The Experts below are selected from a list of 57219 Experts worldwide ranked by ideXlab platform
Robin J.m. Franklin - One of the best experts on this subject based on the ideXlab platform.
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Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Bartosz Bielecki, Abdel M. Ghoumari, Sakina Mhaouty-kodja, Claudia Mattern, Sumaira Javaid, Kaja Smietanka, Charly Abi Ghanem, M. Said Ghandour, Etienne-emile Baulieu, Robin J.m. FranklinAbstract:Lost myelin can be replaced after injury or during demyelinating diseases in a regenerative process called remyelination. In the central nervous system (CNS), the myelin sheaths, which protect axons and allow the fast propagation of electrical impulses, are produced by oligodendrocytes. The abundance and widespread distribution of oligodendrocyte progenitors (OPs) within the adult CNS account for this remarkable regenerative potential. Here, we report a key role for the male gonad, testosterone, and androgen receptor (AR) in CNS remyelination. After lysolecithin-induced Demyelination of the male mouse ventral spinal cord white matter, the recruitment of glial fibrillary acidic protein-expressing astrocytes was compromised in the absence of testes and testosterone signaling via AR. Concomitantly, the differentiation of OPs into oligodendrocytes forming myelin basic protein (MBP)(+) and proteolipid protein-positive myelin was impaired. Instead, in the absence of astrocytes, axons were remyelinated by protein zero (P0)(+) and peripheral myelin protein 22-kDa (PMP22)(+) myelin, normally only produced by Schwann cells in the peripheral nervous system. Thus, testosterone favors astrocyte recruitment and spontaneous oligodendrocyte-mediated remyelination. This finding may have important implications for demyelinating diseases, psychiatric disorders, and cognitive aging. The testosterone dependency of CNS oligodendrocyte remyelination may have roots in the evolutionary history of the AR, because the receptor has evolved from an ancestral 3-keto-steroid receptor through gene duplication at the time when myelin appeared in jawed vertebrates.
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Demyelination causes adult cns progenitors to revert to an immature state and express immune cues that support their migration
The Journal of Neuroscience, 2015Co-Authors: Sarah Moyon, Jeffrey K. Huang, Marie-stéphane Aigrot, Christophe Kerninon, Anne Laure Dubessy, Matthew Trotter, Luce Dauphinot, Marieclaude Potier, Stephane Melik Parsadaniantz, Robin J.m. FranklinAbstract:The declining efficiency of myelin regeneration in individuals with multiple sclerosis has stimulated a search for ways by which it might be therapeutically enhanced. Here we have used gene expression profiling on purified murine oligodendrocyte progenitor cells (OPCs), the remyelinating cells of the adult CNS, to obtain a comprehensive picture of how they become activated after Demyelination and how this enables them to contribute to remyelination. We find that adult OPCs have a transcriptome more similar to that of oligodendrocytes than to neonatal OPCs, but revert to a neonatal-like transcriptome when activated. Part of the activation response involves increased expression of two genes of the innate immune system, IL1β and CCL2, which enhance the mobilization of OPCs. Our results add a new dimension to the role of the innate immune system in CNS regeneration, revealing how OPCs themselves contribute to the postinjury inflammatory milieu by producing cytokines that directly enhance their repopulation of areas of Demyelination and hence their ability to contribute to remyelination.
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Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells
Neurotherapeutics, 2011Co-Authors: Jeffrey K. Huang, Stephen P.j. Fancy, Chao Zhao, Charles Ffrench-constant, David H Rowitch, Robin J.m. FranklinAbstract:Regeneration of myelin sheaths (remyelination) after central nervous system Demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.
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Remyelination - An effective means of neuroprotection.
Hormones and Behavior, 2009Co-Authors: Charlotte C. Bruce, Chao Zhao, Robin J.m. FranklinAbstract:Remyelination following central nervous system (CNS) Demyelination restores rapid saltatory conduction of action potentials and contributes to the maintenance of axonal integrity. This robust regenerative phenomenon stands in contrast to the limited repair capacity that is characteristic of CNS neuronal injury. However, despite its efficiency in experimental models and some clinical diseases, remyelination failure becomes an increasingly pronounced feature of the pathology of chronic multiple sclerosis (MS) lesions. Chronic Demyelination predisposes axons to atrophy, an irreversible event that is a major pathological correlate of progressive functional decline. This has created a compelling case for developing therapies that promote remyelination: evidence from experimental animal models suggests that hormones may have a beneficial role to play in this regard.
