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IFN gamma regulates proliferation and neuronal differentiation by STAT1 in adult SVZ niche.

Pereira L, Medina R, Baena M, Planas AM, Pozas E - Front Cell Neurosci (2015)

Bottom Line: Interferon gamma (IFNγ) has somewhat controversially been associated with SVZ progenitor proliferation and neurogenesis.The final result is deficient recruitment of newborn neurons to the olfactory bulb (OB), indicating that IFNγ-induced stimulation of neuronal differentiation does not compensate for its antiproliferative effect.We conclude that IFNγ signaling via STAT1 in the SVZ acts dually as an antiproliferative and proneurogenic factor, and thereby regulates neurogenesis in normal adult brains.

View Article: PubMed Central - PubMed

Affiliation: Unit of Brain Ischemia, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain ; Department of Brain Ischemia and Neurodegeneration, Institute of Biomedical Research of Barcelona, Consejo Superior de Investigaciones Científicas (CSIC) Barcelona, Spain.

ABSTRACT
The adult subventricular zone (SVZ) is the main neurogenic niche in normal adult brains of mice and rats. Interferon gamma (IFNγ) has somewhat controversially been associated with SVZ progenitor proliferation and neurogenesis. The in vivo involvement of IFNγ in the physiology of the adult SVZ niche is not fully understood and its intracellular mediators are unknown. Here we show that IFNγ, through activation of its canonical signal transducer and activator of transcription 1 (STAT1) pathway, acts specifically on Nestin+ progenitors by decreasing both progenitor proliferation and the number of cycling cells. In addition, IFNγ increases the number of neuroblasts generated without shifting glial fate determination. The final result is deficient recruitment of newborn neurons to the olfactory bulb (OB), indicating that IFNγ-induced stimulation of neuronal differentiation does not compensate for its antiproliferative effect. We conclude that IFNγ signaling via STAT1 in the SVZ acts dually as an antiproliferative and proneurogenic factor, and thereby regulates neurogenesis in normal adult brains.

No MeSH data available.


Related in: MedlinePlus

IFNγ regulates proliferation and differentiation of NSCs from SVZ through STAT1. (A) Brightfield pictures showing how the number of secondary neurospheres was dramatically reduced by IFNγ and that STAT1 prevents cytokine actions. (B) Histogram showing how IFNγ impedes neurosphere formation through STAT1 (n = 5). (C) Histogram demostrating the presence of neural cells after 7-day NSCs culture differentiation. The presence of IFNγ did not affect viability (PI incorporation); whereas the number of KI67+ and original Nestin+ cells decreased, and the number of committed neuroblasts (TUBB3+ cells) increased, without affecting oligodendroglial differentiation (NG2+ cells) or the number of GFAP+ cells (n = 5). (D) Photographs illustrating the increased neurogenesis induced by IFNγ through STAT1. IFNγ induced a higher neuroblast (red) differentiation, which reverted in the absence of STAT1. Hoechst (blue) stained all nuclei (n = 5). (E) Histogram demonstrating the presence of neuroblasts (TUBB3+ cells) originated from neural 7-day NSC culture differentiation. IFNγ improves neuronal differentiation in WT cultures but not in STAT1 deficient cells (n = 5) in which a slightly reduction in neuroblasts was detected. Scale bar: (A), 100 μm and (D), 40 μm. Data are represented as mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001.
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Figure 4: IFNγ regulates proliferation and differentiation of NSCs from SVZ through STAT1. (A) Brightfield pictures showing how the number of secondary neurospheres was dramatically reduced by IFNγ and that STAT1 prevents cytokine actions. (B) Histogram showing how IFNγ impedes neurosphere formation through STAT1 (n = 5). (C) Histogram demostrating the presence of neural cells after 7-day NSCs culture differentiation. The presence of IFNγ did not affect viability (PI incorporation); whereas the number of KI67+ and original Nestin+ cells decreased, and the number of committed neuroblasts (TUBB3+ cells) increased, without affecting oligodendroglial differentiation (NG2+ cells) or the number of GFAP+ cells (n = 5). (D) Photographs illustrating the increased neurogenesis induced by IFNγ through STAT1. IFNγ induced a higher neuroblast (red) differentiation, which reverted in the absence of STAT1. Hoechst (blue) stained all nuclei (n = 5). (E) Histogram demonstrating the presence of neuroblasts (TUBB3+ cells) originated from neural 7-day NSC culture differentiation. IFNγ improves neuronal differentiation in WT cultures but not in STAT1 deficient cells (n = 5) in which a slightly reduction in neuroblasts was detected. Scale bar: (A), 100 μm and (D), 40 μm. Data are represented as mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001.

Mentions: To explore the effects of IFNγ on NSCs, we performed neurosphere assays and assessed the effects of this molecule on the stem cell population (see “Materials and Methods” Section, Ferron et al., 2007). The number of secondary neurospheres formed was severely decreased by the presence of IFNγ (Figures 4A,B). Cell viability was evaluated using Trypan blue and no differences were observed between treated and untreated neurospheres, thus showing that survival was not affected by this cytokine (data not shown). It was not possible to determine the impact of IFNγ on self-renewal, since secondary neurospheres previously treated with IFNγ were unable to form tertiary neurospheres, indicating that the antiproliferative effect it exerts is irreversible.


