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| August 2002 | Inside IOVS | Volume 43/8 |
| Targeting Specific Cell Types in Ocular Disease |
Endothelial Markers on Uveal Melanoma Cells
A high microvascular density has been used as a marker of aggressive tumor behavior. Previous studies have shown that high microvascular density is associated with metastatic uveal melanoma. However, aggressive uveal melanoma cells are known to express endothelial cell markers. In a series of 200 uveal melanomas, as reported by Chen et al. (p. 2533), the labeling of tumor cells by CD34 was associated with a high microvascular density. Therefore, microvascular density is not an exclusive measure of tumor vascularity and may also reflect the inappropriate expression of markers by genetically deregulated aggressive tumor cells.
RPE and Oxidative Injury
The injury of retinal pigment epithelium (RPE) is generally assumed to contribute to the pathogenesis of age-related macular degeneration (AMD). Studies have shown that oxidative stress may cause the damage of RPE. However, most of these studies are performed in cultured proliferating RPE cells and may not reflect accurately a process that occurs in the non-dividing cells seen in vivo. Jiang et al. (p. 2546) show that a long-term confluent culture creates non-dividing human RPE (hRPE) cells. As in proliferating hRPE cells, oxidant triggers apoptosis in non-dividing cells and a Fas pathway mediates this process. However, the non-dividing hRPE cells are more sensitive to oxidant-induced apoptosis. A greater oxidized glutathione pool and a higher FasL expression are also observed. This study suggests that intracellular oxidation and up-regulation of FasL may sensitize hRPE cells to oxidant-induced apoptosis and this may serve as one of mechanisms in the development of AMD.
Corneal Limbal Stem Cells
Total limbal stem cell deficiency is one of the most challenging and difficult ocular surface disorders. A new surgical approach is to transplant limbal epithelial stem cells ex vivo expanded on amniotic membrane cultures. Ti et al. (p. 2584) for the first time completed a long-term pre-clinical testing of this surgical procedure in a rabbit model of total limbal stem cell deficiency. Their results demonstrate that such a new approach is safe and efficacious to restore a normal corneal surface, and can achieve a long-term success if surgical variables are controlled. This paves the way for clinical trials in humans using an improved protocol, and will lead to tissue engineering of a variety of mucosal epithelial tissues and possible gene therapies targeted at the epithelial stem cell in the future.
Fibroblasts in Corneal Wound Healing
Corneal fibroblasts were cultured on a collagen gel in an insert dish containing a membrane permeable to soluble factors but not to cells. Cultures were incubated with or without uninjured corneal epithelial cells, or with partially scraped epithelial cells, on the companion plate on the opposite side of the membrane. Injured epithelial cells stimulated myodifferentiation in fibroblasts through one or more soluble factors, including TGF-b. These data reported by Nakamura et al. (p. 2603) support the importance of the intact corneal epithelium for curbing differentiation of myofibroblasts in corneal wound healing and wound healing complications caused by these cells.
Conjunctival Lymphocytes in Dry Eye
Conjunctival biopsies from dry eye patients with or without Sjögren’s syndrome were immunohistochemically evaluated for T-cell subpopulations (DC3, CD4, CD8) as well as markers of activation (HLA-DR, HLA-DQ) and inflammation (ICAM-1). The numbers of total lymphocytes in both groups and for each marker were not significantly different. This indicates that although both dry eye conditions stem from different etiologies, they share a common inflammatory outcome. Hence, both conditions may be suitable for inflammation-based therapy, contrary to current beliefs. These findings by Stern et al. (p. 2609) allow for development of therapeutics, which are more closely associated with clinical manifestations of dry eye disease.
T Cells and Glaucoma
Earlier studies from Schwartz et al. showed that the ability to resist glutamate toxicity in glaucoma is directly related to the ability to manifest a T cell-dependent protective immune response. Using a rat model of chronically increased intraocular pressure, Bakalash et al. (p. 2648) now show that the ability to resist the degenerative consequences of increased pressure, which lead to death of retinal ganglion cells, is also affected by the immune system, i.e., by the ability to manifest a well-controlled autoimmune response. These findings may explain the differences in the abilities of different individuals to cope with a disease like glaucoma, and suggest that genetically determined immune factors play a role in progression of the disease and should be taken into account in the planning of therapy. They also support the strategy of therapeutic vaccination, with the aim of boosting self-repair mechanisms while avoiding the risk of autoimmune diseases.