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myelin mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of fyn rhoa and protein kinase c signalling
Brain, 2009Co-Authors: Alexandra S Baer, Robin J.m. Franklin, Yasir Ahmed Syed, Sung Ung Kang, Dieter Mitteregger, Raluca Vig, Charles Ffrenchconstant, Friedrich Altmann, Gert Lubec, Mark R N KotterAbstract:Failure of oligodendrocyte precursor cell (OPC) differentiation contributes significantly to failed myelin sheath regeneration (remyelination) in chronic demyelinating diseases. Although the reasons for this failure are not completely understood, several lines of evidence point to factors present following Demyelination that specifically inhibit differentiation of cells capable of generating remyelinating oligodendrocytes. We have previously demonstrated that myelin debris generated by Demyelination inhibits remyelination by inhibiting OPC differentiation and that the inhibitory effects are associated with myelin proteins. In the present study, we narrow down the spectrum of potential protein candidates by proteomic analysis of inhibitory protein fractions prepared by CM and HighQ column chromatography followed by BN/SDS/SDS–PAGE gel separation using Nano-HPLC-ESI-Q-TOF mass spectrometry. We show that the inhibitory effects on OPC differentiation mediated by myelin are regulated by Fyn-RhoA-ROCK signalling as well as by modulation of protein kinase C (PKC) signalling. We demonstrate that pharmacological or siRNA-mediated inhibition of RhoA-ROCK-II and/or PKC signalling can induce OPC differentiation in the presence of myelin. Our results, which provide a mechanistic link between myelin, a mediator of OPC differentiation inhibition associated with demyelinating pathologies and specific signalling pathways amenable to pharmacological manipulation, are therefore of significant potential value for future strategies aimed at enhancing CNS remyelination.
Martin Stangel - One of the best experts on this subject based on the ideXlab platform.
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Investigation of Cuprizone Inactivation by Temperature
Neurotoxicity Research, 2017Co-Authors: Sandra Heckers, Nadine Held, Jessica Kronenberg, André Bleich, Thomas Skripuletz, Viktoria Gudi, Martin StangelAbstract:Animal models, such as cuprizone (bis-cyclohexanone oxaldihydrazone) feeding, are helpful to study experimental Demyelination and remyelination in the context of diseases like multiple sclerosis. Cuprizone is a copper chelator, which when supplemented to the normal food of C57BL/6J mice in a concentration of 0.2% leads to oligodendroglial loss, subsequent microglia and astrocyte activation, resulting in Demyelination. Termination of the cuprizone diet results in remyelination, promoted by newly formed mature oligodendrocytes. The exact mode of cuprizone’s action is not well understood, and information about its inactivation and cleavage are still not available. The knowledge of these processes could lead to a better understanding of cuprizone’s mode of action, as well as a safer handling of this toxin. We therefore performed experiments with the aim to inactivate cuprizone by thermal heating, since it was suggested in the past that cuprizone is heat sensitive. C57BL/6J mice were fed for 4 weeks with 0.2% cuprizone, either thermally pretreated (60, 80, 105, 121 °C) or not heated. In addition, primary rat oligodendrocytes, as a known selective toxic target of cuprizone, were incubated with 350 μM cuprizone solutions, which were either thermally pretreated or not. Our results demonstrate that none of the tested thermal pretreatment conditions could abrogate or restrict the toxic and demyelinating effects of cuprizone, neither in vitro nor in vivo. In conclusion, the current study rebuts the hypothesis of cuprizone as a heat-sensitive compound, as well as the assumption that heat exposure is a reason for an insufficient Demyelination of cuprizone-containing pellets.
