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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 CNS inflammation induces quiescence of neural stem cells in vitro and in vivo. (A) NCFC assay performed on primary SVZ NPCs in the presence of either Th1 cytokines (IFN-γ, 500 U/ml; TNF-α, 200 U/ml; IL-1β 100 U/ml) or Th2 cytokines (IL-4, IL-5 and IL-13, all 10 ng/ml). SVZ cells were plated at clonal density in cytokine-enriched NeuroCult for either the last 48 h (white bars) or for the whole length of the assay (black bars). No difference in the percentage(s) of generated colonies were found upon 48 h of conditioning either with Th1 or Th2 cytokines, while longer (3 weeks) Th1 cytokine conditioning induced a complete failure of the generation of large-size colonies. Data are represented as mean percentage of colonies/size over total plated cells ± SEM and have been obtained from a total of n ≥ 3 independent experiments. °P ≤ 0.0001; *P ≤ 0.05. (B–D) Proliferation analysis of NPCs grown in vitro with CGM enriched with cytokines. (B) Th1 (white circles) or Th2 cytokines (grey circles) are compared with CGM alone (black circles). Note the significant decrease of proliferation rate of Th1 conditioned cells appearing as early as after n = 2 passages of amplification, while no difference was observed in neurospheres cultured in Th2-enriched CGM. (C) After Th1 cytokines withdrawal, NPCs are kept growing in CGM alone for further n = 6 passage of amplification and no differences in growth efficiency are observed when previously exposed NPCs to Th1 cytokines (white circles) are compared with control NPCs (black circles). (D) Proliferation analysis of NPCs grown in vitro in CGM enriched with single Th1 cytokines. IFN-γ alone (white diamonds) induces a significant reduction of growth rate (from four to six passages of amplification), while cells conditioned with either TNF-α or IL1-β do not show difference in growing efficiency at any time point. Data are represented as absolute numbers of cells ± SEM from a total of n ≥ 3 independent experiments. *P ≤ 0.05, when compared with controls. (E) NPCs were cultured for 48 h in CGM enriched with either Th1 (white bars) or Th2 cytokines (grey bars). NPCs cultured in CGM alone were used as controls (black bars). Note the significant shift (33–46% of cells) in the cells toward G0/G1, and a decline in cells in S phase upon exposure to Th1 but not Th2 cytokines. Data are represented as mean percentage of gated cells ± SEM for a total of n ≥ 5 independent experiments. **P ≤ 0.05, when compared with controls. (F) FACS analysis for Ki67. Note the significant increase of G0-confined Ki67– cells (grey bars) in Th1 cytokine-conditioned but not in unconditioned (Ctrl), or Th2-cytokine conditioned NPCs. Black bars indicate Ki67+ cell. Data are represented as mean percentage of gated cells ± SEM for a total of n ≥ 10 independent experiments. P ≤ 0.0001, when compared with controls. (G) Significant reduction of the GF upon focal injection of IFN-γ/TNF-α into the dorsolateral SVZ was observed in both HC or EAE 20 dpi mice 3 days (grey bars) after cytokine injection, compared with baseline values. Ten days after cytokine injection (white bars), the GF still remained significantly lower than normal values in HC only. NPCs proliferation was assayed by continuous exposure to systemic IddU for a total of 10 h before the sacrifice and evaluated by counting only IddU+/Iba1– (green and red cells in the panels, respectively) cells in the SVZ. Black bars represent baseline time points. Data are represented as mean labelling index (L.I.) ± SEM from a total of n ≥ 3 mice. In the panels, images of the SVZs of two representative HC and EAE mice injected with IFN-γ/TNF-α are shown. Nuclei are counterstained with DAPI. Scale bars: 50 μm. *P ≤ 0.05; **P ≤ 0.005. LV = lateral ventricle.
