ABSTRACT
The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system (CNS). Based on a variety of studies, it is now well established that impairment of oligodendrocyte precursor cells (OPCs) to differentiate and remyelinate axons is a vital event in the failed treatment of demyelinating diseases. Recent evidence suggests that Foxg1 is essential for the proliferation of certain precursors and inhibits premature neurogenesis during brain development. To date, very little attention has been paid to the role of Foxg1 in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects of Foxg1 on demyelination and remyelination in the brain using a cuprizone (CPZ)-induced mouse model. In this work, 7-week-old Foxg1 conditional knockout and wild-type (WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination. Our results demonstrated that, compared with WT mice, Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found that Foxg1 knockout decreased the proliferation of OPCs and accelerated their differentiation into mature oligodendrocytes both in vivo and in vitro. Wnt signaling plays a critical role in development and in a variety of diseases. GSK-3β, a key regulatory kinase in the Wnt pathway, regulates the ability of β-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763, a selective inhibitor of GSK-3β activity, to further demonstrate the regulatory mechanism by which Foxg1 affects OPCs in vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3β, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxg1. These results suggest that Foxg1 is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest that Foxg1 is a new therapeutic target for the treatment of demyelinating diseases of the CNS.
ABSTRACT
@# Vascular endothelial growth factor (VEGF) is angiogenic and neurotrophic factor. It is now known that VEGF also plays an importmant role in neurogenesis and neuroprotection in addition to angiogenesis. VEGF and VEGF receptor increase in the ischemic brain, promote vascular endothelial cell proliferation and decrease infarct volume. VEGF plays neuroprotective and neurotrophic roles by the modulation of the phosphatidylinositol3-kinase (PI3K)/Akt/nuclear factor-κB and MAPK/ERK signaling pathways. VEGF reduces ischemic neuronal apoptosis, promotes neural stem cells proliferation, migration and differentiation and improves nerve functions. In the other hands, VEGF increases permeability of blood vessel which may aggravate cerebral edema early.
ABSTRACT
Objective To compare the ratios of neuron and glia differentiated from the embryonic human neural stem cells(hNSCs) at different times in vitro. Methods The cells from hippocampus of aborted human embryo tissue(8-12 weeks after conception) were mechanically dissociated and cultured with DMEM/F 12 medium containing h-EGF,h-bFGF,h-LIF.The NSCs were induced to differentiate by 1%FBS and identified by Musashil,?-Ⅲ Tubulin,GFAP and Galc immuno-cytochemical staining at different times. Results The cell spheres were Musashil positive at the 12th hour after differentiation.On the 2nd day after differentiation,a few cells exhibited ?-Ⅲ Tubulin and GFAP immunoreactivities,but no Galc positive cells.The number of ?-Ⅲ Tubulin immuno-positive cells reached the highest on the 7(th) day and the percent was 48.2%.The number of GFAP immuno-positive cells increased from the 2nd to the 23rd day and the positive ratio reached 65.3%.A few Galc immuno-positive cells were detected with time passing.Conclusion 1% FBS may promote human NSCs to differentiate into three cell types of central nervous system,and the ratios of differentiated neuron and glia are significantly different at various times.