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Revital B. Avraham Lubin, Tamilla Sadikov, Nadir Askenasy, Nitza Goldenberg Cohen; VEGF Induces Neural and Astrocytic Differentiation and Angiogenesis in Bone Marrow-derived Stem Cells and Promotes Microglia Conversion Following Mobilization With GM-CSF. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5895.
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This study sought to assess the impact of vascular endothelial growth factor (VEGF) on the differentiation and incorporation of bone-marrow-derived stem cells in a murine model of anterior ischemic optic neuropathy (AION).
One day after AION induction, a small-sized subset of bone marrow cells isolated by elutriation and depleted of hematopoietic lineage markers was administered by inoculation into the vitreous body (2.5x105) or intravenous injection (0.2 ml), alone or with intravitreal injection of VEGF (5 μg). Cell engraftment and phenotype were examined by histologic and microscopic analysis and real-time quantitative polymerase chain reaction after 30 and 180 days. In a second experiment, granulocyte-macrophage colony-stimulating factor (GM-CSF) or stem cell factor was administered intravitreally before cell implantation and VEGF injection to determine the impact of bone marrow mobilization.
VEGF did not affect quantitative cell engraftment. However, it induced early neural differentiation of the donor cells incorporated in the retinal ganglion cell layer and increased the absolute numbers of astrocytes, endothelial cells, and immune cells in the retinal vasculature. These changes were signaled through VEGF-R1/flt-1, predominantly in cells inoculated directly into the vitreous body. VEGF-induced neuroglial differentiation was considerably slowed by cell mobilization with GM-CSF relative to intravenous stem cell infusion or mobilization with stem cell factor. Although VEGF synergized with GM-CSF, cell differentiation in the ischemic retina was narrowed to the microglia.
VEGF signaling through Flt-1 is a significant mediator of neural and astrocytic differentiation of adult bone-marrow-derived stem cells during stabilization of the ischemic retinal architecture.
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