Key Features
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Absorption of scattered light.
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Control of fluid and nutrients in the subretinal space (blood–retinal barrier function).
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Visual pigment regeneration and synthesis.
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Synthesis of growth factors to modulate adjacent structures.
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Maintenance of retinal adhesion.
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Phagocytosis and digestion of photoreceptor wastes.
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Electrical homeostasis.
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Regeneration and repair for degenerative disease.
Introduction
The retinal pigment epithelium (RPE) is a vital tissue for the maintenance of photoreceptor function. It is also affected by many diseases of the retina and choroid. Embryologically, the RPE is derived from the same neural tube tissue that forms the neural retina, but the cells differentiate into a transporting epithelium, the main functions of which are to metabolically insulate and support the overlying neural retina. As a cellular monolayer, the RPE is now an attractive target for therapeutic modification and transplantation.
Structure and Metabolism
Cellular Architecture and Blood–Retinal Barrier
The RPE is a monolayer of interlocking hexagonal cells that are joined by tight junctions (zonulae occludens), which block the free passage of water and ions. This junctional barrier is the equivalent of the blood–retinal barrier of the neuroretina.
In the macular region, RPE cells are small (roughly 10–14 µm in diameter), whereas toward the periphery, they become flatter and broader (diameter up to 60 µm). The density of photoreceptors also varies across the retina, but the number of photoreceptors that overlie each RPE cell remains roughly constant (about 45 photoreceptors per RPE cell).
In cross-section, the RPE cell is differentiated into apical and basal configurations. On the apical side (facing the photoreceptors), long microvilli reach up between (and envelop) the outer segments of the photoreceptors ( Fig. 6.2.1 ). Melanin granules are concentrated in the apical end of the cell. The basal membrane has convoluted infolds to increase the surface area for the absorption and secretion of material. The cell structure is stabilized by a cytoskeleton of microfilaments and microtubules.
Pigments
The pigment that gives the RPE its name is melanin, found in cytoplasmic granules called melanosomes. In older age, melanin granules often fuse with lysosomes and break down, so the fundus in older adults typically appears less pigmented. The role of melanin in the eye remains somewhat speculative. The pigment serves to absorb stray light and minimize scatter within the eye, which has theoretical optical benefits. Visual acuity is, however, not degraded in the fundi of the very blond. Further, the appearance of the fundus can be misleading with respect to the RPE because the greatest racial differences are a result of choroidal pigmentation. Melanin also serves as a free radical stabilizer and can bind toxins and retinotoxic drugs, such as chloroquine and thioridazine, although it is unclear whether this effect is beneficial or harmful.
The other major RPE pigment is lipofuscin, which accumulates gradually with age, although it is not clear whether it is directly damaging to RPE cells as it is a component of both normal and pathological aging.
Metabolism and Growth Factors
A number of growth factors are elaborated by RPE cells and serve to modulate not only the behavior of the RPE but also the behavior of surrounding tissues. Knowledge of these interactions is growing rapidly, and it is now recognized that the RPE is a critical part of a complex system of cellular cross-talk that controls vascular supply, permeability, growth, immunological responses, repair, and other processes vital to retinal function. Dysfunction within these systems contributes to disorders, such as age-related macular degeneration. Factors produced by the RPE include, among others, platelet-derived growth factor, which modulates cell growth and healing; pigment epithelium-derived factor, which acts as a neuroprotectant and vascular inhibitor; vascular endothelial growth factor, which can stimulate normal or pathological neovascular growth; fibroblast growth factor, which can be neurotropic; transforming growth factor, which moderates inflammation; ciliary neurotrophic factor, which supports and rescues cells; and other immune regulating components, such as Toll-like receptors and complement factors.
Cellular Architecture and Blood–Retinal Barrier
The RPE is a monolayer of interlocking hexagonal cells that are joined by tight junctions (zonulae occludens), which block the free passage of water and ions. This junctional barrier is the equivalent of the blood–retinal barrier of the neuroretina.
In the macular region, RPE cells are small (roughly 10–14 µm in diameter), whereas toward the periphery, they become flatter and broader (diameter up to 60 µm). The density of photoreceptors also varies across the retina, but the number of photoreceptors that overlie each RPE cell remains roughly constant (about 45 photoreceptors per RPE cell).
In cross-section, the RPE cell is differentiated into apical and basal configurations. On the apical side (facing the photoreceptors), long microvilli reach up between (and envelop) the outer segments of the photoreceptors ( Fig. 6.2.1 ). Melanin granules are concentrated in the apical end of the cell. The basal membrane has convoluted infolds to increase the surface area for the absorption and secretion of material. The cell structure is stabilized by a cytoskeleton of microfilaments and microtubules.
Pigments
The pigment that gives the RPE its name is melanin, found in cytoplasmic granules called melanosomes. In older age, melanin granules often fuse with lysosomes and break down, so the fundus in older adults typically appears less pigmented. The role of melanin in the eye remains somewhat speculative. The pigment serves to absorb stray light and minimize scatter within the eye, which has theoretical optical benefits. Visual acuity is, however, not degraded in the fundi of the very blond. Further, the appearance of the fundus can be misleading with respect to the RPE because the greatest racial differences are a result of choroidal pigmentation. Melanin also serves as a free radical stabilizer and can bind toxins and retinotoxic drugs, such as chloroquine and thioridazine, although it is unclear whether this effect is beneficial or harmful.
The other major RPE pigment is lipofuscin, which accumulates gradually with age, although it is not clear whether it is directly damaging to RPE cells as it is a component of both normal and pathological aging.
Metabolism and Growth Factors
A number of growth factors are elaborated by RPE cells and serve to modulate not only the behavior of the RPE but also the behavior of surrounding tissues. Knowledge of these interactions is growing rapidly, and it is now recognized that the RPE is a critical part of a complex system of cellular cross-talk that controls vascular supply, permeability, growth, immunological responses, repair, and other processes vital to retinal function. Dysfunction within these systems contributes to disorders, such as age-related macular degeneration. Factors produced by the RPE include, among others, platelet-derived growth factor, which modulates cell growth and healing; pigment epithelium-derived factor, which acts as a neuroprotectant and vascular inhibitor; vascular endothelial growth factor, which can stimulate normal or pathological neovascular growth; fibroblast growth factor, which can be neurotropic; transforming growth factor, which moderates inflammation; ciliary neurotrophic factor, which supports and rescues cells; and other immune regulating components, such as Toll-like receptors and complement factors.
Membrane Properties and Fluid Transport
Ion Channels and Transport Systems
The RPE membrane contains selective ion channels, and active or facilitative transport systems for ions and for metabolites, such as glucose and amino acids. Different channels and transporters are present on the apical and basal membranes. The net effects of the asymmetrical transport systems are a movement of water across the RPE in the apical-to-basal direction and the generation of voltage across the RPE, as well as control of protein access to the subretinal space.
The ability of the RPE to transport water actively is very powerful, but water also moves out if the RPE barrier function is broken because of intraocular pressure and osmotic suction from the choroid. One clinical implication is that a small RPE break will not cause a serous detachment unless there is also a diffuse loss of RPE transport. Central serous chorioretinopathy involves broad dysfunction in the RPE-choroid complex ( Fig. 6.2.2 ).
