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Interleukin-15 regulates proliferation and self-renewal of adult neural stem cells.

Gómez-Nicola D, Valle-Argos B, Pallas-Bazarra N, Nieto-Sampedro M - Mol. Biol. Cell (2011)

Bottom Line: Moreover, IL-15-deficient NSCs were more prone to differentiate than wild-type NSCs, not affecting the cell population balance.Lack of IL-15 led to a defective activation of the JAK/STAT and ERK pathways, key for the regulation of proliferation and differentiation of NSCs.The results show that IL-15 is a key regulator of neurogenesis in the adult and is essential to understanding diseases with an inflammatory component.

View Article: PubMed Central - PubMed

Affiliation: Functional and Systems Neurobiology Department, Cajal Institute (CSIC), Madrid, Spain. dgomeznicola@gmail.com

ABSTRACT
The impact of inflammation is crucial for the regulation of the biology of neural stem cells (NSCs). Interleukin-15 (IL-15) appears as a likely candidate for regulating neurogenesis, based on its well-known mitogenic properties. We show here that NSCs of the subventricular zone (SVZ) express IL-15, which regulates NSC proliferation, as evidenced by the study of IL-15-/- mice and the effects of acute IL-15 administration, coupled to 5-bromo-2'-deoxyuridine/5-ethynyl-2'-deoxyuridine dual-pulse labeling. Moreover, IL-15 regulates NSC differentiation, its deficiency leading to an impaired generation of neuroblasts in the SVZ-rostral migratory stream axis, recoverable through the action of exogenous IL-15. IL-15 expressed in cultured NSCs is linked to self-renewal, proliferation, and differentiation. IL-15-/- NSCs presented deficient proliferation and self-renewal, as evidenced in proliferation and colony-forming assays and the analysis of cell cycle-regulatory proteins. Moreover, IL-15-deficient NSCs were more prone to differentiate than wild-type NSCs, not affecting the cell population balance. Lack of IL-15 led to a defective activation of the JAK/STAT and ERK pathways, key for the regulation of proliferation and differentiation of NSCs. The results show that IL-15 is a key regulator of neurogenesis in the adult and is essential to understanding diseases with an inflammatory component.

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Intraventricular IL-15 increases NSC proliferation and rescues IL-15−/− phenotype. Dual-pulse (BrDU/EdU) analysis of the effect of IL-15 on NSC proliferation in WT and IL-15−/− mice (see experimental scheme at top right corner). (A–L) Double immunofluorescence for EdU (green) and BrdU (red) in the SVZ of WT (A–C, G–I) and IL-15−/− (D–F, J–L) mice after treatment with ICV PBS (A–F) or IL-15 (1 μg/5 μl; G–L). (M) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the proliferative activity in the SVZ of WT or IL-15−/− mice, as mean ± SEM of BrdU/EdU+ nuclei ratio. (N–Q) Double immunofluorescence for EdU (green) and BrdU (red) in the RMS of WT (N, P) and IL-15−/− (O, P) mice after treatment with ICV PBS (N, O) or IL-15 (1 μg/5 μl; P, Q). (R) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the proliferative activity in the RMS of WT or IL-15−/−mic, as mean ± SEM of BrdU/EdU+ nuclei ratio. Magnifications are shown in the low right-hand insert. Nuclei are stained with Hoechst (blue). Immunopositive nuclei counting was delimited to the RMS perimeter (dotted line), established using Hoechst staining. Fluorescent sections were evaluated with confocal microscopy. Scale bar in A–L, 20 μm (shown in L); in N–Q, 50 μm (shown in Q). Statistical differences of PBS vs. IL-15: **p < 0.01. Data were analyzed with an ANOVA and a post hoc Tukey test.
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Figure 3: Intraventricular IL-15 increases NSC proliferation and rescues IL-15−/− phenotype. Dual-pulse (BrDU/EdU) analysis of the effect of IL-15 on NSC proliferation in WT and IL-15−/− mice (see experimental scheme at top right corner). (A–L) Double immunofluorescence for EdU (green) and BrdU (red) in the SVZ of WT (A–C, G–I) and IL-15−/− (D–F, J–L) mice after treatment with ICV PBS (A–F) or IL-15 (1 μg/5 μl; G–L). (M) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the proliferative activity in the SVZ of WT or IL-15−/− mice, as mean ± SEM of BrdU/EdU+ nuclei ratio. (N–Q) Double immunofluorescence for EdU (green) and BrdU (red) in the RMS of WT (N, P) and IL-15−/− (O, P) mice after treatment with ICV PBS (N, O) or IL-15 (1 μg/5 μl; P, Q). (R) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the proliferative activity in the RMS of WT or IL-15−/−mic, as mean ± SEM of BrdU/EdU+ nuclei ratio. Magnifications are shown in the low right-hand insert. Nuclei are stained with Hoechst (blue). Immunopositive nuclei counting was delimited to the RMS perimeter (dotted line), established using Hoechst staining. Fluorescent sections were evaluated with confocal microscopy. Scale bar in A–L, 20 μm (shown in L); in N–Q, 50 μm (shown in Q). Statistical differences of PBS vs. IL-15: **p < 0.01. Data were analyzed with an ANOVA and a post hoc Tukey test.

