Authors: Xing Li Yuan Zhang Yaping Yan Bogoljub Ciric CunGen Ma Jeannie Chin Mark Curtis Abdolmohamad Rostami GuangXian Zhang
Publish Date: 2016/06/25
Volume: 54, Issue: 6, Pages: 4365-4378
Abstract
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 LINGO1 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 eg injected at day 40 postimmunization However NSCs engineered to produce LINGO1Fc a soluble LINGO1 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 LINGO1Fcproducing NSC Moreover differentiation of LINGO1Fcproducing NSCs into oligodendrocytes in vitro was largely diminished by an NAMPT inhibitor indicating that LINGO1Fc enhances the NAMPT/NAD/Sirt2 pathway Together our study establishes a CNStargeted novel LINGO1Fc delivery system using NSCs which represents a novel and effective NSCbased gene therapy approach for the chronic stage of MSThis study was supported by the NIH R01NS075260 and the Groff Foundation XL and YZ are partly supported by the Chinese National Natural Science Foundation grant no 81501062 and the Overseas Scholarship Program of Shaanxi Normal University We thank Katherine Regan for editorial assistance None of the authors have conflicts of interestXL YZ YPY and GXZ conceived and designed the experiments XL and YZ carried out the experiments and wrote the paper CGM discussed the hypothesis and interpreted the data JC assisted with experimental design and manuscript preparation BC and AR provided critical input and cosupervised the study All authors read and approved the final manuscript
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