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Comparative Study
. 2007 Oct 22:8:88.
doi: 10.1186/1471-2202-8-88.

The hematopoietic factor GM-CSF (granulocyte-macrophage colony-stimulating factor) promotes neuronal differentiation of adult neural stem cells in vitro

Carola Krüger  1 , Rico Laage, Claudia Pitzer, Wolf-Rüdiger Schäbitz, Armin Schneider
Affiliations
Comparative Study

The hematopoietic factor GM-CSF (granulocyte-macrophage colony-stimulating factor) promotes neuronal differentiation of adult neural stem cells in vitro

Carola Krüger et al. BMC Neurosci. .

Abstract

Background: Granulocyte-macrophage colony stimulating factor (GM-CSF) is a hematopoietic growth factor involved in the generation of granulocytes, macrophages, and dendritic cells from hematopoietic progenitor cells. We have recently demonstrated that GM-CSF has anti-apoptotic functions on neurons, and is neuroprotective in animal stroke models.

Results: The GM-CSF receptor alpha is expressed on adult neural stem cells in the rodent brain, and in culture. Addition of GM-CSF to NSCs in vitro increased neuronal differentiation in a dose-dependent manner as determined by quantitative PCR, reporter gene assays, and FACS analysis.

Conclusion: Similar to the hematopoietic factor Granulocyte-colony stimulating factor (G-CSF), GM-CSF stimulates neuronal differentiation of adult NSCs. These data highlight the astonishingly similar functions of major hematopoietic factors in the brain, and raise the clinical attractiveness of GM-CSF as a novel drug for neurological disorders.

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Figures

Figure 1
Figure 1
GM-CSFR alpha is present on adult neural stem cells. A, B, GM-CSF receptor α is expressed on cells in the subgranular zone of the dentate gyrus, and in cells with extended processes in the granular cell layer that are reminiscent of migrating neural stem cells (A, 10× original magnification; B, 40× original magnification). C-E Hippocampal adult neural stem cells in culture also express the GM-CSF receptor α. The expression of the GM-CSF α receptor (C) colocalizes with the expression of the stem cell marker nestin (D) on an adult neural stem cell. E, merged image (all size bars 50 μm). F, RT-PCR demonstrates presence of the GM-CSF receptor on naive NSCs from the hippocampus (HC) and subventricular zone (SVZ) in vitro.
Figure 2
Figure 2
GM-CSF induces neuronal differentiation of adult neural stem cells. A, Expression of neural markers in stem cells. 3d after GM-CSF treatment of adult neural stem cells, the upregulation of the neuronal markers β III-tubulin and NSE (neuron specific enolase) was measured by qPCR. Note that there is significant induction of β III-tubulin (*, p<0.05, two-tailed t-test) whereas regulation of PLP or GFAP was not detectable. B, GM-CSF drives concentration-dependent neuronal differentiation of NSCs. For the luciferase reporter assay, adult neural stem cells were transfected with the pGL3-p-βIII-tubulin reporter vector and stimulated with increasing concentrations of GM-CSF. 48 h after stimulation, a concentration-dependent activation of the βIII-tubulin promoter was detected. As positive control, NSCs were treated with the standard differentiation protocol involving withdrawal of EGF and bFGF, and addition of FCS (*, p<0.05 by ANOVA and Newman-Keuls post-hoc test). C, Analysis of neuronal differentiation on the cellular level. FACS analysis demonstrating stem cells positive for the neuronal marker MAP-2 after treatment with GM-CSF. The percentage of MAP-2-positive cells is doubled under GM-CSF treatment (*, p<0.05, two-tailed t-test). All data are shown as mean ± SEM.
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