Mentions: Taking into account the observed loss of neurogenic potential in IL-15−/− mice, we proceeded to address the potential of IL-15 to promote neurogenesis in a gain-of-function experimental paradigm (Figure 3). The effect of the intraventricular administration of IL-15 was evaluated by sequential administration of 5-ethynyl-2′-deoxyuridine (EdU) and BrDU and immunohistochemical analysis in IL-15−/− and WT animals (Figure 3; see experimental scheme). The comparison of the pattern of incorporation of EdU in WT or IL-15−/− mice (Figure 3, A, D, N, and O) correlated with that observed previously with BrDU (Figure 2) at both the SVZ and RMS levels, supporting the observed deficit in neurogenesis of IL-15−/− mice. When recombinant IL-15 was administered intraventricularly (ICV) a rescue in the phenotype of IL-15−/− mice was observed. Thus intraventricular IL-15 caused an increase in the proliferation in the SVZ both in WT (Figure 3, G–I) and IL-15−/− (Figure 3, J–L) mice when compared with the injection of phosphate-buffered saline (PBS) (Figure 3, A–C and D–F). On considering the BrDU/EdU ratio of incorporation, a significant increase in IL-15−/− injected with IL-15 when compared with PBS was found, pointing to a recovery of the normal function (Figure 3M).


Interleukin-15 regulates proliferation and self-renewal of adult neural stem cells.

Gómez-Nicola D, Valle-Argos B, Pallas-Bazarra N, Nieto-Sampedro M - Mol. Biol. Cell (2011)

Intraventricular IL-15 increases NSC proliferation and rescues IL-15−/− phenotype. Dual-pulse (BrDU/EdU) analysis of the effect of IL-15 on NSC proliferation in WT and IL-15−/− mice (see experimental scheme at top right corner). (A–L) Double immunofluorescence for EdU (green) and BrdU (red) in the SVZ of WT (A–C, G–I) and IL-15−/− (D–F, J–L) mice after treatment with ICV PBS (A–F) or IL-15 (1 μg/5 μl; G–L). (M) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the proliferative activity in the SVZ of WT or IL-15−/− mice, as mean ± SEM of BrdU/EdU+ nuclei ratio. (N–Q) Double immunofluorescence for EdU (green) and BrdU (red) in the RMS of WT (N, P) and IL-15−/− (O, P) mice after treatment with ICV PBS (N, O) or IL-15 (1 μg/5 μl; P, Q). (R) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the proliferative activity in the RMS of WT or IL-15−/−mic, as mean ± SEM of BrdU/EdU+ nuclei ratio. Magnifications are shown in the low right-hand insert. Nuclei are stained with Hoechst (blue). Immunopositive nuclei counting was delimited to the RMS perimeter (dotted line), established using Hoechst staining. Fluorescent sections were evaluated with confocal microscopy. Scale bar in A–L, 20 μm (shown in L); in N–Q, 50 μm (shown in Q). Statistical differences of PBS vs. IL-15: **p < 0.01. Data were analyzed with an ANOVA and a post hoc Tukey test.
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Related In: Results  -  Collection

