Enhance neural stem cell chemoxis toward CNS inflammatory foci in EAE

描述（由申请人提供）：神经干细胞（NSC）已被证明可有效抑制实验性自身免疫性脑脊髓炎（EAE），一种多发性硬化症（MS）的动物模型。在这些研究中，同一小组的两份令人兴奋的报告（Pluchino等人，Nature，2003和2005）显示，全身和局部注射来自成年小鼠脑室下区（SVZ）的NSC促进EAE中的多灶性髓鞘再生和功能恢复。然而，这种方法具有明显的缺点，具有相对缓慢且有限的临床益处。神经干细胞上特定趋化因子受体的缺乏或低表达可能是导致这些弱点的重要因素。此外，由于SVZ-NSC的相对不可及性，收获这些细胞是高度侵入性的。因此，骨髓（BM）来源的神经干细胞可能是临床环境中的最佳选择。鉴于不同阶段/类型的MS/EAE的炎性病灶处不同趋化因子的高水平，我们假设经工程化以表达选定趋化因子受体的BM-NSC将引导NSC更有效和快速地迁移到炎性部位，在一定程度上抑制局部炎症并促进髓鞘再生，从而更有效地抑制EAE。为了验证这一假设，我们将通过在这些NSC上表达选定的趋化因子受体来增强BM-NSC对炎症部位的趋化性。我们相信，这种方法将赋予BM-NSC快速和引导迁移到EAE病灶，从而加速NSC促进髓鞘再生和神经元恢复的内在能力，并阻断进一步的髓鞘/神经元损伤。这种方法可能为MS治疗的一种新的、容易获得的和高效的方法奠定基础。 公共卫生相关性：通过遗传工程改造神经干细胞以表达对应于炎性病灶中升高水平的趋化因子的受体，可以实现对MS的更快速和更有效的抑制。从伦理学的角度来看，使用来自骨髓的神经干细胞是非常可取的。我们的研究可以为MS患者的新的，更快速，更有效的治疗奠定基础。

DESCRIPTION (provided by applicant): Neural stem cells (NSCs) have been shown to be effective in suppressing experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Among the studies, two exciting reports by the same group (Pluchino et al., Nature, 2003 and 2005) showed that both systemic and local injection of NSCs from the subventicular zone (SVZ) of adult mice promotes multifocal remyelination and functional recovery in EAE. However, this approach has obvious drawbacks, with a relatively slow and limited clinical benefit. Lack or low expression of particular chemokine receptors on NSCs could be an important factor underlying these weaknesses. Further, due to the relative inaccessibility of SVZ-NSCs, harvesting these cells is highly invasive. Thus, bone marrow (BM)- derived NSCs may be the best alternative in a clinical setting. Given the high levels of different chemokines at the inflammatory foci of various stages/types of MS/EAE, we hypothesize that BM-NSCs engineered to express selected chemokine receptors will guide NSCs to migrate more efficiently and rapidly to inflammatory sites, inhibit local inflammation to a certain extent and promote remyelination, thus more effectively suppressing EAE. To test this hypothesis, we will augment BM-NSC chemotaxis towards inflammatory sites by expressing selected chemokine receptors on these NSCs. We believe that this approach will endow BM-NSCs with rapid and guided migration to EAE foci, thus accelerating the intrinsic capacity of NSCs to promote remyelination and neuronal recovery, and blocking further myelin/neuron damage. This approach may lay the groundwork for a novel, easily accessible and highly effective approach to MS therapy. PUBLIC HEALTH RELEVANCE: A more rapid and more effective suppression of MS may be achieved by genetically engineering neural stem cells to express a receptor corresponding to the elevated level of chemokines in inflammatory foci. From an ethical standpoint, the use of neural stem cells derived from bone marrow is high desirable. Our study could lay the groundwork for a novel, more rapid and more effective therapy for MS patients.