyelination in experimental animals [52,74], whereas others showed that repeated episodes of demyelination did not slow down remyelination [75]. In pathological specimens of chronic MS lesions in human patients, neither decrease nor reactive increase was observed relative to normal white matter [39,[76][77][78]. This suggests that the response of the progenitor cell population to the demyelinating process in the human brain is deficient.…”

Section: Myelin Regeneration Fails In Msmentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.

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Premyelinating Oligodendrocytes in Chronic Lesions of Multiple Sclerosis

Cited by 901 publications

References 38 publications

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis

Distinctive Properties of Human Adult Brain-Derived Myelin Progenitor Cells

Cell Therapy for Multiple Sclerosis

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