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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 the pool of neuroblasts and rescues IL-15−/− phenotype. Analysis of the effect of IL-15 on neurogenesis in WT and IL-15−/− mice (see experimental scheme at top right corner). (A–L) Double immunofluorescence for DCX (green) and GFAP (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, N) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the expression of DCX (M) and GFAP (N) in the SVZ of WT or IL-15–/– mice, as mean ± SEM of percent positive area. (O–R) Double immunofluorescence for DCX (green) and GFAP (red) in the RMS of WT (O, Q) and IL-15−/− (P, R) mice after treatment with ICV PBS (O, P) or IL-15 (1 μg/5 μl; Q, R). (S, T) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the expression of DCX (M) and GFAP (N) in the RMS of WT or IL-15−/− mice as mean ± SEM of percent positive area. Nuclei are stained with Hoechst (blue). Fluorescent sections are evaluated with confocal microscopy. Scale bar in A–L, 20 μm (shown in L); in O–R, 50 μm (shown in R). Statistical differences of PBS vs. IL-15: *p < 0.05, **p < 0.01. Data were analyzed with an ANOVA and a post hoc Tukey test.
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Figure 4: Intraventricular IL-15 increases the pool of neuroblasts and rescues IL-15−/− phenotype. Analysis of the effect of IL-15 on neurogenesis in WT and IL-15−/− mice (see experimental scheme at top right corner). (A–L) Double immunofluorescence for DCX (green) and GFAP (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, N) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the expression of DCX (M) and GFAP (N) in the SVZ of WT or IL-15–/– mice, as mean ± SEM of percent positive area. (O–R) Double immunofluorescence for DCX (green) and GFAP (red) in the RMS of WT (O, Q) and IL-15−/− (P, R) mice after treatment with ICV PBS (O, P) or IL-15 (1 μg/5 μl; Q, R). (S, T) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the expression of DCX (M) and GFAP (N) in the RMS of WT or IL-15−/− mice as mean ± SEM of percent positive area. Nuclei are stained with Hoechst (blue). Fluorescent sections are evaluated with confocal microscopy. Scale bar in A–L, 20 μm (shown in L); in O–R, 50 μm (shown in R). Statistical differences of PBS vs. IL-15: *p < 0.05, **p < 0.01. Data were analyzed with an ANOVA and a post hoc Tukey test.

Mentions: We compared next the effect of the ICV injection of IL-15 on the neurogenic potential of both WT and IL-15−/− mice (Figure 4). IL-15−/− mice presented, as previously described (Figure 2), a decreased population of DCX+ cells within the SVZ (Figure 4, A and D) and the RMS (Figure 4, O and P). The administration of IL-15 caused an increase in the DCX+ population in both the WT (Figure 4, G–I) and the IL-15−/− (Figure 4, J–L) mice, with the latter recovering the WT phenotype. Quantification of the DCX+ area within the SVZ showed a significant increase on treatment with IL-15 in both the WT and IL-15−/− mice (Figure 4M). The analysis of the RMS correlated with that observed in the SVZ. ICV IL-15 caused a significant increase in the DCX+ population in both WT (Figure 4, O and Q) and IL-15−/− mice (Figure 4, P and R), leading to a recovery of the WT phenotype in the latter (Figure 4S).


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 the pool of neuroblasts and rescues IL-15−/− phenotype. Analysis of the effect of IL-15 on neurogenesis in WT and IL-15−/− mice (see experimental scheme at top right corner). (A–L) Double immunofluorescence for DCX (green) and GFAP (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, N) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the expression of DCX (M) and GFAP (N) in the SVZ of WT or IL-15–/– mice, as mean ± SEM of percent positive area. (O–R) Double immunofluorescence for DCX (green) and GFAP (red) in the RMS of WT (O, Q) and IL-15−/− (P, R) mice after treatment with ICV PBS (O, P) or IL-15 (1 μg/5 μl; Q, R). (S, T) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the expression of DCX (M) and GFAP (N) in the RMS of WT or IL-15−/− mice as mean ± SEM of percent positive area. Nuclei are stained with Hoechst (blue). Fluorescent sections are evaluated with confocal microscopy. Scale bar in A–L, 20 μm (shown in L); in O–R, 50 μm (shown in R). Statistical differences of PBS vs. IL-15: *p < 0.05, **p < 0.01. Data were analyzed with an ANOVA and a post hoc Tukey test.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 4: Intraventricular IL-15 increases the pool of neuroblasts and rescues IL-15−/− phenotype. Analysis of the effect of IL-15 on neurogenesis in WT and IL-15−/− mice (see experimental scheme at top right corner). (A–L) Double immunofluorescence for DCX (green) and GFAP (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, N) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the expression of DCX (M) and GFAP (N) in the SVZ of WT or IL-15–/– mice, as mean ± SEM of percent positive area. (O–R) Double immunofluorescence for DCX (green) and GFAP (red) in the RMS of WT (O, Q) and IL-15−/− (P, R) mice after treatment with ICV PBS (O, P) or IL-15 (1 μg/5 μl; Q, R). (S, T) Quantification of the effect of the ICV injection of PBS (black bars) or IL-15 (white bars) on the expression of DCX (M) and GFAP (N) in the RMS of WT or IL-15−/− mice as mean ± SEM of percent positive area. Nuclei are stained with Hoechst (blue). Fluorescent sections are evaluated with confocal microscopy. Scale bar in A–L, 20 μm (shown in L); in O–R, 50 μm (shown in R). Statistical differences of PBS vs. IL-15: *p < 0.05, **p < 0.01. Data were analyzed with an ANOVA and a post hoc Tukey test.
Mentions: We compared next the effect of the ICV injection of IL-15 on the neurogenic potential of both WT and IL-15−/− mice (Figure 4). IL-15−/− mice presented, as previously described (Figure 2), a decreased population of DCX+ cells within the SVZ (Figure 4, A and D) and the RMS (Figure 4, O and P). The administration of IL-15 caused an increase in the DCX+ population in both the WT (Figure 4, G–I) and the IL-15−/− (Figure 4, J–L) mice, with the latter recovering the WT phenotype. Quantification of the DCX+ area within the SVZ showed a significant increase on treatment with IL-15 in both the WT and IL-15−/− mice (Figure 4M). The analysis of the RMS correlated with that observed in the SVZ. ICV IL-15 caused a significant increase in the DCX+ population in both WT (Figure 4, O and Q) and IL-15−/− mice (Figure 4, P and R), leading to a recovery of the WT phenotype in the latter (Figure 4S).

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