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astrocytes regulate myelin clearance through recruitment of microglia during cuprizone induced Demyelination
Brain, 2013Co-Authors: Thomas Skripuletz, Viktoria Gudi, Refik Pul, Diane Hackstette, Katharina Bauer, Elke Voss, Katharina Berger, Markus Kipp, Wolfgang Baumgartner, Martin StangelAbstract:Recent evidence suggests that astrocytes play an important role in regulating de- and remyelination in multiple sclerosis. The role of astrocytes is controversial, and both beneficial as well as detrimental effects are being discussed. We performed loss-of-function studies based on astrocyte depletion in a cuprizone-induced rodent model of Demyelination. This led to strong astrogliosis accompanied by microgliosis and Demyelination in C57BL/6 wild-type mice. Ablation of astrocytes in glial fibrillary acidic protein-thymidine kinase transgenic mice was associated with a failure of damaged myelin removal and a consecutive delay in remyelination. Despite oligodendrocyte death, myelin was still present, but ultrastructual investigations showed that the myelin structure was loosened and this damaged myelin did not protect axons. These alterations were associated with a decrease in microglial activation. Thus, our results show that astrocyte loss does not prevent myelin damage, but clearance of damaged myelin through recruitment of microglia is impaired. Further studies suggest that this process is regulated by the chemokine CXCL10. As a consequence of the delayed removal of myelin debris, remyelination and oligodendrocyte precursor cell proliferation were impaired. Experiments omitting the influence of myelin debris demonstrated an additional beneficial effect of astrocytes on oligodendrocyte regeneration during remyelination. In conclusion, these data demonstrate for the first time in vivo that astrocytes provide the signal environment that forms the basis for the recruitment of microglia to clear myelin debris, a process required for subsequent repair mechanisms. This is of great importance to understanding regenerative processes in demyelinating diseases such as multiple sclerosis.
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regional differences between grey and white matter in cuprizone induced Demyelination
Brain Research, 2009Co-Authors: Viktoria Gudi, Thomas Skripuletz, Corinna Trebst, Paraskevi N. Koutsoudaki, Alexandra Kotsiari, Darius Moharreghkhiabani, Jelena Skuljec, Martin StangelAbstract:Cuprizone feeding is a commonly used model to study experimental de- and remyelination, with the corpus callosum being the most frequently investigated white matter tract. We have previously shown that Demyelination is also extensive in the cerebral cortex in the cuprizone model. In the current study, we have performed a detailed analysis of the dynamics of Demyelination in the cortex in comparison to the corpus callosum. Prominent and almost complete Demyelination in the corpus callosum was observed after 4.5-5 weeks of 0.2% cuprizone feeding, whereas complete cortical Demyelination was only observed after 6 weeks of cuprizone feeding. Interestingly, remyelination in the corpus callosum occurred even before the termination of cuprizone administration. Accumulation of microglia in the corpus callosum started as early as week 3 reaching its maximum at week 4.5 and was still significantly elevated at week 6 of cuprizone treatment. Within the cortex only a few scattered activated microglial cells were found. Furthermore, the intensity of astrogliosis, accumulation of oligodendrocyte progenitor cells and nestin positive cells differed between the two areas investigated. The time course and dynamics of Demyelination differ in the corpus callosum and in the cortex, suggesting different underlying pathomechanisms.
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Cerebellar cortical Demyelination in the murine cuprizone model.
Brain pathology (Zurich Switzerland), 2009Co-Authors: Thomas Skripuletz, Viktoria Gudi, Maren Lindner, Paraskevi N. Koutsoudaki, Jens-heiko Bussmann, Refik Pul, Darius Moharregh-khiabani, Martin StangelAbstract:In multiple sclerosis, Demyelination occurs beside the white-matter structures and in the cerebral and cerebellar cortex. We have previously shown that, in the cuprizone model, Demyelination is present not only in the corpus callosum but also in the cerebral cortex. Here, we have performed a detailed analysis of the dynamics of de- and remyelination in the cerebellar cortex and white matter at nine timepoints in two cerebellar regions. To induce Demyelination, C57BL/6 mice were fed with 0.2% cuprizone for 12 weeks followed by a recovery of 8 weeks. Both cortex and white-matter structures were significantly demyelinated after 12 weeks of cuprizone feeding. Remyelination occurred after withdrawal of cuprizone but was less prominent in the more caudal cerebellar region. Microglia infiltration was prominent in all analyzed cerebellar areas, preceding Demyelination by approximately 2-4 weeks, and was delayed in the more caudal cerebellar region. Astrogliosis was also seen but did not reach the extent observed in the cerebrum. In summary, cuprizone feeding provides an excellent model for the investigation of de- and remyelination processes in the cerebellar cortex and white matter. Furthermore, Demyelination, microglia and astrocyte changes were different in the cerebellum as compared with the cerebrum, indicating region-dependent pathomechanisms.