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Figure 7: Chronic CNS inflammation induces quiescence of neural stem cells in vitro and in vivo. (A) NCFC assay performed on primary SVZ NPCs in the presence of either Th1 cytokines (IFN-γ, 500 U/ml; TNF-α, 200 U/ml; IL-1β 100 U/ml) or Th2 cytokines (IL-4, IL-5 and IL-13, all 10 ng/ml). SVZ cells were plated at clonal density in cytokine-enriched NeuroCult for either the last 48 h (white bars) or for the whole length of the assay (black bars). No difference in the percentage(s) of generated colonies were found upon 48 h of conditioning either with Th1 or Th2 cytokines, while longer (3 weeks) Th1 cytokine conditioning induced a complete failure of the generation of large-size colonies. Data are represented as mean percentage of colonies/size over total plated cells ± SEM and have been obtained from a total of n ≥ 3 independent experiments. °P ≤ 0.0001; *P ≤ 0.05. (B–D) Proliferation analysis of NPCs grown in vitro with CGM enriched with cytokines. (B) Th1 (white circles) or Th2 cytokines (grey circles) are compared with CGM alone (black circles). Note the significant decrease of proliferation rate of Th1 conditioned cells appearing as early as after n = 2 passages of amplification, while no difference was observed in neurospheres cultured in Th2-enriched CGM. (C) After Th1 cytokines withdrawal, NPCs are kept growing in CGM alone for further n = 6 passage of amplification and no differences in growth efficiency are observed when previously exposed NPCs to Th1 cytokines (white circles) are compared with control NPCs (black circles). (D) Proliferation analysis of NPCs grown in vitro in CGM enriched with single Th1 cytokines. IFN-γ alone (white diamonds) induces a significant reduction of growth rate (from four to six passages of amplification), while cells conditioned with either TNF-α or IL1-β do not show difference in growing efficiency at any time point. Data are represented as absolute numbers of cells ± SEM from a total of n ≥ 3 independent experiments. *P ≤ 0.05, when compared with controls. (E) NPCs were cultured for 48 h in CGM enriched with either Th1 (white bars) or Th2 cytokines (grey bars). NPCs cultured in CGM alone were used as controls (black bars). Note the significant shift (33–46% of cells) in the cells toward G0/G1, and a decline in cells in S phase upon exposure to Th1 but not Th2 cytokines. Data are represented as mean percentage of gated cells ± SEM for a total of n ≥ 5 independent experiments. **P ≤ 0.05, when compared with controls. (F) FACS analysis for Ki67. Note the significant increase of G0-confined Ki67– cells (grey bars) in Th1 cytokine-conditioned but not in unconditioned (Ctrl), or Th2-cytokine conditioned NPCs. Black bars indicate Ki67+ cell. Data are represented as mean percentage of gated cells ± SEM for a total of n ≥ 10 independent experiments. P ≤ 0.0001, when compared with controls. (G) Significant reduction of the GF upon focal injection of IFN-γ/TNF-α into the dorsolateral SVZ was observed in both HC or EAE 20 dpi mice 3 days (grey bars) after cytokine injection, compared with baseline values. Ten days after cytokine injection (white bars), the GF still remained significantly lower than normal values in HC only. NPCs proliferation was assayed by continuous exposure to systemic IddU for a total of 10 h before the sacrifice and evaluated by counting only IddU+/Iba1– (green and red cells in the panels, respectively) cells in the SVZ. Black bars represent baseline time points. Data are represented as mean labelling index (L.I.) ± SEM from a total of n ≥ 3 mice. In the panels, images of the SVZs of two representative HC and EAE mice injected with IFN-γ/TNF-α are shown. Nuclei are counterstained with DAPI. Scale bars: 50 μm. *P ≤ 0.05; **P ≤ 0.005. LV = lateral ventricle.

