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Persistent inflammation alters the function of the endogenous brain stem cell compartment.

Pluchino S, Muzio L, Imitola J, Deleidi M, Alfaro-Cervello C, Salani G, Porcheri C, Brambilla E, Cavasinni F, Bergamaschi A, Garcia-Verdugo JM, Comi G, Khoury SJ, Martino G - Brain (2008)

Bottom Line: Despite evidence of increased neurogenesis upon acute inflammatory insults (e.g. ischaemic stroke), the plasticity of the endogenous brain stem cell compartment in chronic CNS inflammatory disorders remains poorly characterized.Here we show that persistent brain inflammation, induced by immune cells targeting myelin, extensively alters the proliferative and migratory properties of subventricular zone (SVZ)-resident NPCs in vivo leading to significant accumulation of non-migratory neuroblasts within the SVZ germinal niche.Together, these data indicate that the inflamed brain microenvironment sustains a non cell-autonomous dysfunction of the endogenous CNS stem cell compartment and challenge the potential efficacy of proposed therapies aimed at mobilizing endogenous precursors in chronic inflammatory brain disorders.

View Article: PubMed Central - PubMed

Affiliation: Neuroimmunology Unit, DIBIT, San Raffaele Scientific Institute, Milano, Italy.

ABSTRACT
Endogenous neural stem/precursor cells (NPCs) are considered a functional reservoir for promoting tissue homeostasis and repair after injury, therefore regenerative strategies that mobilize these cells have recently been proposed. Despite evidence of increased neurogenesis upon acute inflammatory insults (e.g. ischaemic stroke), the plasticity of the endogenous brain stem cell compartment in chronic CNS inflammatory disorders remains poorly characterized. Here we show that persistent brain inflammation, induced by immune cells targeting myelin, extensively alters the proliferative and migratory properties of subventricular zone (SVZ)-resident NPCs in vivo leading to significant accumulation of non-migratory neuroblasts within the SVZ germinal niche. In parallel, we demonstrate a quantitative reduction of the putative brain stem cells proliferation in the SVZ during persistent brain inflammation, which is completely reversed after in vitro culture of the isolated NPCs. Together, these data indicate that the inflamed brain microenvironment sustains a non cell-autonomous dysfunction of the endogenous CNS stem cell compartment and challenge the potential efficacy of proposed therapies aimed at mobilizing endogenous precursors in chronic inflammatory brain disorders.

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CNS inflammation induces expression of cell cycle regulators and neurogenic transcription factors at mRNA level. (A, B) Semi-quantitative analysis of selected mRNAs. The graph in A includes a list of n = 5 selected genes showing significant down-regulation (fold reduction ≥1) at any time point in the SVZ of EAE mice, when compared with CFA-immunized controls. The graph in B includes a list of n = 15 selected genes showing significant up-regulation (fold induction ≥1) at any time point in the SVZ of EAE mice, when compared with CFA-immunized controls. (C–F) In situ hybridization for Dlx2 (C and D) and Cdkn1a/p21 (E and F) on coronal brain sections from both HC (C and E) and EAE 30 dpi (D and F). EAE mice show increased numbers of Dlx2+ and Cdkn1a/p21+ cells within the SVZ, when compared with HC. Autoradiographic grains (red) were captured with 20× objective in a dark field light microscopy and tissue was visualized by DNA staining (DAPI, blue). LV = lateral ventricle. Scale bars: 50 μm. (G–I) Significant increase of IFN-γ and TNF-α mRNA levels (G and H, respectively) in the SVZ of EAE mice at 20 and 30 dpi compared with CFA-immunized controls. The graph in F shows the significant decrease of IL-1β mRNA levels in the SVZ of EAE mice at 20 and 30 dpi. Data are represented as mean arbitrary units ± SEM and have been obtained in single from the SVZs of n ≥ 6 per mice per group per time point. *P ≤ 0.05; **P ≤ 0.0001.
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Figure 6: CNS inflammation induces expression of cell cycle regulators and neurogenic transcription factors at mRNA level. (A, B) Semi-quantitative analysis of selected mRNAs. The graph in A includes a list of n = 5 selected genes showing significant down-regulation (fold reduction ≥1) at any time point in the SVZ of EAE mice, when compared with CFA-immunized controls. The graph in B includes a list of n = 15 selected genes showing significant up-regulation (fold induction ≥1) at any time point in the SVZ of EAE mice, when compared with CFA-immunized controls. (C–F) In situ hybridization for Dlx2 (C and D) and Cdkn1a/p21 (E and F) on coronal brain sections from both HC (C and E) and EAE 30 dpi (D and F). EAE mice show increased numbers of Dlx2+ and Cdkn1a/p21+ cells within the SVZ, when compared with HC. Autoradiographic grains (red) were captured with 20× objective in a dark field light microscopy and tissue was visualized by DNA staining (DAPI, blue). LV = lateral ventricle. Scale bars: 50 μm. (G–I) Significant increase of IFN-γ and TNF-α mRNA levels (G and H, respectively) in the SVZ of EAE mice at 20 and 30 dpi compared with CFA-immunized controls. The graph in F shows the significant decrease of IL-1β mRNA levels in the SVZ of EAE mice at 20 and 30 dpi. Data are represented as mean arbitrary units ± SEM and have been obtained in single from the SVZs of n ≥ 6 per mice per group per time point. *P ≤ 0.05; **P ≤ 0.0001.

