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Judd Michael Cahoon, Paul R Olson, Christina O, Reinhold J Medina, Alan W Stitt, Balamurali Ambati; Vascular stem cell therapy of the diabetic retina with COMP-Ang1 and endothelial progenitor cells. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4002.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal ischemia is a leading cause of blindness. Diabetic retinopathy is the most common vasodegenerative retinopathy. Restoring vascular homeostasis and replacing lost endothelial cells (reparative angiogenesis) could reduce the neurovascular damage that occurs in diabetic retinopathy. Outgrowth endothelial cells (OECs) are a specific subtype of endothelial progenitor cell that have the potential to reintegrate into damaged retinal vascular beds and promote reparative angiogenesis. The purpose of this study was to determine whether a novel angiopoietin-1 analog, COMP-Ang1, could enhance OEC vasculogenic properties in vitro and increase OEC integration into the diabetic retina.
OECs were harvested from the mononuclear layer of donated cord blood and plated on collagen-coated plates supplemented with EBM-2 MV media. OECs were exposed to increasing doses of COMP-Ang1, or control (PBS), and assessed for migration (scratch-migration assay), tube formation (3D Matrigel assay), and intracellular signaling pathways (Western blot). Finally, labeled OECs were administered via intravitreal injection into the eyes of 7 month old diabetic mice treated two weeks previously with an adenovirus expressing COMP-Ang1 (AAV2.COMP-Ang1) or control (AAV2.GFP). Three days later retinas were harvested and analyzed with confocal microscopy to assess OEC integration into the retinal vasculature.
COMP-Ang1 increased OEC migration speed and tube formation in a dose-dependent manner compared to control treated OECs (P < 0.001). Additionally, compared to control, COMP-Ang1 increased Akt phosphorylation, an important downstream effector of the Tie2 receptor, in OECs (P < 0.001). Preliminary results suggest that diabetic mice treated with COMP-Ang1 had increased OEC integration into the retinal vasculature compared to control treated mice.
COMP-Ang1 increases vasculogenic properties of OECs and may be of use in therapeutic angiogenic strategies to treat retinal ischemic diseases (e.g., diabetic retinopathy). Future studies will determine the effect OECs and COMP-Ang1 have on the cytokine millieu of the diabetic retina (e.g., VEGF, HIF-1α, TNF-α) and whether OECs and COMP-Ang1 can play a functional reparative role in diabetic retinopathy by decreasing leakage and promoting neural function.
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