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The chemokine receptor CXCR2 is differentially regulated on glial cells in vivo but is not required for successful remyelination after cuprizone‐induced Demyelination
Glia, 2008Co-Authors: Maren Lindner, Thomas Skripuletz, Sandra Heine, Corinna Trebst, Paraskevi N. Koutsoudaki, Martin StangelAbstract:Unravelling the factors that can positively influence remyelination is one of the major challenges in multiple sclerosis research. Expression of the chemokine receptor CXCR2 on oligodendrocytes both in vitro and in MS lesions has suggested a possible role for CXCR2 in the recruitment of oligodendrocyte precursor cells (OPC). To investigate the function of CXCR2 during remyelination in vivo, we studied this receptor in cuprizone-induced Demyelination and subsequent remyelination. We found that CXCR2 is constitutively expressed on OPC, whereas on macrophages/microglia CXCR2 is upregulated upon activation during Demyelination. Hence, the expression of CXCR2 is differentially regulated in oligodendrocytes and macrophages/microglia. Furthermore, we subjected CXCR2−/− mice to the cuprizone model demonstrating that remyelination was not altered in comparison to wildtype controls. In addition, the number of OPC and the amount of microglial accumulation were similar in both CXCR2−/− and wildtype animals during the whole Demyelination and remyelination process. These results suggest that despite expression on OPC and microglia CXCR2 plays only a minor role during remyelination. © 2008 Wiley-Liss, Inc.
Hans S. Keirstead - One of the best experts on this subject based on the ideXlab platform.
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Spinal cord injury is accompanied by chronic progressive Demyelination.
The Journal of comparative neurology, 2005Co-Authors: Minodora O. Totoiu, Hans S. KeirsteadAbstract:Preceding the development of therapeutic strategies for spinal cord injury is an identification of those pathological processes that might serve as therapeutic targets. Although Demyelination has been documented as a secondary degenerative component of spinal cord injury in several species including humans, the extent of Demyelination and its functional consequence remain unknown. In this report, we document the extent of Demyelination and remyelination up to 450 days following contusive spinal cord injury in adult rats. The overall number of demyelinated axons peaked at 1 day post injury, declined by 7-14 days post injury, and then progressively increased up to 450 days post injury. Oligodendrocyte and Schwann cell remyelinated axons appeared by 14 days post injury. Although remyelinated axons were present from 14 to 450 days post injury, remyelination was incomplete, as indicated by the presence of demyelinated axons at every time point examined. These studies demonstrate for the first time that spinal cord injury is accompanied by chronic progressive Demyelination, and they substantiate Demyelination as a target for therapeutic intervention.
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spinal cord injury is accompanied by chronic progressive Demyelination
The Journal of Comparative Neurology, 2005Co-Authors: Minodora O. Totoiu, Hans S. KeirsteadAbstract:Preceding the development of therapeutic strategies for spinal cord injury is an identification of those pathological processes that might serve as therapeutic targets. Although Demyelination has been documented as a secondary degenerative component of spinal cord injury in several species including humans, the extent of Demyelination and its functional consequence remain unknown. In this report, we document the extent of Demyelination and remyelination up to 450 days following contusive spinal cord injury in adult rats. The overall number of demyelinated axons peaked at 1 day post injury, declined by 7–14 days post injury, and then progressively increased up to 450 days post injury. Oligodendrocyte and Schwann cell remyelinated axons appeared by 14 days post injury. Although remyelinated axons were present from 14 to 450 days post injury, remyelination was incomplete, as indicated by the presence of demyelinated axons at every time point examined. These studies demonstrate for the first time that spinal cord injury is accompanied by chronic progressive Demyelination, and they substantiate Demyelination as a target for therapeutic intervention. J. Comp. Neurol. 486:373–383, 2005. © 2005 Wiley-Liss, Inc.