Keratocytes and Adenoviruses
Focal adhesion kinase (FAK) is activated by integrin binding. Adenoviruses enter permissive cells by an integrin-mediated mechanism. Natarajan et al. (p. 2685) now demonstrate a relationship between adenovirus infection and tyrosine phosphorylation of FAK in human keratocytes. Adenovirus type 19 infection of cultured keratocytes induced tyrosine phosphorylation of FAK and a shift in the intracellular location of phosphorylated FAK from the cytosol to the cytoskeleton. Treatment with the FAK inhibitor echistatin reduced virus-induced expression of the neutrophil chemotactant IL-8, previously implicated in adenoviral pathogenesis. Activation of FAK may contribute to the inflammatory response to adenovirus infection of the human cornea. Furthermore, signal transduction inhibitors represent a novel approach to the therapy of ocular inflammatory disorders.
Astrocytes and Glaucoma
Optic nerve head astrocytes (ONAs) play an important role in glaucoma in that they undergo proliferation, hypertrophy, and alter the extracellular matrix, which together can contribute to optic nerve damage. While elevated IOP is an important factor for astrocyte activation in glaucoma, other factors including endothelin-1 (ET-1), a potent vasoactive peptide that is elevated in glaucoma, may be exacerbating this effect in the optic nerve head. Prasanna et al. (p. 2704) demonstrate that ET-1 causes human ONA proliferation via ETA and ETB receptor activation. Thus, ET-1’s effects in neurotrauma and neuropathies (including glaucoma) may include mitogenesis of astroglial cells, which can result in neuronal damage.
Mixed Cell Migration and Epiretinal Membranes
Migration of retinal pigment epithelium (RPE), retinal glia, and fibroblasts is known to play an important role in the early cellular recruitment phase of epiretinal membrane (ERM) formation. Hitherto, due to lack of direct comparison of the migratory abilities of the cell types, RPE have been afforded the dominant role in this process. Hogg et al. (p. 2749) have developed a simple mixed cell migration (MCM) assay, using labeled cells, to distinguish between the migratory responses of different cell types in the same microenvironment. The cells’ subsequent responses to standard chemoattractants have highlighted the important role of retinal glia in the early stages of ERM formation. These results have possible implications for identifying potential target areas in ERM management.
Tenascin-C in Normal and Diabetic Retinal Endothelium
Here, tenascin-C effects on cultured normal and diabetic retinal endothelial cells were examined. Capillary-like tube formation on basement membrane matrix (Matrigel), secondary sprouting on Matrigel, cell migration, survival and proliferation were measured. Castellon et al. (p. 2758) showed that tenascin-C significantly delayed collapse of capillary-like tubes on Matrigel, and decreased tube involution associated with serum deprivation, high glucose and exposure to TGF-b. Tenascin-C also enhanced tube branching after treatment of cells with vascular endothelial growth factor and stimulated cell migration twofold. Tenascin-C promoted secondary sprouting on Matrigel which involved signaling through mitogen-activated kinase (MEK) and p38 mitogen-activated protein kinase. Angiogenic growth factors increased tenascin-C production by cells in an additive manner, which may explain its higher levels in diabetic retinopathy cells. Tenascin-C thus enhanced the effects of angiogenic growth factors, and had distinct proliferative, migratory and protective capacities.
MMPs and RPE Cells
Expression and activity of several matrix metalloproteinases (MMPs) become altered during neovascularization and proliferative retinopathies. A disturbed balance between MMPs and their natural inhibitors may affect integrity of extracellular matrix and probably contributes significantly to the pathogenesis of ocular diseases. This study by Eichler et al. (p. 2767) demonstrates that proinflammatory cytokines and transforming growth factor beta 2 (TGF-b2) play an important role for upregulation of MMP-1, -2 and -3 expression in retinal pigment epithelial (RPE) cells and may account for a directional shift in the balance between MMPs and tissue inhibitors of MMPs. The findings also provide a link between MMP upregulation mediated by cytokines and enhanced cellular migration of RPE cells. The results raise the possibility of targeting cytokine-mediated intracellular signaling pathways for treatment of sight-threatening disorders which are associated with excessive MMP activity and matrix degradation.
PGD2 and Pericyte Growth
The process of chronic inflammation and angiogenesis are closely related. The inflammatory mediators, such as cytokines and prostaglandins, may play a role in the development of new vessels. Sakurai et al. (p. 2774) have demonstrated that PGD2 induces the early response gene c-fos and stimulates the growth of retinal capillary pericytes by activating CREB. The expression of VEGF, a key growth factor for angiogenesis, is also increased when pericytes are stimulated by PGD2. The secondary inflammatory process appears to accelerate the process of new vessel growth in retina.
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