Mentions: The gene expression pattern in the SVZ of EAE mice supports the idea that the impairment of proliferation and migration, we observed in vivo, might have occurred as a consequence of a CNS-confined inflammatory process leading to cell cycle deregulation. We found a significant up-regulation of mRNA levels for pro-inflammatory (Th1) cytokines, such as interferon (IFN)-γ and tumour necrosis factor (TNF)-α (Fig. 6G and H, respectively), but not of interleukin (IL)-1β (Fig. 6I), at 20 and 30 dpi in the SVZ from EAE mice (P ≤ 0.005, when compared with CFA-immunized mice). Given the central role played by Th1 cytokines in triggering and perpetuating chronic inflammation in EAE, we thus hypothesized that Th1 cytokines might have contributed to the impaired proliferation of stem/precursor cells observed in the SVZ of EAE mice. Primary SVZ cells from HC were grown in the continuous presence of Th1 (e.g. IFN-γ, TNF-α and IL-1β) or Th2 (e.g. IL-4, IL-5 and IL-13) cytokine mixes. When plated in presence of Th1, but not Th2, cytokines SVZ cells showed dramatic impairment in the formation of large-size neural colony-forming cells (P ≤ 0.0001, when compared with control SVZ cells). This was paralleled by a significant increase of small-sized colonies with low self-renewal capacity (P ≤ 0.05, when compared with control SVZ cells). The observed results were not obtained when cytokines of either type were added to the SVZ cell assay only for 48 h (Fig. 7A). To confirm whether NPC self-renewal could be affected by inflammatory Th1 cytokines, we generated continuous growth curves of neurospheres cultured in complete growth medium (CGM), or in CGM enriched with either Th1 or Th2 cytokines. Only neurospheres cultured in Th1-enriched CGM showed progressive and significant (from two to six passages of amplification) decrease of growth efficiency (Fig. 7B, all P ≤ 0.05, when compared with control neurospheres), while no difference was observed in neurospheres cultured in Th2-enriched CGM. Interestingly, as early Th1 cytokines were removed from the CGM and cell amplification was carried on for n = 6 further passages of amplification, the growth efficiency of neurospheres previously exposed to cytokines returned to control values (Fig. 7C). Among Th1 cytokines, IFN-γ—but not TNF-α and IL-1β—seemed to play a crucial role in the impairment of long-term proliferating capacity of neurospheres (P ≤ 0.05, when compared with control neurospheres) (Fig. 7D). As a further confirmation, we found that exposure of SVZ NPCs to Th1 but not Th2 cytokines lead to significant increase (33–46%) of cells in the G0/G1 phase (P ≤ 0.005) and to a parallel decrease of cells in the S phase (P ≤ 0.005), when compared with controls. No difference was observed in G2/M phase-restricted cells between groups (Fig. 7E).Fig. 7


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 CNS inflammation induces quiescence of neural stem cells in vitro and in vivo. (A) NCFC assay performed on primary SVZ NPCs in the presence of either Th1 cytokines (IFN-γ, 500 U/ml; TNF-α, 200 U/ml; IL-1β 100 U/ml) or Th2 cytokines (IL-4, IL-5 and IL-13, all 10 ng/ml). SVZ cells were plated at clonal density in cytokine-enriched NeuroCult for either the last 48 h (white bars) or for the whole length of the assay (black bars). No difference in the percentage(s) of generated colonies were found upon 48 h of conditioning either with Th1 or Th2 cytokines, while longer (3 weeks) Th1 cytokine conditioning induced a complete failure of the generation of large-size colonies. Data are represented as mean percentage of colonies/size over total plated cells ± SEM and have been obtained from a total of n ≥ 3 independent experiments. °P ≤ 0.0001; *P ≤ 0.05. (B–D) Proliferation analysis of NPCs grown in vitro with CGM enriched with cytokines. (B) Th1 (white circles) or Th2 cytokines (grey circles) are compared with CGM alone (black circles). Note the significant decrease of proliferation rate of Th1 conditioned cells appearing as early as after n = 2 passages of amplification, while no difference was observed in neurospheres cultured in Th2-enriched CGM. (C) After Th1 cytokines withdrawal, NPCs are kept growing in CGM alone for further n = 6 passage of amplification and no differences in growth efficiency are observed when previously exposed NPCs to Th1 cytokines (white circles) are compared with control NPCs (black circles). (D) Proliferation analysis