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neutralization of the chemokine cxcl10 reduces inflammatory cell invasion and Demyelination and improves neurological function in a viral model of multiple sclerosis
Journal of Immunology, 2001Co-Authors: Michael T Liu, Hans S. Keirstead, Thomas E. LaneAbstract:Intracerebral infection of mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by a chronic demyelinating disease with clinical and histological similarities with the human demyelinating disease multiple sclerosis (MS). Following MHV infection, chemokines including CXC chemokine ligand (CXCL)10 (IFN inducible protein 10 kDa), CXCL9 (monokine induced by IFN-γ), and CC chemokine ligand 5 (RANTES) are expressed during both acute and chronic stages of disease suggesting a role for these molecules in disease exacerbation. Previous studies have shown that during the acute phase of infection, T lymphocytes are recruited into the CNS by the chemokines CXCL10 and CXCL9. In the present study, MHV-infected mice with established Demyelination were treated with antisera against these two chemokines, and disease severity was assessed. Treatment with anti-CXCL10 reduced CD4 + T lymphocyte and macrophage invasion, diminished expression of IFN-γ and CC chemokine ligand 5, inhibited progression of Demyelination, and increased remyelination. Anti-CXCL10 treatment also resulted in an impediment of clinical disease progression that was characterized by a dramatic improvement in neurological function. Treatment with antisera against CXCL9 was without effect, demonstrating a critical role for CXCL10 in inflammatory Demyelination in this model. These findings document a novel therapeutic strategy using Ab-mediated neutralization of a key chemokine as a possible treatment for chronic human inflammatory demyelinating diseases such as MS.
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response of the oligodendrocyte progenitor cell population defined by ng2 labelling to Demyelination of the adult spinal cord
Glia, 1998Co-Authors: Hans S. Keirstead, Joel M Levine, W F BlakemoreAbstract:Elucidation of the response of oligodendrocyte progenitor cell populations to Demyelination in the adult central nervous system (CNS) is critical to understanding why remyelination fails in multiple sclerosis. Using the anti-NG2 monoclonal antibody to identify oligodendrocyte progenitor cells, we have documented their response to antibody-induced Demyelination in the dorsal column of the adult rat spinal cord. The number of NG2+ cells in the vicinity of demyelinated lesions increased by 72% over the course of 3 days following the onset of Demyelination. This increase in NG2+ cell numbers did not reflect a nonspecific staining of reactive cells, as GFAP, OX-42, and Rip antibodies did not co-localise with NG2 + cells in double immunostained tissue sections. NG2 + cells incorporated BrdU 48-72 h following the onset of Demyelination. After the onset of remyelination (10-14 days), the number of NG2+ cells decreased to 46% of control levels and remained consistently low for 2 months. When spinal cords were exposed to 40 Grays of x-irradiation prior to Demyelination, the number of NG2+ cells decreased to 48% of control levels by 3 days following the onset of Demyelination and remained unchanged at 3 weeks. Since 40 Grays of x-irradiation kills dividing cells, these studies illustrate a responsive and nonresponsive NG2+ cell population following Demyelination in the adult spinal cord and suggest that the responsive NG2+ cell population does not renew itself.
Chao Zhao - One of the best experts on this subject based on the ideXlab platform.
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the microbiota regulates murine inflammatory responses to toxin induced cns Demyelination but has minimal impact on remyelination
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Christopher E Mcmurran, Alerie Guzman De La Fuente, Rosana Penalva, Ofra Ben Menachemzidon, Yvonne Dombrowski, John Falconer, Ginez A Gonzalez, Chao ZhaoAbstract:The microbiota is now recognized as a key influence on the host immune response in the central nervous system (CNS). As such, there has been some progress toward therapies that modulate the microbiota with the aim of limiting immune-mediated Demyelination, as occurs in multiple sclerosis. However, remyelination—the regeneration of myelin sheaths—also depends upon an immune response, and the effects that such interventions might have on remyelination have not yet been explored. Here, we show that the inflammatory response during CNS remyelination in mice is modulated by antibiotic or probiotic treatment, as well as in germ-free mice. We also explore the effect of these changes on oligodendrocyte progenitor cell differentiation, which is inhibited by antibiotics but unaffected by our other interventions. These results reveal that high combined doses of oral antibiotics impair oligodendrocyte progenitor cell responses during remyelination and further our understanding of how mammalian regeneration relates to the microbiota.
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Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells
Neurotherapeutics, 2011Co-Authors: Jeffrey K. Huang, Stephen P.j. Fancy, Chao Zhao, Charles Ffrench-constant, David H Rowitch, Robin J.m. FranklinAbstract:Regeneration of myelin sheaths (remyelination) after central nervous system Demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.
