Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis.
Paradoxical dysregulation of the neural stem cell pathway sonic hedgehog-Gli1 in autoimmune encephalomyelitis and multiple sclerosis.
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DOI：
10.1002/ana.21457
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发表时间：
2008-10
影响因子：
11.2
通讯作者：
Khoury, Samia J.
中科院分区：
文献类型：
--
作者：
Wang, Yue;Imitola, Jaime;Rasmussen, Stine;O'Connor, Kevin C.;Khoury, Samia J.
神经血管生态位已被认为是神经干细胞（NSC）对急性中枢神经系统（CNS）损伤反应的关键组成部分，然而，尚不清楚这些潜在的修复生态位在慢性损伤期间是否保持功能。在这里，我们询问中枢神经系统炎症损伤如何调节神经干细胞及其生态位的内在特性。我们研究了实验性自身免疫性脑脊髓炎 (EAE) 和多发性硬化症 (MS) 中的音刺猬 (Shh)-Gli1 通路（NSC 的重要信号通路）及其对炎症细胞因子的调节。我们发现，在 MS 病变和 EAE 期间的损伤区域，反应性星形胶质细胞和血管周围星形胶质细胞显着上调 Shh。室下区 (SVZ) 生态位外的星形胶质细胞可以支持 NSC 向神经元和少突胶质细胞分化，而 Shh 是这种效应的关键介质。 Shh 诱导转录因子 Gli1 的差异上调，从而介导 Shh 诱导的 NSC 分化。然而，尽管Shh增加，并且Gli1最初在EAE早期炎症和MS活动性病变期间增加，但在EAE发作后以及MS脑慢性活动性和非活动性病变中，脊髓少突胶质细胞前体细胞（OPC）中的Gli1显着减少。 Th1 细胞因子 IFN-γ 在诱导星形胶质细胞和 NSC 中的 Shh 表达方面具有独特的作用，同时相反地抑制 NSC 中的 Gli1 表达并抑制 Shh 介导的 NSC 分化。我们的数据表明，慢性损伤期间的内源性修复潜力似乎受到炎症诱导的内在 NSC 分子途径（如 Gli1）改变的限制。
Neurovascular niches have been proposed as critical components of the neural stem cell (NSC) response to acute central nervous system (CNS) injury, however, it is unclear whether these potential reparative niches remain functional during chronic injury. Here we asked how CNS inflammatory injury regulates the intrinsic properties of NSCs and their niches. We investigated the sonic hedgehog (Shh)-Gli1 pathway, an important signaling pathway for NSCs, in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) and its regulation of by inflammatory cytokines. We show that Shh is markedly up-regulated by reactive and perivascular astroglia in areas of injury in MS lesions and during EAE. Astroglia outside the subventricular zone (SVZ) niche can support NSC differentiation towards neurons and oligodendrocytes and Shh is a critical mediator of this effect. Shh induces differential upregulation of the transcription factor Gli1, which mediates Shh-induced NSC differentiation. However, despite the increase in Shh and the fact that Gli1 was initially increased during early inflammation of EAE and active lesions of MS, Gli1 was significantly decreased in spinal cord oligodendrocyte precursor cells (OPCs) after onset of EAE and in chronic active and inactive lesions from MS brain. The Th1 cytokine IFN-γ was unique in inducing Shh expression in astroglia and NSCs, while paradoxically suppressing Gli1 expression in NSCs and inhibiting Shh-mediated NSC differentiation. Our data suggest that endogenous repair potential during chronic injury appears to be limited by inflammation-induced alterations in intrinsic NSC molecular pathways such as Gli1.
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影响因子：
16.2
作者：
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通讯作者：
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