of NPCs grown in vitro in CGM enriched with single Th1 cytokines. IFN-γ alone (white diamonds) induces a significant reduction of growth rate (from four to six passages of amplification), while cells conditioned with either TNF-α or IL1-β do not show difference in growing efficiency at any time point. Data are represented as absolute numbers of cells ± SEM from a total of n ≥ 3 independent experiments. *P ≤ 0.05, when compared with controls. (E) NPCs were cultured for 48 h in CGM enriched with either Th1 (white bars) or Th2 cytokines (grey bars). NPCs cultured in CGM alone were used as controls (black bars). Note the significant shift (33–46% of cells) in the cells toward G0/G1, and a decline in cells in S phase upon exposure to Th1 but not Th2 cytokines. Data are represented as mean percentage of gated cells ± SEM for a total of n ≥ 5 independent experiments. **P ≤ 0.05, when compared with controls. (F) FACS analysis for Ki67. Note the significant increase of G0-confined Ki67– cells (grey bars) in Th1 cytokine-conditioned but not in unconditioned (Ctrl), or Th2-cytokine conditioned NPCs. Black bars indicate Ki67+ cell. Data are represented as mean percentage of gated cells ± SEM for a total of n ≥ 10 independent experiments. P ≤ 0.0001, when compared with controls. (G) Significant reduction of the GF upon focal injection of IFN-γ/TNF-α into the dorsolateral SVZ was observed in both HC or EAE 20 dpi mice 3 days (grey bars) after cytokine injection, compared with baseline values. Ten days after cytokine injection (white bars), the GF still remained significantly lower than normal values in HC only. NPCs proliferation was assayed by continuous exposure to systemic IddU for a total of 10 h before the sacrifice and evaluated by counting only IddU+/Iba1– (green and red cells in the panels, respectively) cells in the SVZ. Black bars represent baseline time points. Data are represented as mean labelling index (L.I.) ± SEM from a total of n ≥ 3 mice. In the panels, images of the SVZs of two representative HC and EAE mice injected with IFN-γ/TNF-α are shown. Nuclei are counterstained with DAPI. Scale bars: 50 μm. *P ≤ 0.05; **P ≤ 0.005. LV = lateral ventricle.
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Figure 7: Chronic CNS inflammation induces quiescence of neural stem cells in vitro and in vivo. (A) NCFC assay performed on primary SVZ NPCs in the presence of either Th1 cytokines (IFN-γ, 500 U/ml; TNF-α, 200 U/ml; IL-1β 100 U/ml) or Th2 cytokines (IL-4, IL-5 and IL-13, all 10 ng/ml). SVZ cells were plated at clonal density in cytokine-enriched NeuroCult for either the last 48 h (white bars) or for the whole length of the assay (black bars). No difference in the percentage(s) of generated colonies were found upon 48 h of conditioning either with Th1 or Th2 cytokines, while longer (3 weeks) Th1 cytokine conditioning induced a complete failure of the generation of large-size colonies. Data are represented as mean percentage of colonies/size over total plated cells ± SEM and have been obtained from a total of n ≥ 3 independent experiments. °P ≤ 0.0001; *P ≤ 0.05. (B–D) Proliferation analysis of NPCs grown in vitro with CGM enriched with cytokines. (B) Th1 (white circles) or Th2 cytokines (grey circles) are compared with CGM alone (black circles). Note the significant decrease of proliferation rate of Th1 conditioned cells appearing as early as after n = 2 passages of amplification, while no difference was observed in neurospheres cultured in Th2-enriched CGM. (C) After Th1 cytokines withdrawal, NPCs are kept growing in CGM alone for further n = 6 passage of amplification and no differences in growth efficiency are observed when previously exposed NPCs to Th1 cytokines (white circles) are compared with control NPCs (black circles). (D) Proliferation analysis of NPCs grown in vitro in CGM enriched with single Th1 cytokines. IFN-γ alone (white diamonds) induces a significant reduction of growth rate (from four to six passages of amplification), while cells conditioned with either TNF-α or IL1-β do not show difference in growing efficiency at any time point. Data are represented as absolute numbers of cells ± SEM from a total of n ≥ 3 independent experiments. *P ≤ 0.05, when compared with controls. (E) NPCs were cultured for 48 h in CGM enriched with either Th1 (white bars) or Th2 cytokines (grey bars). NPCs cultured in CGM alone were used as controls (black bars). Note