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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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Chronic autoimmune CNS inflammation impairs migration of SVZ neuroblasts. (A–C) Representative toluidine blue-stained semithin sections of the RMS of EAE mice at 30 (A) and 60 dpi (B) and HC (C). The same sections were taken-off, and ultrathin sections were re-cut. Cells were studied at the EM and identified as neuroblasts or astrocytes (red and green in lower panels). Note the disorganization of the RMS of EAE mice at 30 dpi (A), with significantly low numbers of migrating neuroblasts and numerous astrocytes. The RMS of EAE mice at 60 dpi showed a trend to recovery normal morphology (B), as compared with HC (C). The arrow at 30 dpi shows a microglial cell (purple). Scale bar: 20 μm. (D) Sagittal reconstructions of the whole RMS from a representative HC (left panel) and a mouse with EAE at 30 dpi (right panel). Migratory neuroblasts are detected by PSA-NCAM (red), while astrocytes are detected by GFAP (green). Note normal PSA-NCAM+ chains of migratory cells in the HC mouse (left panel). In contrast, the PSA-NCAM+ cells in the RMS of EAE mice at 30 dpi appear deranged in their migratory path toward olfactory bulbs (right panel). EAE mice also display increased numbers of GFAP+ astrocytes within the parenchyma surrounding the RMS. Coronal sections show clear disorganization of migratory chains with less PSA-NCAM+ neuroblasts (purple cells in the magnified inset) at the dorsal SVZ level in EAE mice. Nuclei in magnified insets have been counterstained with DAPI. Scale bars: 50 μm. LV = lateral ventricle. (E–J) Coronal brain sections showing double immunofluorescence for PSA-NCAM (red) and NG2 (green in E and F) or Olig2 (green in G and H). Note the absence of co-staining for both NG2 and Olig2 in EAE mice at 30 dpi (F and H) and HC (E and G). In I and J, NeuN staining (green) is shown in a HC mouse (I) and in a EAE mouse (J) at 30 dpi, respectively. Note that very few cells are stained in the SVZ (surrounded by a continuous line) of both mice while the majority of striatal neurons are stained (arrowheads). In all panels, nuclei have been counterstained with DAPI and the scale bar is 100 μm.
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Figure 3: Chronic autoimmune CNS inflammation impairs migration of SVZ neuroblasts. (A–C) Representative toluidine blue-stained semithin sections of the RMS of EAE mice at 30 (A) and 60 dpi (B) and HC (C). The same sections were taken-off, and ultrathin sections were re-cut. Cells were studied at the EM and identified as neuroblasts or astrocytes (red and green in lower panels). Note the disorganization of the RMS of EAE mice at 30 dpi (A), with significantly low numbers of migrating neuroblasts and numerous astrocytes. The RMS of EAE mice at 60 dpi showed a trend to recovery normal morphology (B), as compared with HC (C). The arrow at 30 dpi shows a microglial cell (purple). Scale bar: 20 μm. (D) Sagittal reconstructions of the whole RMS from a representative HC (left panel) and a mouse with EAE at 30 dpi (right panel). Migratory neuroblasts are detected by PSA-NCAM (red), while astrocytes are detected by GFAP (green). Note normal PSA-NCAM+ chains of migratory cells in the HC mouse (left panel). In contrast, the PSA-NCAM+ cells in the RMS of EAE mice at 30 dpi appear deranged in their migratory path toward olfactory bulbs (right panel). EAE mice also display increased numbers of GFAP+ astrocytes within the parenchyma surrounding the RMS. Coronal sections show clear disorganization of migratory chains with less PSA-NCAM+ neuroblasts (purple cells in the magnified inset) at the dorsal SVZ level in EAE mice. Nuclei in magnified insets have been counterstained with DAPI. Scale bars: 50 μm. LV = lateral ventricle. (E–J) Coronal brain sections showing double immunofluorescence for PSA-NCAM (red) and NG2 (green in E and F) or Olig2 (green in G and H). Note the absence of co-staining for both NG2 and Olig2 in EAE mice at 30 dpi (F and H) and HC (E and G). In I and J, NeuN staining (green) is shown in a HC mouse (I) and in a EAE mouse (J) at 30 dpi, respectively. Note that very few cells are stained in the SVZ (surrounded by a continuous line) of both mice while the majority of striatal neurons are stained (arrowheads). In all panels, nuclei have been counterstained with DAPI and the scale bar is 100 μm.

Mentions: We found that the RMS of EAE mice at 30 dpi was profoundly disorganized (Fig. 3A), with significantly less migrating neuroblasts (Fig. 3A, red cells in lower panel) and more numerous astrocytes (Fig. 3A, green cells in lower panel). The RMS of EAE mice at 60 dpi (Fig. 3B) showed a trend to recovery to normal morphology (Fig. 3C). EM confirmed cell identities in the RMS of both groups of mice (data not shown). Accordingly, in EAE mice at 20 and 30 dpi, immunofluorescence analysis of sagittal brain sections revealed increased accumulation of PSA-NCAM+ neuroblasts within the more rostral SVZ, which were not clustered in tight rows as detected in HC but appeared scattered within the RMS, possibly indicating migratory defects (Fig. 3D, magnified insets). Indeed, the astrocytic glial tubes surrounding the RMS in EAE mice appeared disrupted with accumulation of GFAP+ cells either inside the RMS or in the lateral parenchyma.Fig. 3


