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, 103 (35), 13174-9

Synergy Between Immune Cells and Adult Neural Stem/Progenitor Cells Promotes Functional Recovery From Spinal Cord Injury

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Synergy Between Immune Cells and Adult Neural Stem/Progenitor Cells Promotes Functional Recovery From Spinal Cord Injury

Yaniv Ziv et al. Proc Natl Acad Sci U S A.

Erratum in

  • Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18380

Abstract

The well regulated activities of microglia and T cells specific to central nervous system (CNS) antigens can contribute to the protection of CNS neural cells and their renewal from adult neural stem/progenitor cells (aNPCs). Here we report that T cell-based vaccination of mice with a myelin-derived peptide, when combined with transplantation of aNPCs into the cerebrospinal fluid (CSF), synergistically promoted functional recovery after spinal cord injury. The synergistic effect was correlated with modulation of the nature and intensity of the local T cell and microglial response, expression of brain-derived neurotrophic factor and noggin protein, and appearance of newly formed neurons from endogenous precursor-cell pools. These results substantiate the contention that the local immune response plays a crucial role in recruitment of aNPCs to the lesion site, and suggest that similar immunological manipulations might also serve as a therapeutic means for controlled migration of stem/progenitor cells to other acutely injured CNS sites.

Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
A myelin-specific T cell response operates synergistically with transplanted aNPCs in promoting functional recovery from SCI. The figure depicts recovery of motor function after SCI in C57BL/6J mice. (A) Mice were vaccinated with MOG-CFA (CFA containing 0.5 mg/ml M. tuberculosis), or injected with PBS. Seven days after SCI, aNPCs were transplanted into the lateral ventricles (MOG-CFA/aNPC or PBS/aNPC). The lateral ventricles of mice in similarly injured and vaccinated control groups were injected with PBS (MOG-CFA/PBS or PBS/PBS). Values of the BMS rating scale are presented (n = 7 in all groups except for the PBS/aNPC group, where n = 6; P < 0.001; F = 15.5, repeated measures ANOVA). (B) Mice were vaccinated with peptide 45D emulsified in CFA with or without transplanted aNPCs. Similarly injured and vaccinated control groups, instead of being transplanted with aNPCs, were injected with PBS (n = 7 for 45D-CFA/aNPCs- and 45D-CFA/PBS-treated mice and n = 8 for PBS/PBS-treated mice; P < 0.001; F = 16.1, repeated measures ANOVA). (C) Injury and aNPC transplantation were as in A, but vaccination was carried out 7 days before SCI and the mice were vaccinated with OVA-CFA (n = 8 for OVA-CFA/PBS and OVA-CFA/aNPCs and n = 7 for PBS/PBS-treated mice; intergroup differences are not significant). (D) Mice were vaccinated immediately after SCI with MOG peptide emulsified in CFA containing 2.5 mg/ml M. tuberculosis with (n = 9) or without (n = 9) transplanted aNPCs. A third group was spinally injured and received only PBS (n = 6; P < 0.001; F = 25.03; repeated measures ANOVA). (E) Mice were vaccinated 1 week before SCI as in D with (n = 9) or without (n = 7) transplanted aNPCs. A control group received only PBS (n = 7; P = 0.026; F = 4.4; repeated-measures ANOVA). Results for all groups in all experiments are means ± SEM (∗, P < 0.05; ∗∗, P < 0.01; ∗∗∗, P < 0.001; analysis by Tukey’s procedure, indicating significant post hoc differences relative to the PBS/PBS-treated group in AD or relative to the MOG-CFA/PBS-treated group in E).
Fig. 2.
Fig. 2.
GFP-labeled aNPCs in the spinal cord parenchyma of MOG-vaccinated mice. (A) GFP-labeled cells (green) lining the ventricle wall adjacent to the hippocampus, 14 days after transplantation of aNPCs into the lateral ventricles. (Scale bar, 50 μm.) Longitudinal sections of spinal cords, excised 7 or 60 days after transplantation, were stained with anti-GFP antibody (red) and counterstained with Hoechst (blue) for detection of nuclei. Seven days after transplantation, GFP-labeled cells were detected laterally near the meninges (B) and in areas adjacent to the lesion site (C). (Scale bar, 20 μm.) (D) GFP-labeled cells adjacent to the lesion site 60 days after transplantation of aNPCs. (Scale bar, 10 μm.)
Fig. 3.
Fig. 3.
Local changes in immune activity correlate with tissue preservation. On the day of SCI, mice were vaccinated with MOG peptide emulsified in CFA containing 0.5 mg/ml M. tuberculosis. Seven days later, the vaccinated and control mice were either transplanted with aNPCs or injected with PBS. Their spinal cords were excised 1 week after cell transplantation. (A) Representative micrographs showing GFAP staining of spinal cords from mice treated with MOG-CFA/aNPC, MOG-CFA/PBS, PBS/aNPC, or PBS/PBS are shown. (B) Quantification of the area delineated by GFAP staining. (C) Representative micrographs of IB4-stained areas. (D) Quantification of IB4 immunoreactivity. (E) Representative micrographs of CD3 staining, identifying infiltrating T cells in the area surrounding the site of injury. (F) Quantification of CD3+ cells in the area surrounding the site of injury (n = 4 for MOG-CFA/aNPC and n = 3 for MOG-CFA/PBS, PBS/aNPC, and PBS/PBS; ∗, P < 0.05; ∗∗, P < 0.01; ∗∗∗, P < 0.001, ANOVA). Data are means ± SEM. (Scale bar, 100 μm in A and C; 20 μm in E.)
Fig. 4.
Fig. 4.
Local microglial production of BDNF and noggin. Quantification of BDNF (A) and noggin (B) immunoreactivity (Upper) (n = 4 for MOG-CFA/aNPC and n = 3 for MOG-CFA/PBS, PBS/aNPC, and PBS/PBS; ∗, P < 0.05; ∗∗, P < 0.01; ∗∗∗, P < 0.001, ANOVA). (Lower) Both BDNF and noggin are colocalized to IB4+ cells. (Scale bar, 20 μm.)
Fig. 5.
Fig. 5.
Increased neurogenesis from endogenous progenitors in the spinal cords of dual-treated mice. The numbers of BrdU/DCX double-positive cells in the vicinity of the site of injury are increased after dual treatment with vaccination and aNPC transplantation. SCI and aNPC transplantation were as in Fig. 1. Seven days after aNPC transplantation, mice were injected with BrdU twice daily for 3 days. Longitudinal sections of spinal cords excised 14 days after cell transplantation and 1 month after contusive SCI were stained for BrdU and DCX. (A) Quantification of BrdU+/DCX+ cells in the injured spinal cord (n = 7 for MOG-CFA/aNPC and n = 5 for MOG-CFA/PBS, PBS/aNPC, and PBS/PBS, pooled data from two independent experiments; ∗, P < 0.05; ∗∗, P < 0.01; ∗∗∗, P < 0.001, ANOVA). (B) Representative images showing newly formed neuronal cells stained for BrdU (green) and DCX (red). (Scale bar, 10 μm.)

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