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G. A. Lutty, T. Hasegawa, T. Prow, C. Merges, D. S. McLeod; Characterization of Vascular Precursors in Developing Human Retina. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5648.
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We have recently demonstrated that CD39 (ectoADPase)-expressing angioblasts are present in the inner retina of the embryonic and fetal human and differentiate and organize to form the initial retinal vasculature by vasculogenesis (McLeod et al, Dev Dynamics, 235:3336, 2006). The purpose of this study was to further characterize these angioblasts and determine ligands [stromal-derived factor-1 (SDF-1) and stem cell factor (SCF)] that could control their migration and differentiation in human retinal vascular development.
Alkaline phosphatase immunohistochemistry was used to localize SDF-1, its receptor CXCR4, SCF, and its receptor c-Kit on sections from 7 to 22 weeks gestation (WG) cryopreserved human eyes. Coexpression of CD39 (marker for retinal angioblasts and endothelial cells) and CXCR4 or c-Kit was investigated by confocal microscopy of flat-mounted retinas and cryosections.
DF-1 was prominent in inner retina with the greatest reaction product adjacent to the internal limiting membrane (ILM) at all ages. SCF immunoreactivity was also confined to inner retina and increased significantly between 7 and 12 WG. The level of both ligands declined by 22 WG. The SCF expression in retina was mirrored by c-Kit+ cells, which were also prominent in the optic nerve. There was a layer of CXCR4+/c-Kit+ precursors in inner retina from 7-12 WG but the number of precursors was greatly reduced by 22 WG. CD39+ cells expressing CXCR4 and c-Kit were present in the layer of precursors in inner retina. Fusiform CD39+ cells that appeared to migrate anterior from the pool of precursors toward the ILM stopped expressing cKit but continued to express CXCR4 as they formed vascular cords. Once the cords became canalized, CXCR4 expression was downregulated.
In summary, embryonic human retina has a large pool of precursors (CXCR4+/c-Kit+) that enlarged centrifugally during fetal development. From this pool emerges CD39+ cells, which migrate anterior into the nerve fiber layer where SDF-1 and SCF levels are highest. C-Kit expression declines with apparent migration of the angioblasts. Cords are eventually formed by the angioblasts (CXCR4+/CD39+) at the edge of the forming blood vessels. Once lumens form, CXCR4 expression in fetal retinal blood vessels declines. It appears that both SCF and SDF-1 are associated with the differentiation of retinal precursors into angioblasts and their migration to sites of fetal human retinal vascular development.
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