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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 cell organization in the SVZ germinal niche. (A) Diagrams of cell organization along the SVZ of HC (a) and EAE mice at 30 (b) and 60 dpi (c). Representative areas are shown at higher magnification. Note the homogeneous organization in HC, while in EAE mice at 30 dpi, cells accumulate and form large cell clusters. These clusters tend to recover at 60 dpi. Ependymal cells are depicted in black, while SVZ cells in grey; (B) Transmision EM of the EAE SVZ region at 30 dpi. A chain of migrating neuroblasts (A) appears in the lateral ventricle (LV), delimited with a discontinuous line. Ventricle walls are covered by ependymal cells (E); (C) EAE mice at 30 dpi show large cell clusters, composed of several layers of accumulated migrating cells (A); (D) The HC SVZ shows a homogeneous group of migrating neuroblasts (A). Arrows indicate the typical free spaces between type A cells, which become less noticeable in EAE mice; (E) Representative images of a single type B cell or astrocyte (B) touching the ventricular cavity (LV) through an expansion (arrows). These astrocytes might be activated in response to proliferation signals and tend to disappear within the SVZ of EAE mice; (F) Representative image of a single microglial cell (Mi). Some of these cells are filled with dense bodies, are frequently located in close proximity to blood vessels (BLV) and tend to increase in the SVZ of EAE mice at 10–30 dpi; (G) Picnotic cells (Pic) are transiently increased in the SVZ of EAE mice. Scale bars in B, C and D: 5 μm, while in E and F: 2 μm.
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Figure 2: Chronic autoimmune CNS inflammation impairs cell organization in the SVZ germinal niche. (A) Diagrams of cell organization along the SVZ of HC (a) and EAE mice at 30 (b) and 60 dpi (c). Representative areas are shown at higher magnification. Note the homogeneous organization in HC, while in EAE mice at 30 dpi, cells accumulate and form large cell clusters. These clusters tend to recover at 60 dpi. Ependymal cells are depicted in black, while SVZ cells in grey; (B) Transmision EM of the EAE SVZ region at 30 dpi. A chain of migrating neuroblasts (A) appears in the lateral ventricle (LV), delimited with a discontinuous line. Ventricle walls are covered by ependymal cells (E); (C) EAE mice at 30 dpi show large cell clusters, composed of several layers of accumulated migrating cells (A); (D) The HC SVZ shows a homogeneous group of migrating neuroblasts (A). Arrows indicate the typical free spaces between type A cells, which become less noticeable in EAE mice; (E) Representative images of a single type B cell or astrocyte (B) touching the ventricular cavity (LV) through an expansion (arrows). These astrocytes might be activated in response to proliferation signals and tend to disappear within the SVZ of EAE mice; (F) Representative image of a single microglial cell (Mi). Some of these cells are filled with dense bodies, are frequently located in close proximity to blood vessels (BLV) and tend to increase in the SVZ of EAE mice at 10–30 dpi; (G) Picnotic cells (Pic) are transiently increased in the SVZ of EAE mice. Scale bars in B, C and D: 5 μm, while in E and F: 2 μm.

Mentions: We did not observe any alteration of the morphological characteristics of each of the different cell types—such as increased smooth or rough endoplasmic reticula, or accumulation of mitochondria or lisosomes—in EAE mice compared with HC at each of the time points analysed. However, significant differences in cell distribution and organization were observed. Both semithin section analysis (Fig. 2A) as well as EM showed accumulation of type A progenitor cells and decrease of both type C and type B cells abutting the ventricle—probably activated type B cells—below the ependymal ribbon in EAE mice at 10–30 dpi (Fig. 2A, B and E).Fig. 2


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 cell organization in the SVZ germinal niche. (A) Diagrams of cell organization along the SVZ of HC (a) and EAE mice at 30 (b) and 60 dpi (c). Representative areas are shown at higher magnification. Note the homogeneous organization in HC, while in EAE mice at 30 dpi, cells accumulate and form large cell clusters. These clusters tend to recover at 60 dpi. Ependymal cells are depicted in black, while SVZ cells in grey; (B) Transmision EM of the EAE SVZ region at 30 dpi. A chain of migrating neuroblasts (A) appears in the lateral ventricle (LV), delimited with a discontinuous line. Ventricle walls are covered by ependymal cells (E); (C) EAE mice at 30 dpi show large cell clusters, composed of several layers of accumulated migrating cells (A); (D) The HC SVZ shows a homogeneous group of migrating neuroblasts (A). Arrows indicate the typical free spaces between type A cells, which become less noticeable in EAE mice; (E) Representative images of a single type B cell or astrocyte (B) touching the ventricular cavity (LV) through an expansion (arrows). These astrocytes might be activated in response to proliferation signals and tend to disappear within the SVZ of EAE mice; (F) Representative image of a single microglial cell (Mi). Some of these cells are filled with dense bodies, are frequently located in close proximity to blood vessels (BLV) and tend to increase in the SVZ of EAE mice at 10–30 dpi; (G) Picnotic cells (Pic) are transiently increased in the SVZ of EAE mice. Scale bars in B, C and D: 5 μm, while in E and F: 2 μm.
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Figure 2: Chronic autoimmune CNS inflammation impairs cell organization in the SVZ germinal niche. (A) Diagrams of cell organization along the SVZ of HC (a) and EAE mice at 30 (b) and 60 dpi (c). Representative areas are shown at higher magnification. Note the homogeneous organization in HC, while in EAE mice at 30 dpi, cells accumulate and form large cell clusters. These clusters tend to recover at 60 dpi. Ependymal cells are depicted in black, while SVZ cells in grey; (B) Transmision EM of the EAE SVZ region at 30 dpi. A chain of migrating neuroblasts (A) appears in the lateral ventricle (LV), delimited with a discontinuous line. Ventricle walls are covered by ependymal cells (E); (C) EAE mice at 30 dpi show large cell clusters, composed of several layers of accumulated migrating cells (A); (D) The HC SVZ shows a homogeneous group of migrating neuroblasts (A). Arrows indicate the typical free spaces between type A cells, which become less noticeable in EAE mice; (E) Representative images of a single type B cell or astrocyte (B) touching the ventricular cavity (LV) through an expansion (arrows). These astrocytes might be activated in response to proliferation signals and tend to disappear within the SVZ of EAE mice; (F) Representative image of a single microglial cell (Mi). Some of these cells are filled with dense bodies, are frequently located in close proximity to blood vessels (BLV) and tend to increase in the SVZ of EAE mice at 10–30 dpi; (G) Picnotic cells (Pic) are transiently increased in the SVZ of EAE mice. Scale bars in B, C and D: 5 μm, while in E and F: 2 μm.
Mentions: We did not observe any alteration of the morphological characteristics of each of the different cell types—such as increased smooth or rough endoplasmic reticula, or accumulation of mitochondria or lisosomes—in EAE mice compared with HC at each of the time points analysed. However, significant differences in cell distribution and organization were observed. Both semithin section analysis (Fig. 2A) as well as EM showed accumulation of type A progenitor cells and decrease of both type C and type B cells abutting the ventricle—probably activated type B cells—below the ependymal ribbon in EAE mice at 10–30 dpi (Fig. 2A, B and E).Fig. 2

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