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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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IL-15 expression in the SVZ and RMS. (A, F–G) Immunostaining of IL-15+ cells in the SVZ (A) and the RMS (F, sagittal; G; coronal). (B, C) Double immunofluorescence for IL-15 (red; B, C) and GFAP (green; C) in the SVZ. (C*) Inset: magnification of IL-15 colocalization in GFAP+ cells (white arrowhead). (D, E) Double immunofluorescence for IL-15Rα (red; D, E) and nestin (green; E) in the SVZ. (H–K) Double immunofluorescence for IL-15 (red; H, J and I, K) and GFAP (green; J) or DCX (green; K) in the RMS. (J*, K*) Inset: magnification of IL-15 colocalization in GFAP− cells (J*; white arrowhead) and DCX+ cells (K*; white arrowhead). Nuclei are stained with Hoechst (blue). Fluorescent sections are evaluated with confocal microscopy. Scale bar in A–E and G–K, 50 μm (shown in A, B, D, G, J, K); in F, 100 μm.
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Figure 1: IL-15 expression in the SVZ and RMS. (A, F–G) Immunostaining of IL-15+ cells in the SVZ (A) and the RMS (F, sagittal; G; coronal). (B, C) Double immunofluorescence for IL-15 (red; B, C) and GFAP (green; C) in the SVZ. (C*) Inset: magnification of IL-15 colocalization in GFAP+ cells (white arrowhead). (D, E) Double immunofluorescence for IL-15Rα (red; D, E) and nestin (green; E) in the SVZ. (H–K) Double immunofluorescence for IL-15 (red; H, J and I, K) and GFAP (green; J) or DCX (green; K) in the RMS. (J*, K*) Inset: magnification of IL-15 colocalization in GFAP− cells (J*; white arrowhead) and DCX+ cells (K*; white arrowhead). Nuclei are stained with Hoechst (blue). Fluorescent sections are evaluated with confocal microscopy. Scale bar in A–E and G–K, 50 μm (shown in A, B, D, G, J, K); in F, 100 μm.

Mentions: Immunohistochemical analysis of IL-15 expression showed immunopositive labeling in both the subventricular zone (SVZ) and the rostral migratory stream (RMS) (Figure 1, A, F, and G). Within the SVZ IL-15 was expressed in glial fibrillary acidic protein (GFAP)-positive NSCs, as shown by immunofluorescent colocalization (Figure 1, B, C, and C*). Moreover, IL-15Rα was found to be expressed in nestin-positive cells of the SVZ (Figure 1, D and E). In the RMS, the expression of IL-15 was found in the migratory mass, colocalizing with doublecortin-positive neuroblasts (DCX+; Figure 1, I, K, and K*), as shown by double immunofluorescence. IL-15 expression was not found in GFAP-positive astrocytes of the RMS (Figure 1, H, J, and J*).


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)

IL-15 expression in the SVZ and RMS. (A, F–G) Immunostaining of IL-15+ cells in the SVZ (A) and the RMS (F, sagittal; G; coronal). (B, C) Double immunofluorescence for IL-15 (red; B, C) and GFAP (green; C) in the SVZ. (C*) Inset: magnification of IL-15 colocalization in GFAP+ cells (white arrowhead). (D, E) Double immunofluorescence for IL-15Rα (red; D, E) and nestin (green; E) in the SVZ. (H–K) Double immunofluorescence for IL-15 (red; H, J and I, K) and GFAP (green; J) or DCX (green; K) in the RMS. (J*, K*) Inset: magnification of IL-15 colocalization in GFAP− cells (J*; white arrowhead) and DCX+ cells (K*; white arrowhead). Nuclei are stained with Hoechst (blue). Fluorescent sections are evaluated with confocal microscopy. Scale bar in A–E and G–K, 50 μm (shown in A, B, D, G, J, K); in F, 100 μm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 1: IL-15 expression in the SVZ and RMS. (A, F–G) Immunostaining of IL-15+ cells in the SVZ (A) and the RMS (F, sagittal; G; coronal). (B, C) Double immunofluorescence for IL-15 (red; B, C) and GFAP (green; C) in the SVZ. (C*) Inset: magnification of IL-15 colocalization in GFAP+ cells (white arrowhead). (D, E) Double immunofluorescence for IL-15Rα (red; D, E) and nestin (green; E) in the SVZ. (H–K) Double immunofluorescence for IL-15 (red; H, J and I, K) and GFAP (green; J) or DCX (green; K) in the RMS. (J*, K*) Inset: magnification of IL-15 colocalization in GFAP− cells (J*; white arrowhead) and DCX+ cells (K*; white arrowhead). Nuclei are stained with Hoechst (blue). Fluorescent sections are evaluated with confocal microscopy. Scale bar in A–E and G–K, 50 μm (shown in A, B, D, G, J, K); in F, 100 μm.
Mentions: Immunohistochemical analysis of IL-15 expression showed immunopositive labeling in both the subventricular zone (SVZ) and the rostral migratory stream (RMS) (Figure 1, A, F, and G). Within the SVZ IL-15 was expressed in glial fibrillary acidic protein (GFAP)-positive NSCs, as shown by immunofluorescent colocalization (Figure 1, B, C, and C*). Moreover, IL-15Rα was found to be expressed in nestin-positive cells of the SVZ (Figure 1, D and E). In the RMS, the expression of IL-15 was found in the migratory mass, colocalizing with doublecortin-positive neuroblasts (DCX+; Figure 1, I, K, and K*), as shown by double immunofluorescence. IL-15 expression was not found in GFAP-positive astrocytes of the RMS (Figure 1, H, J, and J*).

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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