Multiple sclerosis: Re-expression of a developmental pathway that restricts oligodendrocyte maturation

Abstract

During mammalian central nervous system (CNS) development, contact-mediated activation of Notch1 receptors on oligodendrocyte precursors by the ligand Jagged1 induces Hes5, which inhibits maturation of these cells. Here we tested whether the Notch pathway is re-expressed in the adult CNS in multiple sclerosis (MS), an inflammatory demyelinating disease in which remyelination is typically limited. We found that transforming growth factor-beta 1 (TGF-beta 1), a cytokine upregulated in MS, specifically re-induced Jagged1 in primary cultures of human astrocytes. Within and around active MS plaques lacking remyelination, Jagged1 was expressed at high levels by hypertrophic astrocytes, whereas Notch1 and Hes5 localized to cells with an immature oligodendrocyte phenotype, and TGF-beta 1 was associated with perivascular extracellular matrix in the same areas. In contrast, there was negligible Jagged1 expression in remyelinated lesions. Experiments in vitro showed that Jagged1 signaling inhibited process outgrowth from primary human oligodendrocytes. These data are the first to implicate the Notch pathway in the limited remyelination in MS. Thus, Notch may represent a potential target for therapeutic intervention in this disease.

Cell Therapy for Multiple Sclerosis

“…Active inhibition of resident OPCs is suggested by the sharp border of demyelinated plaque, surrounded by OPCs [39,76,77]. 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].…”

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

“…But more importantly, given the growing interest to develop pharmacological inhibitors against the Wnt pathway in cancer therapy [59], it might be possible in the near future to use Wnt inhibitors to stimulate OPC differentiation and improve CNS remyelination in MS. One of the potential contributors of remyelination efficiency in MS is thought to be reactive astrocytosis in lesions, which can potentially have both beneficial and detrimental roles [60,61]. In search of putative astrocytic inhibitors of remyelination, a microarray analysis was performed on purified human astrocytes treated with cytokines that are known to be significantly upregulated in the brains of MS patients [62]. This led to the identification of the Notch ligand, Jagged in astrocytes, which is upregulated in response to the cytokine TGF-β.…”

“…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].…”

“…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]. However, the role of Notch1 signaling on OPC differentiation during remyelination in vivo has remained inconclusive for several reasons.…”

Intergenomic consensus in multifactorial inheritance loci: the case of multiple sclerosis

“…12 The NOTCH pathway is most probably involved in a limited remyelination process taking place during MS. 13 The complement 4 (C4A/B) is known to be involved in the demyelination process of MS. 14 A dysfunction of NEU1 gene may lead to neurological disorders. 15 PSMB8 and PSMB9 play a role in the aforementioned ubiquitinproteasome system.…”