Notch1 and Jagged1 are expressed after CNS demyelination, but are not a major rate-determining factor during remyelination

Stidworthy, Mark F.; Genoud, Stéphane; Li, Wenwu; Leone, Dino P.; Mantei, Ned; Suter, Ueli; Franklin, Robin J.M.

doi:10.1093/brain/awh217

Cited by 147 publications

(123 citation statements)

References 56 publications

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“…Conditional ablation of Notch from olig1-positive oligodendroglial cells results in accelerated remyelination after LPC-induced focal demyelination in the corpus callosum [36] . An earlier study using 2',3'-cyclic nucleotide phosphodiesterase promoter (CNP)-cre-driven deletion failed to show any effect on the rate of remyelination [37] . This discrepancy of outcomes may be due to the promoter used to drive the deletion of Notch, since CNP is only expressed from premature oligodendrocytes onwards.…”

Section: Notchmentioning

confidence: 96%

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Zhang

Guo

2013

Neurosci. Bull.

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Multiple sclerosis (MS) is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability. Increasing evidence has pointed to innate immunity, axonal damage and neuronal loss as important contributors to disease progression. Remyelination of denuded axons is considered an effective way to protect neurons from damage and to restore neuronal function. The identification of several key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and myelination has yielded clues for the development of drug candidates that directly target remyelination and neuroprotection. The long-term efficacy of this strategy remains to be evaluated in clinical trials. Here, we provide an overview of current and emerging therapeutic concepts, with a focus on the opportunities and challenges for the remyelination approach to the treatment of MS.

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Section: Notchmentioning

confidence: 96%

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Zhang

Guo

2013

Neurosci. Bull.

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“…It was suggested, for example, that re-expression of Notch1, a regulator of oligodendrocyte progenitor differentiation, inhibits remyelination in MS [85]. Yet targeted ablation of Notch1 did not enhance remyelination in experimental animals [86]. It was further recently shown that failure of OPC differentiation was due to cytoplasmic entrapment of the intracellular domain of Notch1 as a result of abnormal expression of TAT-interacting protein 30 kDa (TIP30), an inhibitor of importin-mediated nuclear transport [87].…”

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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“…This led to the identification of the Notch ligand, Jagged in astrocytes, which is upregulated in response to the cytokine TGF-β. Notch1 and its effector Hes5 were detected in immature oligodendrocytes of MS lesions and following demyelination in mice [62,63]. When cultured human OPCs were exposed to Jagged, these OPCs failed to mature [62].…”

Section: Wnt Signalingmentioning

confidence: 99%

“…However, the role of Notch1 signaling on OPC differentiation during remyelination in vivo has remained inconclusive for several reasons. First, remyelination can occur with great efficiency despite the expression of Notch in precursor cells and Jagged expression within the demyelinated environment [63,64]. Second, conditional ablation of Notch in precursors leads to no [63] or a relatively minor effect on remyelination efficiency [65].…”

Section: Wnt Signalingmentioning

confidence: 99%

“…First, remyelination can occur with great efficiency despite the expression of Notch in precursor cells and Jagged expression within the demyelinated environment [63,64]. Second, conditional ablation of Notch in precursors leads to no [63] or a relatively minor effect on remyelination efficiency [65]. Third, when mice with experimental autoimmune encephalomyelitis (a model of immune mediated demyelination) were treated with a γ-secretase inhibitor, MW167, which prevents Notch signaling, myelin repair and axonal survival were improved [66].…”

Section: Wnt Signalingmentioning

confidence: 99%

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Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

et al. 2011

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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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Notch1 and Jagged1 are expressed after CNS demyelination, but are not a major rate-determining factor during remyelination

Cited by 147 publications

References 56 publications

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Cell Therapy for Multiple Sclerosis

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

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