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Retinoid X receptor gamma signaling accelerates CNS remyelination
Nature Neuroscience, 2010Co-Authors: Jeffrey K. Huang, Andrew A. Jarjour, Chao Zhao, Brahim Nait Oumesmar, Christophe Kerninon, Anna Williams, Wojciech Krezel, Hiroyuki Kagechika, Julien Bauer, Anne Baron-van EvercoorenAbstract:The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. Here we generate a comprehensive transcriptional profile of the separate stages of spontaneous remyelination following focal Demyelination in the rat CNS and show transcripts encoding retinoid acid receptor RXR-gamma is highly differentially expressed during remyelination. We find that oligodendrocyte lineage cells express RXR-gamma in rat tissues undergoing remyelination and in active and remyelinated MS lesions. RXR-gamma knockdown by RNA interference or RXR-specific antagonists severely inhibit oligodendrocyte differentiation in culture. In RXR-gamma deficient mice, adult oligodendrocyte precursor cells efficiently repopulate lesions following Demyelination, but display delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats following Demyelination results in more remyelinated axons. RXR-gamma is therefore a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination, and may be a pharmacological target for CNS regenerative therapy.
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Remyelination - An effective means of neuroprotection.
Hormones and Behavior, 2009Co-Authors: Charlotte C. Bruce, Chao Zhao, Robin J.m. FranklinAbstract:Remyelination following central nervous system (CNS) Demyelination restores rapid saltatory conduction of action potentials and contributes to the maintenance of axonal integrity. This robust regenerative phenomenon stands in contrast to the limited repair capacity that is characteristic of CNS neuronal injury. However, despite its efficiency in experimental models and some clinical diseases, remyelination failure becomes an increasingly pronounced feature of the pathology of chronic multiple sclerosis (MS) lesions. Chronic Demyelination predisposes axons to atrophy, an irreversible event that is a major pathological correlate of progressive functional decline. This has created a compelling case for developing therapies that promote remyelination: evidence from experimental animal models suggests that hormones may have a beneficial role to play in this regard.
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increased expression of nkx2 2 and olig2 identifies reactive oligodendrocyte progenitor cells responding to Demyelination in the adult cns
Molecular and Cellular Neuroscience, 2004Co-Authors: Stephen P.j. Fancy, Chao Zhao, Robin J.m. FranklinAbstract:Within the adult CNS, a quiescent population of oligodendrocyte progenitor cells (OPCs) become activated in response to Demyelination and give rise to remyelinating oligodendrocytes. During development, OPC differentiation is controlled by several transcription factors including Olig1 and Olig2, and Nkx2.2. We hypothesized that these genes may serve similar functions in activated adult OPCs allowing them to become remyelinating oligodendrocytes and tested this hypothesis by examining their expression during the remyelination of a toxin-induced rodent model of Demyelination. During the acute phase of Demyelination, OPCs within the lesion increased their expression of Nkx2.2 and Olig2, two transcription factors that in combination are critical for oligodendrocyte differentiation during developmental myelination. This activation was not associated with increases in Sonic hedgehog (Shh) expression, which does not appear essential for CNS remyelination. Consistent with a role in the activation and differentiation of OPCs, these increases were delayed in old adult animals where the rate of remyelination is slowed. Our data suggest the hypothesis that increased expression of Nkx2.2 and Olig2 plays a critically important role in the differentiation of adult OPCs into remyelinating oligodendrocytes and that these genes may present novel targets for therapeutic manipulation in cases where remyelination is impaired.
Hans Lassmann - One of the best experts on this subject based on the ideXlab platform.
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Demyelination versus remyelination in progressive multiple sclerosis
Brain, 2010Co-Authors: Stephan Bramow, Josa M Frischer, Hans Lassmann, Nils Kochhenriksen, Claudia F Lucchinetti, Per Soelberg Sorensen, Henning LaursenAbstract:The causes of incomplete remyelination in progressive multiple sclerosis are unknown, as are the pathological correlates of the different clinical characteristics of patients with primary and secondary progressive disease. We analysed brains and spinal cords from 51 patients with progressive multiple sclerosis by planimetry. Thirteen patients with primary progressive disease were compared with 34 with secondary progressive disease. In patients with secondary progressive multiple sclerosis, we found larger brain plaques, more Demyelination in total and higher brain loads of active Demyelination compared with patients with primary progressive disease. In addition, the brain density of plaques with high-grade inflammation and active Demyelination was highest in secondary progressive multiple sclerosis and remained ∼18% higher than in primary progressive multiple sclerosis after adjustments for other plaque types and plaque number ( P < 0.05). Conversely, the proportion of remyelinated shadow plaques ( P < 0.05) and the overall remyelination capacity ( P < 0.01) per brain were higher in primary, compared with secondary, progressive multiple sclerosis. By contrast, there were no group differences in the brain load or frequency of low-grade inflammatory plaques with slowly expanding Demyelination. Spinal cord lesion loads and remyelination capacity were also comparable in the two patient groups. Remyelinated areas were more vulnerable than the normal-appearing white matter to new Demyelination, including active Demyelination in secondary progressive multiple sclerosis. ‘Recurrent’ slowly expanding Demyelination, affecting remyelinated areas, and the load of slowly expanding Demyelination correlated with incomplete remyelination in both groups. In turn, incomplete remyelination in the spinal cord correlated with higher disease-related disability (determined retrospectively; r = −0.53; P < 0.05 for remyelination capacity versus disease severity). By contrast, such a correlation was not observed in the brain. We propose that regulatory and reparative properties could protect the white matter of the brain in patients with primary progressive multiple sclerosis. These patients may, thereby, be spared symptoms until the spinal cord is affected. By contrast, recurrent active Demyelination of repaired myelin could explain why similar symptoms often develop in consecutive relapses in relapsing-remitting/secondary progressive multiple sclerosis. Our data also indicate that slowly expanding Demyelination may irreparably destroy normal and repaired myelin, supporting the concept of slowly expanding Demyelination as an important pathological correlate of clinical progression.
