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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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Retroviral cell tracing shows impaired migratory behaviour of SVZ progeny. (A) A replication-defective retrovirus expressing the green fluorescent protein (GFP) was injected stereotaxically in the lateral ventricle so to infect S-phase confined cells. The green line shows the needle track, while the red line indicates the RMS. Nineteen days after the injection, GFP+ cells migrating along the RMS were numbered in a region spanning from the anterior SVZ to the OB. OB, CTX = cortex; LV = lateral ventricle. (B) EAE mice display a significant reduction of the subset of GFP+ cells migrating to the OB and an increase in non-migrating GFP+ cells detected very close to the SVZ, when compared with HC. Data are expressed as mean percentage of detected cells (over total labelled) ± SEM from n = 3 mice per group. *P ≤ 0.05. (C–F) GFP+ cells (green) are detected both in the SVZ lining and in the OB from HC (C and D) and EAE at 20 dpi (E and F). The arrows in C and E indicate SVZ GFP+ cells. The arrowheads in D and F show OB GFP+ cells. Nuclei are counterstained with DAPI. Scale bar: 150 μm. LV, lateral ventricle.
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Figure 4: Retroviral cell tracing shows impaired migratory behaviour of SVZ progeny. (A) A replication-defective retrovirus expressing the green fluorescent protein (GFP) was injected stereotaxically in the lateral ventricle so to infect S-phase confined cells. The green line shows the needle track, while the red line indicates the RMS. Nineteen days after the injection, GFP+ cells migrating along the RMS were numbered in a region spanning from the anterior SVZ to the OB. OB, CTX = cortex; LV = lateral ventricle. (B) EAE mice display a significant reduction of the subset of GFP+ cells migrating to the OB and an increase in non-migrating GFP+ cells detected very close to the SVZ, when compared with HC. Data are expressed as mean percentage of detected cells (over total labelled) ± SEM from n = 3 mice per group. *P ≤ 0.05. (C–F) GFP+ cells (green) are detected both in the SVZ lining and in the OB from HC (C and D) and EAE at 20 dpi (E and F). The arrows in C and E indicate SVZ GFP+ cells. The arrowheads in D and F show OB GFP+ cells. Nuclei are counterstained with DAPI. Scale bar: 150 μm. LV, lateral ventricle.

Mentions: Finally, we directly analysed how the newly generated SVZ cells migrate towards physiological (e.g. the OB) routes of migration. To do this we used a replication-defective retrovirus expressing the green fluorescent protein (GFP). The vector was injected into the right ventricle of both HC and EAE mice at 20 dpi and the number of GFP+ cells was quantified 19 days after the injection in a region spanning from the anterior SVZ to the OB (Fig. 4A). When compared with HC, EAE mice showed a significant (P ≤ 0.05) reduction of GFP+ cells migrating tangentially along the RMS up to the OB and differentiating into granule and periglomerular neurons (Fig. 4B). In contrast, we did not observe any quantitative difference—between EAE 20 dpi and HC—in the subset of non-migratory GFP+ cells being detected at the level of the SVZ (Fig. 4B–F).Fig. 4


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)

Retroviral cell tracing shows impaired migratory behaviour of SVZ progeny. (A) A replication-defective retrovirus expressing the green fluorescent protein (GFP) was injected stereotaxically in the lateral ventricle so to infect S-phase confined cells. The green line shows the needle track, while the red line indicates the RMS. Nineteen days after the injection, GFP+ cells migrating along the RMS were numbered in a region spanning from the anterior SVZ to the OB. OB, CTX = cortex; LV = lateral ventricle. (B) EAE mice display a significant reduction of the subset of GFP+ cells migrating to the OB and an increase in non-migrating GFP+ cells detected very close to the SVZ, when compared with HC. Data are expressed as mean percentage of detected cells (over total labelled) ± SEM from n = 3 mice per group. *P ≤ 0.05. (C–F) GFP+ cells (green) are detected both in the SVZ lining and in the OB from HC (C and D) and EAE at 20 dpi (E and F). The arrows in C and E indicate SVZ GFP+ cells. The arrowheads in D and F show OB GFP+ cells. Nuclei are counterstained with DAPI. Scale bar: 150 μm. LV, lateral ventricle.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 4: Retroviral cell tracing shows impaired migratory behaviour of SVZ progeny. (A) A replication-defective retrovirus expressing the green fluorescent protein (GFP) was injected stereotaxically in the lateral ventricle so to infect S-phase confined cells. The green line shows the needle track, while the red line indicates the RMS. Nineteen days after the injection, GFP+ cells migrating along the RMS were numbered in a region spanning from the anterior SVZ to the OB. OB, CTX = cortex; LV = lateral ventricle. (B) EAE mice display a significant reduction of the subset of GFP+ cells migrating to the OB and an increase in non-migrating GFP+ cells detected very close to the SVZ, when compared with HC. Data are expressed as mean percentage of detected cells (over total labelled) ± SEM from n = 3 mice per group. *P ≤ 0.05. (C–F) GFP+ cells (green) are detected both in the SVZ lining and in the OB from HC (C and D) and EAE at 20 dpi (E and F). The arrows in C and E indicate SVZ GFP+ cells. The arrowheads in D and F show OB GFP+ cells. Nuclei are counterstained with DAPI. Scale bar: 150 μm. LV, lateral ventricle.
Mentions: Finally, we directly analysed how the newly generated SVZ cells migrate towards physiological (e.g. the OB) routes of migration. To do this we used a replication-defective retrovirus expressing the green fluorescent protein (GFP). The vector was injected into the right ventricle of both HC and EAE mice at 20 dpi and the number of GFP+ cells was quantified 19 days after the injection in a region spanning from the anterior SVZ to the OB (Fig. 4A). When compared with HC, EAE mice showed a significant (P ≤ 0.05) reduction of GFP+ cells migrating tangentially along the RMS up to the OB and differentiating into granule and periglomerular neurons (Fig. 4B). In contrast, we did not observe any quantitative difference—between EAE 20 dpi and HC—in the subset of non-migratory GFP+ cells being detected at the level of the SVZ (Fig. 4B–F).Fig. 4

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