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| June 2004 | Inside IOVS | Volume 45/6 |
Genetic Variability in ROP
The proliferative stages of retinopathy of prematurity involve neovascularization of the retina and are controlled by a number of factors such as VEGF. Variation within the genes controlling their production may result in milder or more severe disease. Cooke et al. (p. 1712) show that the VEGF -634 G allele, associated with higher VEGF production was seen significantly more often in infants with threshold retinopathy compared to preterms with mild or no retinopathy. The determination of this and other similar polymorphisms may aid the identification of individuals at risk of progression to threshold disease, and offer therapeutic possibilities for VEGF blockade.
Lowering p27kip1 Levels Promotes Rat Corneal Endothelial Cell Proliferation
Corneal endothelium is responsible for maintaining corneal transparency, which can be lost when endothelial cell density is reduced below a critical level. Corneal endothelial cells (CECs) in vivo are arrested in G1-phase of the cell cycle and normally do not proliferate. Kikuchi et al. (p. 1763) demonstrate that treatment with p27kip1 antisense oligonucleotides followed by post-incubation in 10% serum lowers endogenous p27kip1 protein levels and promotes proliferation in confluent cultures of rat CECs. These results suggest that lowering of p27kip1 protein levels in the endothelium of donor human corneas may help increase the density of human CECs prior to transplantation.
A Serum-Free Protocol for Culturing Conjunctival Epithelial Cells
Ang et al. (p. 1789) describe the development of a human conjunctival epithelial equivalent, using a multistep serum-free culture system to enhance cell proliferation, differentiation and attachment for clinical transplantation and tissue regeneration. The cultivated cells demonstrated a greater in vitro and in vivo proliferative capacity compared to cells cultivated in serum-containing media. The elimination of serum and feeder cells is a substantial improvement over existing serum-containing methods of cultivating cells for clinical transplantation. This has important clinical implications in the development of safe and effective bioengineered tissue-equivalents for clinical transplantation.
TAT Fusion Proteins and Cell Proliferation
One of the problems in corneal research is the lack of methods to demonstrate the functional role of proteins of interest. In the current investigation, TAT fusion protein technology was examined for its usefulness in the study of corneal epithelium. This technology allows a functionally active protein to be easily ferried across a cell membrane. Guo et al. (p. 1804) demonstrated that TAT-p15INK4b, an inhibitor of the cell cycle, efficiently transferred into the cells, blocked corneal epithelial cell proliferation, and stimulated cell migration. Thus, TAT fusion proteins may be extremely useful in studies of corneal homeostasis and wound healing.
Differential PI3 Kinase Involvement in RPE MCP-1 and IL-8 Expression
Inflammation is a recognized component of age-related macular degeneration (ARMD) human and experimental lesions. Mononuclear phagocytes are the most abundant of the leukocytes in ARMD lesions. RPE cells secrete chemokines that attract and activate leukocytes. Bian et al. (p. 1887) show selective PI3 kinase mediation of RPE MCP-1 expression and of transcription factors regulating MCP-1 gene activation. This study describes additional key pathways regulating RPE MCP-1, the major RPE cell chemokine for mononuclear phagocytes, which is also known to be present in human ARMD lesions. Identification of this intracellular signaling pathway may illuminate targets for the treatment of ARMD.
Corneal Immune Privilege and CD95 (Fas) Ligand
CD95 ligand (CD95L), a cell surface molecule that induces apoptosis in T lymphocytes, promotes acceptance of allogeneic cornea grafts, whether placed on the ocular surface or into the anterior chamber. Osawa et al. (p. 1908) demonstrate that CD95L expression on corneal endothelium alone accounts for the universal acceptance of orthotopic cornea grafts, whereas CD95L expression on corneal epithelium alone is responsible for acceptance of cornea grafts placed in the anterior chamber. Thus, the ability of CD95L to promote corneal allograft acceptance is enhanced if the graft itself confronts an immune privileged site such as the anterior chamber of the eye.
New Constructs Improve Promoter Activity in Lens Epithelium
Despite the presence of aA-crystallin in both lens fiber and epithelial cells, transgenic mice made with the common 325 bp murine aA-crystallin promoter typically fail to express transgenes in the lens epithelium. Zhao et al. (p. 1930) tested several different promoter constructs designed to achieve reliable transgene expression in lens epithelial cells. They engineered the traditional aA-crystallin promoter with the insertion of a single Pax6 consensus binding site resulting in a dramatic and specific improvement of promoter activity within the lens epithelium. This work demonstrates the utility of rational promoter engineering and introduces several Cre transgenic lines that may be useful in future conditional gene deletion strategies.
Retinal Pericyte Alpha-Crystallin, Oxidative Stress, and Diabetic Retinopathy
Hyperglycemia-triggered biochemical mechanisms such as oxidative stress and the Maillard reaction have been implicated in capillary pericyte death, an early event in diabetic retinopathy. Liu et al. (p. 1983) have demonstrated that the carbonyl compounds, methylglyoxal and glyoxal, which are formed in higher amounts in diabetes, can modify fibronectin, an extracellular protein of the retinal capillaries, through Maillard reactions and cause apoptosis of pericytes. Oxidative stress appears to mediate such apoptosis. They also show that alpha-crystallin, a protein best known by its presence in the lens, is present in pericytes. Alpha-crystallin prevents apoptosis induced by dicarbonyl-modified fibronectin. This study links Maillard reaction and oxidative stress to pericyte loss in diabetic retinopathy.
Astrocyte Precursors, Angioblasts, and Retinal Vascular Development
The development of the retina involves the highly coordinated differentiation and interaction of many cell types. Chan-Ling et al. (p. 2020) investigated the interaction and differentiation of astrocyte precursors and angioblasts, vascular precursors, during development of the human retinal vasculature. Angioblasts (ADPase positive) are present well in advance of the formed blood vessels and their position predicts where the vascular arcades will form. They appear to differentiate in inner retina as they coalesce to form blood vessels. Astrocyte precursors precede the formed blood vessels by only a short distance and differentiate as they associate with the blood vessels. The process described is consistent with the primary human retinal vasculature forming by vasculogenesis.
Epiretinal Membranes in Latinos
In this population-based study of Latinos (primarily Mexican-Americans) in Los Angeles, Fraser-Bell et al. (p. 1732) estimate that epiretinal membranes (cellophane macular reflex and premacular fibrosis) are common and bilateral in Latinos. Factors associated with an increased prevalence of epiretinal membranes include older age, previous cataract surgery, proliferative diabetic retinopathy, macular holes and other retinal diseases. While cellophane macular reflex is not associated with a decrease in visual acuity, visual acuity is decreased in eyes with central premacular fibrosis.
Analysis of Choriocapillaris Flow Patterns in Monkeys
Hirata et al. (p. 1954) performed laser-targeted angiography (LTA) by applying continuous heat beam to monkey fundus and releasing locally a bolus of dye which was encapsulated in heat-sensitive liposomes. Three distinct phases of choriocapillaris (filling, plateau and draining) were observed. Continuous LTA demonstrated clusters of lobules fed by a common arteriole, and each cluster was found to be functionally independent. We demonstrated regional differences of choriocapillaris flow patterns, which suggest that the choriocapillaris provides a more highly efficient system of outflow in posterior regions than in peripheral regions.
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