Adult neural stem cells expressing IL-10 confer potent immunomodulation and remyelination in experimental autoimmune encephalitis
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
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
View: Text | PDF | Retraction
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

×

Figure 4

Engraftment and enhanced antiinflammatory effect of IL-10–aNSCs in the CNS.

Options: View larger image (or click on image) Download as PowerPoint
Engraftment and enhanced antiinflammatory effect of IL-10–aNSCs in the C...
Mice described in Figure 2A (i.v. injection at day 22 p.i.) were sacrificed 2 weeks p.t., and lumbar spinal cords were harvested for immunostaining. The same region of the ventral column at L3 was examined in all groups, as shown in Supplemental Figure 3. (A) GFP+ aNSCs were found in the white matter of spinal cords in both groups of aNSC-treated mice, colocalization of strong IL-10 expression (red) and GFP (green) were detected in IL-10–aNSC–treated mice but not GFP-aNSC–treated mice. Nuclei in A were stained with DAPI (blue). (B) Immunostaining with anti-CD45 antibody to detect CNS inflammation. Reduced numbers of CD68+ (red) and CD4+ (blue) cells (C) and CD8+ (red) cells (D) and an increased number of LAMP2+ (red) cells (E) were found in spinal cord lesions of IL-10–aNSC–treated mice. None of the GFP+-NSCs (green) express LAMP2. Original magnification, ×40 (A and C–E); ×20 (B). (F) Quantitative analysis of CNS-infiltrating cells, as shown in B–D, and LAMP2+ cells, as shown in E. Symbols represent mean ± SD; n = 6–8 mice per group. *P < 0.05, **P < 0.01, comparisons between sham-EAE group and other groups; #P < 0.05, comparison between GFP-aNSCs i.v. and IL-10–aNSCs i.v.