the significant shift (33–46% of cells) in the cells toward G0/G1, and a decline in cells in S phase upon exposure to Th1 but not Th2 cytokines. Data are represented as mean percentage of gated cells ± SEM for a total of n ≥ 5 independent experiments. **P ≤ 0.05, when compared with controls. (F) FACS analysis for Ki67. Note the significant increase of G0-confined Ki67– cells (grey bars) in Th1 cytokine-conditioned but not in unconditioned (Ctrl), or Th2-cytokine conditioned NPCs. Black bars indicate Ki67+ cell. Data are represented as mean percentage of gated cells ± SEM for a total of n ≥ 10 independent experiments. P ≤ 0.0001, when compared with controls. (G) Significant reduction of the GF upon focal injection of IFN-γ/TNF-α into the dorsolateral SVZ was observed in both HC or EAE 20 dpi mice 3 days (grey bars) after cytokine injection, compared with baseline values. Ten days after cytokine injection (white bars), the GF still remained significantly lower than normal values in HC only. NPCs proliferation was assayed by continuous exposure to systemic IddU for a total of 10 h before the sacrifice and evaluated by counting only IddU+/Iba1– (green and red cells in the panels, respectively) cells in the SVZ. Black bars represent baseline time points. Data are represented as mean labelling index (L.I.) ± SEM from a total of n ≥ 3 mice. In the panels, images of the SVZs of two representative HC and EAE mice injected with IFN-γ/TNF-α are shown. Nuclei are counterstained with DAPI. Scale bars: 50 μm. *P ≤ 0.05; **P ≤ 0.005. LV = lateral ventricle.
Mentions: The gene expression pattern in the SVZ of EAE mice supports the idea that the impairment of proliferation and migration, we observed in vivo, might have occurred as a consequence of a CNS-confined inflammatory process leading to cell cycle deregulation. We found a significant up-regulation of mRNA levels for pro-inflammatory (Th1) cytokines, such as interferon (IFN)-γ and tumour necrosis factor (TNF)-α (Fig. 6G and H, respectively), but not of interleukin (IL)-1β (Fig. 6I), at 20 and 30 dpi in the SVZ from EAE mice (P ≤ 0.005, when compared with CFA-immunized mice). Given the central role played by Th1 cytokines in triggering and perpetuating chronic inflammation in EAE, we thus hypothesized that Th1 cytokines might have contributed to the impaired proliferation of stem/precursor cells observed in the SVZ of EAE mice. Primary SVZ cells from HC were grown in the continuous presence of Th1 (e.g. IFN-γ, TNF-α and IL-1β) or Th2 (e.g. IL-4, IL-5 and IL-13) cytokine mixes. When plated in presence of Th1, but not Th2, cytokines SVZ cells showed dramatic impairment in the formation of large-size neural colony-forming cells (P ≤ 0.0001, when compared with control SVZ cells). This was paralleled by a significant increase of small-sized colonies with low self-renewal capacity (P ≤ 0.05, when compared with control SVZ cells). The observed results were not obtained when cytokines of either type were added to the SVZ cell assay only for 48 h (Fig. 7A). To confirm whether NPC self-renewal could be affected by inflammatory Th1 cytokines, we generated continuous growth curves of neurospheres cultured in complete growth medium (CGM), or in CGM enriched with either Th1 or Th2 cytokines. Only neurospheres cultured in Th1-enriched CGM showed progressive and significant (from two to six passages of amplification) decrease of growth efficiency (Fig. 7B, all P ≤ 0.05, when compared with control neurospheres), while no difference was observed in neurospheres cultured in Th2-enriched CGM. Interestingly, as early Th1 cytokines were removed from the CGM and cell amplification was carried on for n = 6 further passages of amplification, the growth efficiency of neurospheres previously exposed to cytokines returned to control values (Fig. 7C). Among Th1 cytokines, IFN-γ—but not TNF-α and IL-1β—seemed to play a crucial role in the impairment of long-term proliferating capacity of neurospheres (P ≤ 0.05, when compared with control neurospheres) (Fig. 7D). As a further confirmation, we found that exposure of SVZ NPCs to Th1 but not Th2 cytokines lead to significant increase (33–46%) of cells in the G0/G1 phase (P ≤ 0.005) and to a parallel decrease of cells in the S phase (P ≤ 0.005), when compared with controls. No difference was observed in G2/M phase-restricted cells between groups (Fig. 7E).Fig. 7

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