Multiple sclerosis: Re-expression of a developmental pathway that restricts oligodendrocyte maturation
Multiple sclerosis: Re-expression of a developmental pathway that restricts oligodendrocyte maturation
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DOI：
10.1038/nm781
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发表时间：
2002-10-01
期刊：
影响因子：
82.9
通讯作者：
Brosnan, CF
中科院分区：
文献类型：
--
作者：
John, GR;Shankar, SL;Brosnan, CF
在哺乳动物中枢神经系统（CNS）发育过程中，少突胶质细胞前体上的Notch1受体通过Jagged1的接触介导激活诱导Hes5，从而抑制这些细胞的成熟。在这里，我们测试了Notch通路是否在多发性硬化症（MS）的成人中枢神经系统中重新表达，多发性硬化症是一种炎症性脱髓鞘疾病，其髓鞘再生通常受到限制。我们发现转化生长因子- β 1 (tgf - β 1)，一种在MS中上调的细胞因子，在人星形胶质细胞原代培养中特异性地重新诱导Jagged1。在缺乏髓鞘再生的MS斑块内部和周围，Jagged1在肥大星形胶质细胞中高水平表达，而Notch1和Hes5定位于未成熟少突胶质细胞表型的细胞，TGF-beta1在相同区域与血管周围细胞外基质相关。相比之下，在髓鞘再生病变中，Jagged1的表达可以忽略不计。体外实验表明，Jagged1信号通路抑制人少突胶质细胞的生长。这些数据首次揭示了Notch通路与多发性硬化症有限的髓鞘再生有关。因此，Notch可能是多发性硬化症治疗干预的潜在靶点。
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-beta1 (TGF-beta1), 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-beta1 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.