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Demyelination versus remyelination in progressive multiple sclerosis
Brain : a journal of neurology, 2010Co-Authors: Stephan Bramow, Josa M Frischer, Hans Lassmann, Claudia F Lucchinetti, Per Soelberg Sorensen, Nils Koch-henriksen, Henning LaursenAbstract:The causes of incomplete remyelination in progressive multiple sclerosis are unknown, as are the pathological correlates of the different clinical characteristics of patients with primary and secondary progressive disease. We analysed brains and spinal cords from 51 patients with progressive multiple sclerosis by planimetry. Thirteen patients with primary progressive disease were compared with 34 with secondary progressive disease. In patients with secondary progressive multiple sclerosis, we found larger brain plaques, more Demyelination in total and higher brain loads of active Demyelination compared with patients with primary progressive disease. In addition, the brain density of plaques with high-grade inflammation and active Demyelination was highest in secondary progressive multiple sclerosis and remained ∼18% higher than in primary progressive multiple sclerosis after adjustments for other plaque types and plaque number ( P
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multiple sclerosis in situ evidence for antibody and complement mediated Demyelination
Annals of Neurology, 1998Co-Authors: Maria K Storch, Sara J Piddlesden, Matti Haltia, Matti Iivanainen, Paul Morgan, Hans LassmannAbstract:We describe a case of multiple sclerosis characterized by deposition of immunoglobulin and complement in the areas of active Demyelination. This was particularly evident for the C9neo antigen, which is a marker for the activated lytic complement complex and was exclusively deposited in the areas of active myelin destruction. In addition, macrophages in the lesions contained degradation products that were immunoreactive for myelin antigens, immunoglobulins, and C9neo antigen. Destruction of myelin sheaths was associated with incomplete loss of oligodendrocytes in the active areas and reappearance of oligodendrocytes with remyelination in the inactive plaque center.
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inflammatory central nervous system Demyelination correlation of magnetic resonance imaging findings with lesion pathology
Annals of Neurology, 1997Co-Authors: Wolfgang Bruck, Andreas Bitsch, Herbert Kolenda, Y Bruck, Michael Stiefel, Hans LassmannAbstract:Magnetic resonance imaging (MRI) is widely used to evaluate and monitor disease activity in inflammatory demyelinating central nervous system (CNS) diseases such as multiple sclerosis. The present study aimed at correlating MRI findings with histological parameters in 6 cases of biopsy-proven inflammatory Demyelination of the CNS. The earliest stages of demyelinating activity manifested as almost isointense lesions with a massive gadolinium-DTPA (Gd-DTPA) enhancement in T1-weighted scans. In T2-weighted scans, early active lesions formed a border of decreased intensity compared with the lesion center and the perifocal edema. The morphological correlate of this pattern in our patients was activated macrophages in the zone of myelin destruction at the plaque border. Late active lesions were hypointense in T1 and hyperintense in T2 scans. Inactive demyelinated and remyelinating lesions were hyperintense in T2 scans and enhanced inhomogenously after Gd-DTPA application. T1 scans revealed major differences in the degree of hypointensity that correlated with the extent of axonal damage, extracellular edema, and the degree of Demyelination or remyelination.
