LINGO-1-Fc-Transduced Neural Stem Cells Are Effective Therapy for Chronic Stage Experimental Autoimmune Encephalomyelitis
LINGO-1-Fc-Transduced Neural Stem Cells Are Effective Therapy for Chronic Stage Experimental Autoimmune Encephalomyelitis
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LINGO-1-Fc 转导的神经干细胞是慢性期实验性自身免疫性脑脊髓炎的有效治疗方法
DOI：
10.1007/s12035-016-9994-z
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发表时间：
2017-08-01
影响因子：
5.1
通讯作者：
Zhang, Guang-Xian
中科院分区：
文献类型：
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作者：
Li, Xing;Zhang, Yuan;Zhang, Guang-Xian
慢性期多发性硬化症（MS）是一种中枢神经系统（CNS）炎症性脱髓鞘疾病，目前的治疗方法仍然难以治愈。这种难治性可能是由于目前的治疗主要是免疫调节，可以防止进一步脱髓鞘，但缺乏促进髓鞘再生的能力。多种方法，包括移植神经干细胞 (NSC) 或 LINGO-1 拮抗剂（神经再生抑制剂受体复合物的关键部分），可有效抑制实验性自身免疫性脑脊髓炎 (EAE)（一种多发性硬化症动物模型）的急性期。然而，它们对慢性期 EAE 的影响尚不清楚。在这里，我们表明，当治疗在 EAE 慢性阶段开始时（例如，在免疫后 40 天注射），NSC 移植仅具有轻微的治疗效果。然而，经改造后的 NSC 产生 LINGO-1-Fc（一种可溶性 LINGO-1 拮抗剂），显着促进神经功能恢复，临床症状改善、轴突完整性改善、少突胶质细胞成熟和神经元再生增强。在用产生 LINGO-1-Fc 的 NSC 治疗的小鼠的中枢神经系统中，还发现 NAD 产生和 Sirt2 表达显着增强。此外，NAMPT 抑制剂在体外大大削弱了产生 LINGO-1-Fc 的 NSC 向少突胶质细胞的分化，表明 LINGO-1-Fc 增强了 NAMPT/NAD/Sirt2 通路。我们的研究共同建立了一种利用 NSC 靶向 CNS 的新型 LINGO-1-Fc 递送系统，这代表了一种针对 MS 慢性期的新型有效的基于 NSC 的基因治疗方法。
The chronic stage multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), remains refractory to current treatments. This refractory nature may be due to the fact that current treatments are primarily immunomodulatory, which prevent further demyelination but lack the capacity to promote remyelination. Several approaches, including transplantation of neural stem cells (NSCs) or antagonists to LINGO-1, a key part of the receptor complex for neuroregeneration inhibitors, have been effective in suppressing the acute stage of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, their effect on the chronic stage EAE is not known. Here, we show that transplantation of NSCs had only a slight therapeutic effect when treatment started at the chronic stage of EAE (e.g., injected at day 40 postimmunization). However, NSCs engineered to produce LINGO-1-Fc, a soluble LINGO-1 antagonist, significantly promoted neurological recovery as demonstrated by amelioration of clinical signs, improvement in axonal integrity, and enhancement of oligodendrocyte maturation and neuron repopulation. Significantly enhanced NAD production and Sirt2 expression were also found in the CNS of mice treated with LINGO-1-Fc-producing NSC. Moreover, differentiation of LINGO-1-Fc-producing NSCs into oligodendrocytes in vitro was largely diminished by an NAMPT inhibitor, indicating that LINGO-1-Fc enhances the NAMPT/NAD/Sirt2 pathway. Together, our study establishes a CNS-targeted, novel LINGO-1-Fc delivery system using NSCs, which represents a novel and effective NSC-based gene therapy approach for the chronic stage of MS.