Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis
Jingxian Yang, … , Abdolmohamad Rostami, Guang-Xian Zhang
Jingxian Yang, … , Abdolmohamad Rostami, Guang-Xian Zhang
Published November 2, 2009
Citation Information: J Clin Invest. 2009;119(12):3678-3691. https://doi.org/10.1172/JCI37914.
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Research Article Autoimmunity

Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis

Abstract

Adult neural stem cells (aNSCs) derived from the subventricular zone of the brain show therapeutic effects in EAE, an animal model of the chronic inflammatory neurodegenerative disease MS; however, the beneficial effects are modest. One critical weakness of aNSC therapy may be an insufficient antiinflammatory effect. Here, we demonstrate that i.v. or i.c.v. injection of aNSCs engineered to secrete IL-10 (IL-10–aNSCs), a potent immunoregulatory cytokine, induced more profound functional and pathological recovery from ongoing EAE than that with control aNSCs. IL-10–aNSCs exhibited enhanced antiinflammatory effects in the periphery and inflammatory foci in the CNS compared with control aNSCs, more effectively reducing myelin damage, a hallmark of MS. When compared with mice treated with control aNSCs, those treated with IL-10–aNSCs demonstrated differentiation of transplanted cells into greater numbers of oligodendrocytes and neurons but fewer astrocytes, thus enhancing exogenous remyelination and neuron/axonal growth. Finally, IL-10–aNSCs converted a hostile environment to one supportive of neurons/oligodendrocytes, thereby promoting endogenous remyelination. Thus, aNSCs engineered to express IL-10 show enhanced ability to induce immune suppression, remyelination, and neuronal repair and may represent a novel approach that can substantially improve the efficacy of neural stem cell–based therapy in EAE/MS.

Authors

Jingxian Yang, Zhilong Jiang, Denise C. Fitzgerald, Cungen Ma, Shuo Yu, Hongmei Li, Zhao Zhao, Yonghai Li, Bogoljub Ciric, Mark Curtis, Abdolmohamad Rostami, Guang-Xian Zhang

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Figure 5

Enhanced immunoregulatory effect of IL-10–aNSCs in the periphery.

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Enhanced immunoregulatory effect of IL-10–aNSCs in the periphery. (A) Se...
(A) Serum IL-10 levels in mice 2 weeks p.t. were assayed by ELISA. Symbols represent mean ± SD; n = 6–8 mice per group. ***P < 0.001 and ###P < 0.001, comparisons between IL-10–aNSCs i.v. and sham-EAE or GFP-aNSCs i.v., respectively. (B) Splenocytes of mice described in Figure 2A (i.v. at day 22 p.i.) were harvested 2 weeks p.t. and stimulated with 10 μg/ml MOG35–55 for 3 days. Concentrations of IL-17, IFN-γ, IL-4, IL-5, and IL-13 in culture supernatants were analyzed by ELISA. Symbols represent mean ± SD; n = 6–8 mice per group. *P < 0.05, **P < 0.01, comparisons among sham-EAE group and other groups; #P < 0.05, ##P < 0.01, comparison between GFP-aNSCs i.v. and IL-10–aNSCs i.v. (C) Splenic CD4+ T cells of naive MOG TCR transgenic mice, of which all CD4+ T cells are specific to MOG35–55, were cultured in conditioned supernatants of GFP-aNSCs or IL-10–aNSCs at a dilution of 1:4 (NSC supernatants/culture medium), which was optimal in our preliminary study (data not shown). Three days after stimulation with 10 μg/ml MOG35–55, supernatants were harvested to measure IL-17, IFN-γ, IL-4, IL-5, and IL-13 by ELISA. Symbols represent mean ± SEM of 4 independent experiments. *P < 0.05, **P < 0.01, comparisons between splenocytes alone and others; #P < 0.05, ##P < 0.01, comparisons between splenocytes plus supernatants of GFP-aNSCs and splenocytes plus supernatants of IL-10–aNSCs. ND, not detectable.