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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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Neurospheres from mice with chronic autoimmune CNS inflammation display reduced self-renewal. (A) Quantitative analysis of clonal efficiency of HC (black circles) and CFA-immunized controls (white circles) as well as EAE mice (grey circles). Note the significant and persistent impairment of clonal efficiency of primary neurospheres from EAE mice at 20, 30, 60, 120 and 240 dpi, when compared with controls. (B) The clonal efficiency of primary neurospheres from EAE mice is completely reverted after n = 10 passages of amplification in vitro and it is comparable HC and CFA-immunized controls. A total of three to six mice per group per experiments were analysed per time point. Data are represented as mean clonal efficiency ± SEM from a total of n ≤ 3 independent experiments. **P ≤ 0.0001. (C–E) Neural Colony Forming Cell (NCFC) assay-based quantification of large- (C), medium- (D) and small-sized (E) colonies. Note the significant and persistent reduction of large- and medium-sized colonies, while increase in small-sized colonies in EAE mice (grey bars), when compared with HC (black bars). Data are represented as mean percentage of colonies ± SEM over the total number of plated cells from a total of n ≥ 3 independent experiments. A total of six mice per group per experiments were analysed per time point. *P ≤ 0.05; °P ≤ 0.005. Ø, colony diameter.
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Figure 5: Neurospheres from mice with chronic autoimmune CNS inflammation display reduced self-renewal. (A) Quantitative analysis of clonal efficiency of HC (black circles) and CFA-immunized controls (white circles) as well as EAE mice (grey circles). Note the significant and persistent impairment of clonal efficiency of primary neurospheres from EAE mice at 20, 30, 60, 120 and 240 dpi, when compared with controls. (B) The clonal efficiency of primary neurospheres from EAE mice is completely reverted after n = 10 passages of amplification in vitro and it is comparable HC and CFA-immunized controls. A total of three to six mice per group per experiments were analysed per time point. Data are represented as mean clonal efficiency ± SEM from a total of n ≤ 3 independent experiments. **P ≤ 0.0001. (C–E) Neural Colony Forming Cell (NCFC) assay-based quantification of large- (C), medium- (D) and small-sized (E) colonies. Note the significant and persistent reduction of large- and medium-sized colonies, while increase in small-sized colonies in EAE mice (grey bars), when compared with HC (black bars). Data are represented as mean percentage of colonies ± SEM over the total number of plated cells from a total of n ≥ 3 independent experiments. A total of six mice per group per experiments were analysed per time point. *P ≤ 0.05; °P ≤ 0.005. Ø, colony diameter.

Mentions: Neurospheres (both primary and secondary) from EAE mice did not show differences in size at any time point, compared with neurospheres from both HC and CFA-immunized mice (Supplementary Fig. 4), thus suggesting that SVZ stem cells from symptomatic EAE mice do not differ in their mitogenic capacity from cells derived from controls. However, the clonal efficiency of SVZ primary neurospheres—while comparable between asymptomatic (e.g. 10 dpi) EAE mice and HC—became different once clinical EAE started. In fact, significantly less primary neurospheres were derived from EAE mice at 20, 30, 60, 120 and 240 dpi (all P ≤ 0.0001), when compared with controls (Fig. 5A).Fig. 5


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)

Neurospheres from mice with chronic autoimmune CNS inflammation display reduced self-renewal. (A) Quantitative analysis of clonal efficiency of HC (black circles) and CFA-immunized controls (white circles) as well as EAE mice (grey circles). Note the significant and persistent impairment of clonal efficiency of primary neurospheres from EAE mice at 20, 30, 60, 120 and 240 dpi, when compared with controls. (B) The clonal efficiency of primary neurospheres from EAE mice is completely reverted after n = 10 passages of amplification in vitro and it is comparable HC and CFA-immunized controls. A total of three to six mice per group per experiments were analysed per time point. Data are represented as mean clonal efficiency ± SEM from a total of n ≤ 3 independent experiments. **P ≤ 0.0001. (C–E) Neural Colony Forming Cell (NCFC) assay-based quantification of large- (C), medium- (D) and small-sized (E) colonies. Note the significant and persistent reduction of large- and medium-sized colonies, while increase in small-sized colonies in EAE mice (grey bars), when compared with HC (black bars). Data are represented as mean percentage of colonies ± SEM over the total number of plated cells from a total of n ≥ 3 independent experiments. A total of six mice per group per experiments were analysed per time point. *P ≤ 0.05; °P ≤ 0.005. Ø, colony diameter.
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Figure 5: Neurospheres from mice with chronic autoimmune CNS inflammation display reduced self-renewal. (A) Quantitative analysis of clonal efficiency of HC (black circles) and CFA-immunized controls (white circles) as well as EAE mice (grey circles). Note the significant and persistent impairment of clonal efficiency of primary neurospheres from EAE mice at 20, 30, 60, 120 and 240 dpi, when compared with controls. (B) The clonal efficiency of primary neurospheres from EAE mice is completely reverted after n = 10 passages of amplification in vitro and it is comparable HC and CFA-immunized controls. A total of three to six mice per group per experiments were analysed per time point. Data are represented as mean clonal efficiency ± SEM from a total of n ≤ 3 independent experiments. **P ≤ 0.0001. (C–E) Neural Colony Forming Cell (NCFC) assay-based quantification of large- (C), medium- (D) and small-sized (E) colonies. Note the significant and persistent reduction of large- and medium-sized colonies, while increase in small-sized colonies in EAE mice (grey bars), when compared with HC (black bars). Data are represented as mean percentage of colonies ± SEM over the total number of plated cells from a total of n ≥ 3 independent experiments. A total of six mice per group per experiments were analysed per time point. *P ≤ 0.05; °P ≤ 0.005. Ø, colony diameter.
Mentions: Neurospheres (both primary and secondary) from EAE mice did not show differences in size at any time point, compared with neurospheres from both HC and CFA-immunized mice (Supplementary Fig. 4), thus suggesting that SVZ stem cells from symptomatic EAE mice do not differ in their mitogenic capacity from cells derived from controls. However, the clonal efficiency of SVZ primary neurospheres—while comparable between asymptomatic (e.g. 10 dpi) EAE mice and HC—became different once clinical EAE started. In fact, significantly less primary neurospheres were derived from EAE mice at 20, 30, 60, 120 and 240 dpi (all P ≤ 0.0001), when compared with controls (Fig. 5A).Fig. 5

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