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)

Chronic autoimmune CNS inflammation impairs migration of SVZ neuroblasts. (A–C) Representative toluidine blue-stained semithin sections of the RMS of EAE mice at 30 (A) and 60 dpi (B) and HC (C). The same sections were taken-off, and ultrathin sections were re-cut. Cells were studied at the EM and identified as neuroblasts or astrocytes (red and green in lower panels). Note the disorganization of the RMS of EAE mice at 30 dpi (A), with significantly low numbers of migrating neuroblasts and numerous astrocytes. The RMS of EAE mice at 60 dpi showed a trend to recovery normal morphology (B), as compared with HC (C). The arrow at 30 dpi shows a microglial cell (purple). Scale bar: 20 μm. (D) Sagittal reconstructions of the whole RMS from a representative HC (left panel) and a mouse with EAE at 30 dpi (right panel). Migratory neuroblasts are detected by PSA-NCAM (red), while astrocytes are detected by GFAP (green). Note normal PSA-NCAM+ chains of migratory cells in the HC mouse (left panel). In contrast, the PSA-NCAM+ cells in the RMS of EAE mice at 30 dpi appear deranged in their migratory path toward olfactory bulbs (right panel). EAE mice also display increased numbers of GFAP+ astrocytes within the parenchyma surrounding the RMS. Coronal sections show clear disorganization of migratory chains with less PSA-NCAM+ neuroblasts (purple cells in the magnified inset) at the dorsal SVZ level in EAE mice. Nuclei in magnified insets have been counterstained with DAPI. Scale bars: 50 μm. LV = lateral ventricle. (E–J) Coronal brain sections showing double immunofluorescence for PSA-NCAM (red) and NG2 (green in E and F) or Olig2 (green in G and H). Note the absence of co-staining for both NG2 and Olig2 in EAE mice at 30 dpi (F and H) and HC (E and G). In I and J, NeuN staining (green) is shown in a HC mouse (I) and in a EAE mouse (J) at 30 dpi, respectively. Note that very few cells are stained in the SVZ (surrounded by a continuous line) of both mice while the majority of striatal neurons are stained (arrowheads). In all panels, nuclei have been counterstained with DAPI and the scale bar is 100 μm.
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Figure 3: Chronic autoimmune CNS inflammation impairs migration of SVZ neuroblasts. (A–C) Representative toluidine blue-stained semithin sections of the RMS of EAE mice at 30 (A) and 60 dpi (B) and HC (C). The same sections were taken-off, and ultrathin sections were re-cut. Cells were studied at the EM and identified as neuroblasts or astrocytes (red and green in lower panels). Note the disorganization of the RMS of EAE mice at 30 dpi (A), with significantly low numbers of migrating neuroblasts and numerous astrocytes. The RMS of EAE mice at 60 dpi showed a trend to recovery normal morphology (B), as compared with HC (C). The arrow at 30 dpi shows a microglial cell (purple). Scale bar: 20 μm. (D) Sagittal reconstructions of the whole RMS from a representative HC (left panel) and a mouse with EAE at 30 dpi (right panel). Migratory neuroblasts are detected by PSA-NCAM (red), while astrocytes are detected by GFAP (green). Note normal PSA-NCAM+ chains of migratory cells in the HC mouse (left panel). In contrast, the PSA-NCAM+ cells in the RMS of EAE mice at 30 dpi appear deranged in their migratory path toward olfactory bulbs (right panel). EAE mice also display increased numbers of GFAP+ astrocytes within the parenchyma surrounding the RMS. Coronal sections show clear disorganization of migratory chains with less PSA-NCAM+ neuroblasts (purple cells in the magnified inset) at the dorsal SVZ level in EAE mice. Nuclei in magnified insets have been counterstained with DAPI. Scale bars: 50 μm. LV = lateral ventricle. (E–J) Coronal brain sections showing double immunofluorescence for PSA-NCAM (red) and NG2 (green in E and F) or Olig2 (green in G and H). Note the absence of co-staining for both NG2 and Olig2 in EAE mice at 30 dpi (F and H) and HC (E and G). In I and J, NeuN staining (green) is shown in a HC mouse (I) and in a EAE mouse (J) at 30 dpi, respectively. Note that very few cells are stained in the SVZ (surrounded by a continuous line) of both mice while the majority of striatal neurons are stained (arrowheads). In all panels, nuclei have been counterstained with DAPI and the scale bar is 100 μm.
Mentions: We found that the RMS of EAE mice at 30 dpi was profoundly disorganized (Fig. 3A), with significantly less migrating neuroblasts (Fig. 3A, red cells in lower panel) and more numerous astrocytes (Fig. 3A, green cells in lower panel). The RMS of EAE mice at 60 dpi (Fig. 3B) showed a trend to recovery to normal morphology (Fig. 3C). EM confirmed cell identities in the RMS of both groups of mice (data not shown). Accordingly, in EAE mice at 20 and 30 dpi, immunofluorescence analysis of sagittal brain sections revealed increased accumulation of PSA-NCAM+ neuroblasts within the more rostral SVZ, which were not clustered in tight rows as detected in HC but appeared scattered within the RMS, possibly indicating migratory defects (Fig. 3D, magnified insets). Indeed, the astrocytic glial tubes surrounding the RMS in EAE mice appeared disrupted with accumulation of GFAP+ cells either inside the RMS or in the lateral parenchyma.Fig. 3

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