Enhance neural stem cell chemoxis toward CNS inflammatory foci in EAE

描述(申请人提供)：神经干细胞(NSCs)已被证明在抑制实验性自身免疫性脑脊髓炎(EAE)方面有效，EAE是多发性硬化症(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，自然，2003年和2005年)表明，从成年小鼠的静脉下带(SVZ)全身和局部注射神经干细胞都促进了EAE的多灶性髓鞘形成和功能恢复。然而，这种方法有明显的缺点，相对缓慢和有限的临床好处。神经干细胞上缺乏或低表达特定的趋化因子受体可能是导致这些弱点的一个重要因素。此外，由于SVZ-NSCs相对难以获得，获取这些细胞是非常有侵入性的。因此，骨髓来源的神经干细胞在临床上可能是最好的选择。鉴于不同阶段/类型的MS/EAE炎症灶中不同趋化因子的水平较高，我们推测，表达特定趋化因子受体的BM-NSCs将引导NSCs更有效、更快速地迁移到炎症部位，在一定程度上抑制局部炎症，促进再髓鞘形成，从而更有效地抑制EAE。为了验证这一假设，我们将通过在BM-NSC上表达特定的趋化因子受体来增强这些NSC对炎症部位的趋化作用。我们认为，这种方法将赋予BM-NSCs快速和引导的迁移到EAE灶，从而加速NSCs促进髓鞘再生和神经元恢复的内在能力，并阻止进一步的髓鞘/神经元损伤。这种方法可能为一种新的、容易获得和高效的多发性硬化症治疗方法奠定基础。 公共卫生相关性：通过对神经干细胞进行基因工程，使其表达一种与炎症灶中升高的趋化因子水平相对应的受体，可以更快、更有效地抑制多发性硬化。从伦理的角度来看，使用来自骨髓的神经干细胞是非常可取的。我们的研究可能为MS患者的一种新的、更快速、更有效的治疗方法奠定基础。

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.