HB-GAM inhibits proliferation and enhances differentiation of neural stem cells
ABSTRACT Proliferation of neural stem cells in the embryonic cerebral cortex is regulated by many growth factors and their receptors. Among the key molecules stimulating stem cell proliferation are FGF-2 and the FGF receptor-1. This ligand-receptor system is highly dependent on the surrounding heparan sulfates. We have found that heparin-binding growth-associated molecule (HB-GAM, also designated as pleiotrophin) regulates neural stem cell proliferation in vivo and in vitro. Deficiency of HB-GAM results in a pronounced, up to 50% increase in neuronal density in the adult mouse cerebral cortex. This phenotype arises during cortical neurogenesis, when HB-GAM knockout embryos display an enhanced proliferation rate as compared to wild-type embryos. Further, our in vitro studies show that exogenously added HB-GAM inhibits formation and growth of FGF-2, but not EGF, stimulated neurospheres, restricts the number of nestin-positive neural stem cells, and inhibits FGF receptor phosphorylation. We propose that HB-GAM functions as an endogenous inhibitor of FGF-2 in stem cell proliferation in the developing cortex.
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ABSTRACT: Y-P30, the 30 amino acid N-terminal peptide of the dermcidin gene, has been found to promote neuronal survival and differentiation. Its early presence in development and import to the fetal brain led to the hypothesis that Y-P30 has an influence on proliferation, differentiation and migration. Neurospheres derived from neural stem cells isolated from E13 mouse cortex and striatal ganglionic eminences were treated with Y-P30, however, the proportion of progenitors, neurons and astrocytes generated in differentiation assays was not altered. A short Y-P30 treatment of undifferentiated striatal and cortical neurospheres failed to alter the proportion of BrdU-positive cells. A longer treatment reduced the percentage of BrdU-positive cells and GABA-immunoreactive neurons only in striatal spheres. The presence of Y-P30 enhanced migration of T24 human bladder carcinoma cells in a wound-healing assay in vitro. Further, Y-P30 enhanced migration of T24 cells, rat primary cortical astrocytes and PC12 cells in chemotactic Boyden chamber assays. Together, these findings suggest that a major function of Y-P30 is to promote migration of neural and non-neural cell types.Molecular and Cellular Neuroscience 07/2011; 48(3):195-204. DOI:10.1016/j.mcn.2011.07.005 · 3.73 Impact Factor
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ABSTRACT: We have shown that neuropeptide Y (NPY), a peptide neurotransmitter released by hippocampal interneurons, is proliferative for hippocampal neural stem progenitor cells (NSPCs) via the Y1 receptor. Fibroblast growth factor (FGF) 2, released predominantly by astrocytes, is also a powerful mitogen for postnatal and adult NSPCs, via the FGFR1 receptor. Knockout studies show that NPY and FGF2 are individually necessary, but not sufficient, for seizure-induced neurogenesis, suggesting a possible interaction. Here, we examined for interactions between NPY and FGF2 on NSPCs from the postnatal hippocampus and report that the combination of NPY and FGF2 significantly shortens the cell cycle time of nestin positive NSPCs, more than either factor alone. This augmentation of proliferation rate is NPY Y1 receptor mediated, and Y1 receptor activation increases both FGFR1 mRNA and protein in NSPC cultures. NSPCs immunostain for both Y1 and FGFR1 receptors and the interaction is specific for dentate NSPCs. This is the first report of a proliferative factor that augments the proliferative effect of FGF2 and is the first evidence of a positive proliferative interaction between a glial growth factor and a neuronal transmitter, identifying a novel neural activity driven mechanism for modulating the proliferation of hippocampal NSPCs.Journal of Neurochemistry 05/2010; 113(3):615-27. DOI:10.1111/j.1471-4159.2010.06633.x · 4.24 Impact Factor
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ABSTRACT: HB-GAM (also known as pleiotrophin) is a cell matrix-associated protein that is highly expressed in bone. It affects osteoblast function, and might therefore play a role in bone development and remodeling. We aimed to investigate the role of HB-GAM in bone in vivo and in vitro. The bones of HB-GAM deficient mice with an inbred mouse background were studied by histological, histomorphometrical, radiological, biomechanical and mu-CT analyses and the effect of immobilization was evaluated. HB-GAM localization in vivo was studied. MLO-Y4 osteocytes were subjected to fluid shear stress in vitro, and gene and protein expression were studied by subtractive hybridization, quantitative PCR and Western blot. Human osteoclasts were cultured in the presence of rhHB-GAM and their formation and resorption activities were assayed. In agreement with previous reports, the skeletal structure of the HB-GAM knockout mice developed normally. However, a growth retardation of the weight-bearing bones was observed by 2 months of age, suggesting a link to physical activity. Adult HB-GAM deficient mice were characterized by low bone formation and osteopenia, as well as resistance to immobilization-dependent bone remodeling. HB-GAM was localized around osteocytes and their processes in vivo and furthermore, osteocytic HB-GAM expression was upregulated by mechanical loading in vitro. HB-GAM did not affect on human osteoclast formation or resorption in vitro. Taken together, our results suggest that HB-GAM is an osteocyte-derived factor that could participate in mediating the osteogenic effects of mechanical loading on bone.Bone 06/2009; 44(5):785-94. DOI:10.1016/j.bone.2009.01.004 · 4.46 Impact Factor