Role and Regulation of Neural Stem Cells in Remyelination

项目摘要 脑室下区少突胶质前体细胞(OPC)和神经干细胞(NSCs) 是已知的重新髓鞘少突胶质细胞的来源。它们对髓鞘再生的确切贡献和 限制它们修复有效性的是具有重要治疗作用的活跃研究领域 这意味着什么。我们发现，对Sonic Hedgehog(Shh)反应的成年神经干细胞是一个重要的来源 再髓鞘细胞的数量。这些富含在腹侧SVZ的神经干细胞通常会引起 实质星形胶质细胞和中间神经元。它们只有在脱髓鞘后才进入白质束， 包括脱髓鞘的胼胝体(CC)，在那里他们被强有力地招募和 优先分化为少突胶质细胞。出乎意料的是，他们对这种病变的招募和他们的 基因消融或基因治疗可显著增强向少突胶质细胞的分化 Shh依赖的转录因子Gli1的药理抑制。此外，药理学 抑制Gli1可增强成人的再髓鞘形成并促进功能恢复 炎症性脱髓鞘。重要的问题包括它们对髓鞘再生的贡献是否 在修复过程中受到与实质OPC竞争的影响，是什么促使这些细胞脱髓鞘 损伤，以及Gli1如何限制NSC修复。在目标1中，我们考察了NSC是否扩大了他们的贡献 修复OPC再髓鞘形成受阻的情况，以评估NSC和OPC是否竞争重新髓鞘形成 相同的损伤部位。在目标2中，我们评估了小胶质细胞(MG)和星形胶质细胞的作用，这两者都是 在病变部位激活，在神经干细胞的扩张和招募中发挥作用。我们的初步研究表明MG 对于NSC的扩张和招聘是必不可少的，但没有说明这是直接影响还是 继发于星形胶质细胞激活。在目标3中，我们将研究揭示的一种新的NSC表型 仅在脱髓鞘时上调的RNAseq，并且依赖于Gli1。这种表型包括一种 炎症相关介质和C1q复合体的数量。我们将描述这个改变后的国家安全委员会 进一步检测其在调节SVZ中MG的数量和表型中的潜在作用， 并评估其对NSC清除和重新髓鞘形成的潜在影响。这些研究将提供 对调节干细胞贡献的信号(细胞和分子)的重要新见解 修复并由此指导促进髓鞘再生的治疗努力。

Project Summary Both oligodendrocyte progenitors (OPCs) and neural stem cells (NSCs) in the subventricular zone (SVZ) are known sources of remyelinating oligodendrocytes. Their precise contribution to remyelination and what limits their effectiveness in repair are active areas of research with important therapeutic implications. We have found that Sonic hedgehog (Shh)-responsive adult NSCs are a significant source of remyelinating cells. These NSCs, which are enriched in the ventral SVZ, normally give rise to parenchymal astrocytes and interneurons. They only enter white matter tracts upon demyelination, including to the the demyelinated corpus callosum (CC), where they are robustly recruited and differentiate preferentially into oligodendroglia. Unexpectedly, their recruitment to such lesions and their differentiation into remyelinating oligodendrocytes is significantly enhanced by genetic ablation or pharmacological inhibition of the Shh-dependent transcription factor Gli1. Further, pharmacological inhibition of Gli1 enhances remyelination in the adult and improves functional recovery from inflammatory demyelination. Important questions include whether their contribution to remyelination is impacted by competition with parenchymal OPCs during repair, what recruits these cells to demyelinated lesions, and how Gli1 limits NSC repair. In Aim 1, we examine whether NSCs expand their contribution to repair if OPC remyelination is blocked to assess whether NSC and OPCs compete to remyelinate the same lesion sites. In Aim 2, we assess the role of microglia (MG) and astrocytes, which are both activated in lesion sites, in the expansion and recruitment of NSCs. Our preliminary studies suggest MG are essential for NSC expansion and recruitment but do not indicate if this is a direct effect or is secondary to activation of astroglia. In Aim 3, we will investigate a novel NSC phenotype revealed by RNAseq that is only upregulated with demyelination and is Gli1- dependent. This phenotype includes a number of inflammation-related mediators and the C1q complex. We will characterize this altered NSC phenotype further, examine its potential role in regulating the number and phenotype of MG in the SVZ, and assess its potential impact on NSC clearance and remyelination. These studies will provide important, new insights into the signals (cells and molecules) that regulate the contribution of stem cells to repair and may thereby guide therapeutic efforts to promote remyelination.