Enhance neural stem cell chemoxis toward CNS inflammatory foci in EAE

描述（由申请人提供）：神经干细胞（NSCs）已被证明可有效抑制实验性自身免疫性脑脊髓炎（EAE），这是一种多发性硬化症（MS）的动物模型。其中，同一组的两项令人兴奋的研究报告（Pluchino et al., Nature， 2003和2005）表明，成年小鼠全身和局部注射脑室下区（SVZ）的NSCs均可促进EAE的多灶性髓鞘再生和功能恢复。然而，这种方法有明显的缺点，临床获益相对缓慢且有限。在NSCs上缺乏或低表达特定的趋化因子受体可能是这些弱点的重要因素。此外，由于SVZ-NSCs的相对不可接近性，收集这些细胞具有高度侵袭性。因此，骨髓（BM）来源的NSCs可能是临床环境中最好的选择。鉴于不同阶段/类型MS/EAE的炎症灶中不同的趋化因子水平较高，我们假设经过工程化表达特定趋化因子受体的BM-NSCs将引导NSCs更高效、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NSCs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。我们认为，这种方法将使BM-NSCs能够快速、有导向地迁移到EAE病灶，从而加速NSCs促进髓鞘再生和神经元恢复的内在能力，并阻止髓鞘/神经元进一步损伤。这种方法可能为一种新的、容易获得的、高效的多发性硬化症治疗方法奠定基础。

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.