IFN gamma regulates proliferation and neuronal differentiation by STAT1 in adult SVZ niche.

Pereira L, Medina R, Baena M, Planas AM, Pozas E - Front Cell Neurosci (2015)

IFNγ regulates proliferation and differentiation of NSCs from SVZ through STAT1. (A) Brightfield pictures showing how the number of secondary neurospheres was dramatically reduced by IFNγ and that STAT1 prevents cytokine actions. (B) Histogram showing how IFNγ impedes neurosphere formation through STAT1 (n = 5). (C) Histogram demostrating the presence of neural cells after 7-day NSCs culture differentiation. The presence of IFNγ did not affect viability (PI incorporation); whereas the number of KI67+ and original Nestin+ cells decreased, and the number of committed neuroblasts (TUBB3+ cells) increased, without affecting oligodendroglial differentiation (NG2+ cells) or the number of GFAP+ cells (n = 5). (D) Photographs illustrating the increased neurogenesis induced by IFNγ through STAT1. IFNγ induced a higher neuroblast (red) differentiation, which reverted in the absence of STAT1. Hoechst (blue) stained all nuclei (n = 5). (E) Histogram demonstrating the presence of neuroblasts (TUBB3+ cells) originated from neural 7-day NSC culture differentiation. IFNγ improves neuronal differentiation in WT cultures but not in STAT1 deficient cells (n = 5) in which a slightly reduction in neuroblasts was detected. Scale bar: (A), 100 μm and (D), 40 μm. Data are represented as mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001.
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Figure 4: IFNγ regulates proliferation and differentiation of NSCs from SVZ through STAT1. (A) Brightfield pictures showing how the number of secondary neurospheres was dramatically reduced by IFNγ and that STAT1 prevents cytokine actions. (B) Histogram showing how IFNγ impedes neurosphere formation through STAT1 (n = 5). (C) Histogram demostrating the presence of neural cells after 7-day NSCs culture differentiation. The presence of IFNγ did not affect viability (PI incorporation); whereas the number of KI67+ and original Nestin+ cells decreased, and the number of committed neuroblasts (TUBB3+ cells) increased, without affecting oligodendroglial differentiation (NG2+ cells) or the number of GFAP+ cells (n = 5). (D) Photographs illustrating the increased neurogenesis induced by IFNγ through STAT1. IFNγ induced a higher neuroblast (red) differentiation, which reverted in the absence of STAT1. Hoechst (blue) stained all nuclei (n = 5). (E) Histogram demonstrating the presence of neuroblasts (TUBB3+ cells) originated from neural 7-day NSC culture differentiation. IFNγ improves neuronal differentiation in WT cultures but not in STAT1 deficient cells (n = 5) in which a slightly reduction in neuroblasts was detected. Scale bar: (A), 100 μm and (D), 40 μm. Data are represented as mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001.
Mentions: To explore the effects of IFNγ on NSCs, we performed neurosphere assays and assessed the effects of this molecule on the stem cell population (see “Materials and Methods” Section, Ferron et al., 2007). The number of secondary neurospheres formed was severely decreased by the presence of IFNγ (Figures 4A,B). Cell viability was evaluated using Trypan blue and no differences were observed between treated and untreated neurospheres, thus showing that survival was not affected by this cytokine (data not shown). It was not possible to determine the impact of IFNγ on self-renewal, since secondary neurospheres previously treated with IFNγ were unable to form tertiary neurospheres, indicating that the antiproliferative effect it exerts is irreversible.

Bottom Line: Interferon gamma (IFNγ) has somewhat controversially been associated with SVZ progenitor proliferation and neurogenesis.The final result is deficient recruitment of newborn neurons to the olfactory bulb (OB), indicating that IFNγ-induced stimulation of neuronal differentiation does not compensate for its antiproliferative effect.We conclude that IFNγ signaling via STAT1 in the SVZ acts dually as an antiproliferative and proneurogenic factor, and thereby regulates neurogenesis in normal adult brains.

View Article: PubMed Central - PubMed

Affiliation: Unit of Brain Ischemia, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain ; Department of Brain Ischemia and Neurodegeneration, Institute of Biomedical Research of Barcelona, Consejo Superior de Investigaciones Científicas (CSIC) Barcelona, Spain.

ABSTRACT
The adult subventricular zone (SVZ) is the main neurogenic niche in normal adult brains of mice and rats. Interferon gamma (IFNγ) has somewhat controversially been associated with SVZ progenitor proliferation and neurogenesis. The in vivo involvement of IFNγ in the physiology of the adult SVZ niche is not fully understood and its intracellular mediators are unknown. Here we show that IFNγ, through activation of its canonical signal transducer and activator of transcription 1 (STAT1) pathway, acts specifically on Nestin+ progenitors by decreasing both progenitor proliferation and the number of cycling cells. In addition, IFNγ increases the number of neuroblasts generated without shifting glial fate determination. The final result is deficient recruitment of newborn neurons to the olfactory bulb (OB), indicating that IFNγ-induced stimulation of neuronal differentiation does not compensate for its antiproliferative effect. We conclude that IFNγ signaling via STAT1 in the SVZ acts dually as an antiproliferative and proneurogenic factor, and thereby regulates neurogenesis in normal adult brains.

No MeSH data available.


Related in: MedlinePlus