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Exp Eye Res
2014 Jun 01;123:107-14. doi: 10.1016/j.exer.2013.07.009.
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The retinal pigment epithelium: an important player of retinal disorders and regeneration.
Chiba C
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The retinal pigment epithelium (RPE) is a partner of the neural retina and is indispensable for vision. In humans, proliferation and transformation (cell-type switching) of RPE cells after a traumatic injury of the neural retina causes a retinal disorder leading to loss of vision. In contrast, in certain adult amphibians such as Xenopus laevis and the newt, a similar process in RPE cells leads to regeneration of the entire retina. In this review, on the basis of accumulating evidence in basic biology and medical sciences, similarities and differences between these RPE-mediated retinal disorders and regeneration in adult vertebrates are highlighted, providing a connection to future research that should be designed to establish clues for the treatment of pathogenesis caused by RPE while promoting RPE-mediated retinal regeneration in a patient's eyes.
Fig. 1. A process of proliferative vitreoretinopathy, an RPE-mediated retinal disorder in humans. In the intact eye, the neural retina is tightly attached to the RPE lying along Bruch's membrane (A). When the eye suffers from a severe trauma, the neural retina is detached from the RPE and sometimes injured with a tear wound (B). As the RPE cells are exposed to the serum which is leaked from the wound of the neural retina, they leave Bruch's membrane while losing their epithelial characteristics, and migrate toward the vitreous cavity through the tear of the neural retina (C). The migrating RPE cells adhere to both the epi- and subretinal surfaces as well as to the wound surfaces of the neural retina (D), proliferate, and form the epi- and subretinal membranes together with other minor constituent cells including Müller glia-derived cells from the neural retina (E). These RPE-derived cells in the epiretinal membrane exhibit a fibromyocyte-like phenotype. The epiretinal membrane grows and contracts, resulting in the progress of retinal detachment and the loss of vision (F).
Fig. 2. Retinal regeneration in the adult frog Xenopus laevis. After the neural retina is carefully removed from the eye by surgery (retinectomy) while the RPE and the retinal vascular membrane are remained (A to B), RPE cells are detached from each other, and some of them, that express Pax6, leave Bruch's membrane and migrate toward the retinal vascular membrane (C). RPE cells adhered on the retinal vascular membrane proliferate and regenerate a new neural retina, while those left on Bruch's membrane renew the RPE itself (D, E), and eventually an entire retina with correct polarity is regenerated (E–A).
Fig. 3. Retinal regeneration in the adult newt Cynops pyrrhogaster. After the neural retina is carefully removed from the eye by surgery (retinectomy) (A to B), RPE cells are detached from each other and form a layer/aggregates a few cells thick while entering the S-phase of the cell-cycle (Stage-E1) (C). These RPE cells, that are called stem-like cells, are partitioned into two layers (Stage-E2) (D), and then the cells in the inner layer proliferate and regenerate a new neural retina, while those in the outer layer renew the RPE itself (D, E), and eventually an entire retina with correct polarity is regenerated (E–A).
Fig. 4. Behavior of RPE cells after injury of the neural retina in humans (A), adult frog X. laevis (B) and newt (C). In these animals, RPE cells commonly undergo a loss of their epithelial characteristics following a neural retina injury. Through this process RPE cells acquire multipotency and start proliferation. However, the potency of such RPE-derived cells seems to be different between animals. In humans (A), the RPE-derived multipotent cells, called RPE stem cells (RPESCs), can produce, in vitro, mesenchymal cells such as adipocytes, bone cells and cartilage cells, but seem to have a limited potency to differentiate into retinal cells (blue dotted arrow) except for the RPE cell itself (blue arrow), and may differentiate, in proliferative vitreoretinopathy (PVR), into fibroblast-like cells which are a major component of the epiretinal membrane. On the other hand, in adult X. laevis (B), a population of RPE cells acquire multipotency while expressing Pax6 (these cells are called Pax6+ RPE cells), migrate onto the retinal vascular membrane, and eventually transdifferentiate into a neural retina, while remaining RPE cells along Bruch's membrane participate in reforming the RPE. In the adult newt (C), all RPE cells seem to be converted into multipotent cells, called stem-like cells, which eventually generate both a new neural retina and RPE with correct polarity.
