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 3

Localization and migration of transplanted aNSCs in the CNS.

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Localization and migration of transplanted aNSCs in the CNS. Mice treate...
Mice treated with aNSCs i.v. at day 22 p.i. were sacrificed 2, 6, and 11 weeks p.t., and brains were harvested for immunohistology. The same region of the corpus callosum was examined in all groups, as shown in Supplemental Figure 3. (A and B) Transplanted aNSCs (green) were primarily confined to perivascular spaces 2 weeks (Ws) p.t., while the majority of these cells had migrated to the parenchyma by 6 weeks p.t. Blood vessels were stained with anti-laminin antibody (red). (C) GFP+ aNSCs remained in perivascular spaces of inflammatory areas, in which blood-borne CD45+ immune cells (red) that form the CNS inflammatory infiltrate persisted. (D) The majority of aNSCs in perivascular spaces remained positive for nestin (red). Nuclei in A, B, and C were stained with DAPI (blue). The high-magnification images represent the boxed regions (A, C, and D). Original magnification, ×20 (A and B); ×40 (C and D); ×65 (high-magnification images, A, C, and D). (E) Quantitative analysis of aNSCs that reached the parenchyma of EAE at 2, 6, and 11 weeks p.t. Symbols represent mean ± SD; n = 6–8 mice per group. *P < 0.05, **P < 0.01, comparisons between groups 2 weeks p.t. and groups at other time points; #P < 0.05, comparison of groups between 6 and 11 weeks p.t.