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J. L. Kielczewski, A. Afzal, K. Chang, L. Shaw, R. Mames, E. McFarland, T. Chan-Ling, J. Hughes, M. Grant; IGFBP-3 Acts as a Hematopoietic Stem Cell Homing Factor in an Adult Mouse Ocular Neovascularization Model. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4389.
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IGFBP-3 has been shown to have direct pro-angiogenic effects on bone marrow derived hematopoietic stem cells and endothelial progenitor cells (EPC’s). IGFBP-3 stimulates HSC differentiation into endothelial cells and promotes their migration and tube formation in vitro. IGFBP-3 protects the retinal vasculature from oxygen induced damage by promoting vascular stability during hyperoxia exposure and vascular re-growth following return to room air in the oxygen induced retinopathy (OIR) model. In this study, we asked whether IGFBP-3 can also act as a homing factor for circulating HSC’s/EPC’s to establish residence in the retina. To test this we used an adult rodent ocular neovascularization model of laser induced retinal vessel occlusion.
GFP+ chimeric mice were generated by isolating Sca-1+/c-Kit+ cells from GFP+ male mice via FACS sorting. Approximately 5,000 Sca-1+/c-Kit+ cells were injected into the retro-orbital sinus of 12 female mice. Stable engraftment was confirmed by flow cytometry 2 months following cell transplantation. The GFP+ stable chimeric mice were randomized into three treatment groups, laser only (n=4), IGFBP-3 injection only (n=4), and laser immediately followed by intravitreal injection of IGFBP-3 plasmid (n=4) (2ul of IGFBP-3 plasmid prepared in liposomes). The mice were sacrificed 3 weeks later. Flatmounts of the neural retina were prepared for retinal vessel visualization by immunohistochemisty and confocal microscopy.
Lasered mice treated with IGFBP-3 displayed large numbers of GFP+ cells incorporated into retinal vessels compared to fellow control eyes. Similarly mice treated with IGFBP-3 alone showed abundant numbers of GFP+ cells integrated into the retinal vessels even in the absence of laser induced retinal injury.
IGFBP-3 can act as a HSC/EPC homing factor in an adult mouse neovascularization model. HSC’s can incorporate into retinal vessels and participate in repairing damaged vessels and contribute to the formation of new vessels.
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