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Sergio Li Calzi, Lynn Calvin Shaw, Willam C Shelley, Xiaoping Qi, Judith Quigley, Snow Wu, Ivan Mircea, Michael E Boulton, Mervin Yoder, Maria B Grant; Novel Progenitor Cell Combinations for Revascularization of the Retina: Implications for Retinopathy of Prematurity (ROP). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3389.
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© ARVO (1962-2015); The Authors (2016-present)
The incidence of ROP in the developed world increases as the survival rate of extremely premature infants rises. Placement in high oxygen protects the brain from damage, but the increased levels of oxygen result in down-regulation of VEGF and a delay of retinal vascularization relative to neuronal maturation. Our hypothesis is that intravitreal administration of stem/progenitors will restore VEGF levels by providing key growth factors and provide a stimulus for both normal vascular and neuronal maturation.
The murine oxygen-induced retinopathy (OIR) model was used. Each pup received a single intravitreal injection of cells (human CD34+, isolated from peripheral blood, 10,000; human umbilical cord-derived endothelial colony forming cells (ECFCs), 100,000; combination, 110,000). Experimental groups differed based on injection/euthanasia times (P5/P12, P5/P17, P12/P17). Retinal vaso-obliteration and neovascularization on whole retinas stained with collagen IV antibodies was measured using immunofluorescence. Immunohistochemical localization of injected cells was performed using confocal microscopy.
Injection of cells at P5 elicits a hyperoxic response in these cells when the mice are placed at 75% oxygen on P7. This results in the integration of gfp+-ECFCs into the deep vascular plexus (DVP) of the retina seen on P12. Pups injected on P5 with saline, or CD34+ cells alone, do not develop a DVP by P12. Maximum vaso-obliteration was seen in the saline and CD34+ pups of the P5/P12 group (saline=22.3±0.4%; CD34+=23.4±0.8%, p=0.1), while ECFCs and Combination showed slight but significant reduction (ECFCs=18.4±1.3%, p=0.006; Combination=20.0±0.7%, p=0.0006). Injection at P12 reduced vaso-obliteration in all groups when compared to saline (saline=13.9±0.9%; CD34+=5.7±1.0%, p=0.0001; ECFC=8.1±0.7%, p=0.002; Combination=7.4±1.0%, p=0.001). This was also true for neovascularization (saline=13.3±1.3%; CD34+=3.5±1.1%, p=0.00005; ECFC=2.8±0.7%, p=0.03; Combination=4.1±0.6%, p=0.003).
ECFCs stimulate the development of the DVP in OIR pups while exposed to hyperoxic conditions. This unique result does not occur in untreated OIR pups. This clearly points to the therapeutic potential of these cells in the treatment of ROP. Further, treatment with either CD34+ cells and/or ECFCs significantly increases normal vascular regrowth and reduces neovascularization.
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