Mentions: Interestingly, 60.5% (101/167) and 27.5% (46/167) of screened genes either did not change at any time point or were not expressed at more than one time point, respectively. Only 9% (15/167) of screened genes were up regulated in the SVZ of EAE mice at 20 and/or 30 dpi, when compared with HC. On the other hand, 3% (5/167) of the genes were down-regulated in the EAE mice among which we identified at least two major markers for stem/precursor cells of the SVZ germinal niche, such as Prominin-1 and Tenascin-C (Martino and Pluchino, 2006) (Fig. 6A). According to LCM analysis of the SVZ (Supplementary Fig. 3), we did not find any up regulation of (oligodendro)glial cell fate gene determinants, such as Nkx2.2 (Fig. 6A and B).Fig. 6


Persistent inflammation alters the function of the endogenous brain stem cell compartment.

Pluchino S, Muzio L, Imitola J, Deleidi M, Alfaro-Cervello C, Salani G, Porcheri C, Brambilla E, Cavasinni F, Bergamaschi A, Garcia-Verdugo JM, Comi G, Khoury SJ, Martino G - Brain (2008)

CNS inflammation induces expression of cell cycle regulators and neurogenic transcription factors at mRNA level. (A, B) Semi-quantitative analysis of selected mRNAs. The graph in A includes a list of n = 5 selected genes showing significant down-regulation (fold reduction ≥1) at any time point in the SVZ of EAE mice, when compared with CFA-immunized controls. The graph in B includes a list of n = 15 selected genes showing significant up-regulation (fold induction ≥1) at any time point in the SVZ of EAE mice, when compared with CFA-immunized controls. (C–F) In situ hybridization for Dlx2 (C and D) and Cdkn1a/p21 (E and F) on coronal brain sections from both HC (C and E) and EAE 30 dpi (D and F). EAE mice show increased numbers of Dlx2+ and Cdkn1a/p21+ cells within the SVZ, when compared with HC. Autoradiographic grains (red) were captured with 20× objective in a dark field light microscopy and tissue was visualized by DNA staining (DAPI, blue). LV = lateral ventricle. Scale bars: 50 μm. (G–I) Significant increase of IFN-γ and TNF-α mRNA levels (G and H, respectively) in the SVZ of EAE mice at 20 and 30 dpi compared with CFA-immunized controls. The graph in F shows the significant decrease of IL-1β mRNA levels in the SVZ of EAE mice at 20 and 30 dpi. Data are represented as mean arbitrary units ± SEM and have been obtained in single from the SVZs of n ≥ 6 per mice per group per time point. *P ≤ 0.05; **P ≤ 0.0001.
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Related In: Results  -  Collection