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Figure 3: Intraventricular IL-15 increases NSC proliferation and rescues IL-15−/− phenotype. Dual-pulse (BrDU/EdU) analysis of the effect of IL-15 on NSC proliferation in WT and IL-15−/− mice (see experimental scheme at top right corner). (A–L) Double immunofluorescence for EdU (green) and BrdU (red) in the SVZ of WT (A–C, G–I) and IL-15−/− (D–F, J–L) mice after treatment with ICV PBS (A–F) or IL-15 (1 μg/5 μl; G–L). (M) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the proliferative activity in the SVZ of WT or IL-15−/− mice, as mean ± SEM of BrdU/EdU+ nuclei ratio. (N–Q) Double immunofluorescence for EdU (green) and BrdU (red) in the RMS of WT (N, P) and IL-15−/− (O, P) mice after treatment with ICV PBS (N, O) or IL-15 (1 μg/5 μl; P, Q). (R) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the proliferative activity in the RMS of WT or IL-15−/−mic, as mean ± SEM of BrdU/EdU+ nuclei ratio. Magnifications are shown in the low right-hand insert. Nuclei are stained with Hoechst (blue). Immunopositive nuclei counting was delimited to the RMS perimeter (dotted line), established using Hoechst staining. Fluorescent sections were evaluated with confocal microscopy. Scale bar in A–L, 20 μm (shown in L); in N–Q, 50 μm (shown in Q). Statistical differences of PBS vs. IL-15: **p < 0.01. Data were analyzed with an ANOVA and a post hoc Tukey test.
Mentions: Taking into account the observed loss of neurogenic potential in IL-15−/− mice, we proceeded to address the potential of IL-15 to promote neurogenesis in a gain-of-function experimental paradigm (Figure 3). The effect of the intraventricular administration of IL-15 was evaluated by sequential administration of 5-ethynyl-2′-deoxyuridine (EdU) and BrDU and immunohistochemical analysis in IL-15−/− and WT animals (Figure 3; see experimental scheme). The comparison of the pattern of incorporation of EdU in WT or IL-15−/− mice (Figure 3, A, D, N, and O) correlated with that observed previously with BrDU (Figure 2) at both the SVZ and RMS levels, supporting the observed deficit in neurogenesis of IL-15−/− mice. When recombinant IL-15 was administered intraventricularly (ICV) a rescue in the phenotype of IL-15−/− mice was observed. Thus intraventricular IL-15 caused an increase in the proliferation in the SVZ both in WT (Figure 3, G–I) and IL-15−/− (Figure 3, J–L) mice when compared with the injection of phosphate-buffered saline (PBS) (Figure 3, A–C and D–F). On considering the BrDU/EdU ratio of incorporation, a significant increase in IL-15−/− injected with IL-15 when compared with PBS was found, pointing to a recovery of the normal function (Figure 3M).

Bottom Line: Moreover, IL-15-deficient NSCs were more prone to differentiate than wild-type NSCs, not affecting the cell population balance.Lack of IL-15 led to a defective activation of the JAK/STAT and ERK pathways, key for the regulation of proliferation and differentiation of NSCs.The results show that IL-15 is a key regulator of neurogenesis in the adult and is essential to understanding diseases with an inflammatory component.

View Article: PubMed Central - PubMed

Affiliation: Functional and Systems Neurobiology Department, Cajal Institute (CSIC), Madrid, Spain. dgomeznicola@gmail.com

ABSTRACT
The impact of inflammation is crucial for the regulation of the biology of neural stem cells (NSCs). Interleukin-15 (IL-15) appears as a likely candidate for regulating neurogenesis, based on its well-known mitogenic properties. We show here that NSCs of the subventricular zone (SVZ) express IL-15, which regulates NSC proliferation, as evidenced by the study of IL-15-/- mice and the effects of acute IL-15 administration, coupled to 5-bromo-2'-deoxyuridine/5-ethynyl-2'-deoxyuridine dual-pulse labeling. Moreover, IL-15 regulates NSC differentiation, its deficiency leading to an impaired generation of neuroblasts in the SVZ-rostral migratory stream axis, recoverable through the action of exogenous IL-15. IL-15 expressed in cultured NSCs is linked to self-renewal, proliferation, and differentiation. IL-15-/- NSCs presented deficient proliferation and self-renewal, as evidenced in proliferation and colony-forming assays and the analysis of cell cycle-regulatory proteins. Moreover, IL-15-deficient NSCs were more prone to differentiate than wild-type NSCs, not affecting the cell population balance. Lack of IL-15 led to a defective activation of the JAK/STAT and ERK pathways, key for the regulation of proliferation and differentiation of NSCs. The results show that IL-15 is a key regulator of neurogenesis in the adult and is essential to understanding diseases with an inflammatory component.

Show MeSH
Related in: MedlinePlus