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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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 6

Enhanced proapoptotic effect of IL-10–aNSCs on inflammatory cells.

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Enhanced proapoptotic effect of IL-10–aNSCs on inflammatory cells. Mice ...
Mice treated with aNSCs i.v. at day 22 p.i. were sacrificed 2 weeks p.t. Brains, spinal cords, and lymph nodes were harvested. The same region of the corpus callosum was examined in all groups, as shown in Supplemental Figure 3. (A) Colocalization of apoptotic cells (red) and CD45+ (blue) in the brain indicated that the majority of apoptotic cells were CNS-infiltrating cells, while no GFP+ aNSCs (green) underwent apoptosis. (B) GFP+ aNSCs were present in lymph node sections, none of which underwent apoptosis. Nuclei in B were stained with DAPI (blue). The insets show high-magnification images of the boxed regions. Original magnification, ×20 (A); ×10 (B), ×65 (insets, A and B). Quantitative analysis of apoptotic CNS-infiltrating cells (C) and lymph node cells (D). Symbols represent mean ± SD; n = 6–8 mice per group. **P < 0.01, comparisons between sham-EAE group and other groups; ##P < 0.01, comparison between GFP-aNSCs i.v. and IL-10–aNSCs i.v. (E) Block of FasL inhibited the proapoptotic effect of aNSCs on T cells in cocultures. Apoptotic cells were defined as CD4+, Annexin-V+, and DAPI– by flow cytometry. Results are mean ± SEM of 4 independent experiments. #P < 0.05, ##P < 0.01, comparison between T cells cocultured with GFP-aNSCs and with IL-10–aNSCs. †P < 0.05, ††P < 0.01, comparison between T cells cocultured with aNSCs and T cells alone. *P < 0.05, **P < 0.01, comparison between wells unblocked and blocked by anti-FasL antibody.