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Figure 6: CNS inflammation induces expression of cell cycle regulators and neurogenic transcription factors at mRNA level. (A, B) Semi-quantitative analysis of selected mRNAs. The graph in A includes a list of n = 5 selected genes showing significant down-regulation (fold reduction ≥1) at any time point in the SVZ of EAE mice, when compared with CFA-immunized controls. The graph in B includes a list of n = 15 selected genes showing significant up-regulation (fold induction ≥1) at any time point in the SVZ of EAE mice, when compared with CFA-immunized controls. (C–F) In situ hybridization for Dlx2 (C and D) and Cdkn1a/p21 (E and F) on coronal brain sections from both HC (C and E) and EAE 30 dpi (D and F). EAE mice show increased numbers of Dlx2+ and Cdkn1a/p21+ cells within the SVZ, when compared with HC. Autoradiographic grains (red) were captured with 20× objective in a dark field light microscopy and tissue was visualized by DNA staining (DAPI, blue). LV = lateral ventricle. Scale bars: 50 μm. (G–I) Significant increase of IFN-γ and TNF-α mRNA levels (G and H, respectively) in the SVZ of EAE mice at 20 and 30 dpi compared with CFA-immunized controls. The graph in F shows the significant decrease of IL-1β mRNA levels in the SVZ of EAE mice at 20 and 30 dpi. Data are represented as mean arbitrary units ± SEM and have been obtained in single from the SVZs of n ≥ 6 per mice per group per time point. *P ≤ 0.05; **P ≤ 0.0001.
Mentions: Interestingly, 60.5% (101/167) and 27.5% (46/167) of screened genes either did not change at any time point or were not expressed at more than one time point, respectively. Only 9% (15/167) of screened genes were up regulated in the SVZ of EAE mice at 20 and/or 30 dpi, when compared with HC. On the other hand, 3% (5/167) of the genes were down-regulated in the EAE mice among which we identified at least two major markers for stem/precursor cells of the SVZ germinal niche, such as Prominin-1 and Tenascin-C (Martino and Pluchino, 2006) (Fig. 6A). According to LCM analysis of the SVZ (Supplementary Fig. 3), we did not find any up regulation of (oligodendro)glial cell fate gene determinants, such as Nkx2.2 (Fig. 6A and B).Fig. 6

Bottom Line: Despite evidence of increased neurogenesis upon acute inflammatory insults (e.g. ischaemic stroke), the plasticity of the endogenous brain stem cell compartment in chronic CNS inflammatory disorders remains poorly characterized.Here we show that persistent brain inflammation, induced by immune cells targeting myelin, extensively alters the proliferative and migratory properties of subventricular zone (SVZ)-resident NPCs in vivo leading to significant accumulation of non-migratory neuroblasts within the SVZ germinal niche.Together, these data indicate that the inflamed brain microenvironment sustains a non cell-autonomous dysfunction of the endogenous CNS stem cell compartment and challenge the potential efficacy of proposed therapies aimed at mobilizing endogenous precursors in chronic inflammatory brain disorders.

View Article: PubMed Central - PubMed

Affiliation: Neuroimmunology Unit, DIBIT, San Raffaele Scientific Institute, Milano, Italy.

ABSTRACT
Endogenous neural stem/precursor cells (NPCs) are considered a functional reservoir for promoting tissue homeostasis and repair after injury, therefore regenerative strategies that mobilize these cells have recently been proposed. Despite evidence of increased neurogenesis upon acute inflammatory insults (e.g. ischaemic stroke), the plasticity of the endogenous brain stem cell compartment in chronic CNS inflammatory disorders remains poorly characterized. Here we show that persistent brain inflammation, induced by immune cells targeting myelin, extensively alters the proliferative and migratory properties of subventricular zone (SVZ)-resident NPCs in vivo leading to significant accumulation of non-migratory neuroblasts within the SVZ germinal niche. In parallel, we demonstrate a quantitative reduction of the putative brain stem cells proliferation in the SVZ during persistent brain inflammation, which is completely reversed after in vitro culture of the isolated NPCs. Together, these data indicate that the inflamed brain microenvironment sustains a non cell-autonomous dysfunction of the endogenous CNS stem cell compartment and challenge the potential efficacy of proposed therapies aimed at mobilizing endogenous precursors in chronic inflammatory brain disorders.

Show MeSH
Related in: MedlinePlus