Retinal pigment epithelium transplantation: concepts, challenges, and future prospects

Abstract

The retinal pigment epithelium (RPE) is a single layer of cells that supports the light-sensitive photoreceptor cells that are essential for retinal function. Age-related macular degeneration (AMD) is a leading cause of visual impairment, and the primary pathogenic mechanism is thought to arise in the RPE layer. RPE cell structure and function are well understood, the cells are readily sustainable in laboratory culture and, unlike other cell types within the retina, RPE cells do not require synaptic connections to perform their role. These factors, together with the relative ease of outer retinal imaging, make RPE cells an attractive target for cell transplantation compared with other cell types in the retina or central nervous system. Seminal experiments in rats with an inherited RPE dystrophy have demonstrated that RPE transplantation can prevent photoreceptor loss and maintain visual function. This review provides an update on the progress made so far on RPE transplantation in human eyes, outlines potential sources of donor cells, and describes the technical and surgical challenges faced by the transplanting surgeon. Recent advances in the understanding of pluripotent stem cells, combined with novel surgical instrumentation, hold considerable promise, and support the concept of RPE transplantation as a regenerative strategy in AMD.

Figure 1

(a) Healthy RPE: healthy RPE exists as a polarised monolayer with tight junctions (green). Melanin is located in the apical cytoplasm and acts to absorb scattered light, thereby improving the optical quality of the eye. Microvilli on the apical RPE membrane interdigitate with the photoreceptors (rods shown in blue; cones shown in yellow). Microvilli allow phagocytosis of the shed photoreceptor outer segments and recycling of the visual pigments. The tight junctions ensure that the RPE can maintain its function as the outer blood retinal barrier. Bruch's membrane (BrM) is a pentilaminar structure; the innermost layer of BrM is formed by the basement membrane of the RPE. The outer layer of BrM is formed by the basement membrane of the choriocapillaris (CC). Breaches of BrM lead to growth of choroidal vessels into the sub-RPE and subretinal space, known as choroidal neovascularisation. (b) RPE degeneration in AMD: BrM is thickened, impairing diffusion between the choriocapillaris and the neurosensory retina. Drusen are clinically visible deposits that occur beneath the RPE. RPE cell death occurs, and there is loss of tight junctions between the remaining RPE cells, resulting in a discontinuous cell layer. These changes all lead to secondary photoreceptor cell loss, resulting in visual impairment.

Figure 2

(a-c): Schematic diagrams of (a) human eye (b) mouse eye and (c) rabbit eye (shown to scale). Retinal surgery in the human eye is facilitated by the large vitreous cavity. Following surgical pars plana vitrectomy, a subretinal bleb can be created with a 41-gauge cannula, to create a space for the transplanted RPE. The mouse eye (b) is an unsuitable experimental model not only because the eye is so small (axial length approx. 3 mm) but also because the lens is large and spherical and occupies most of the space within the globe. The vitreous cavity in the mouse eye is small and an epiretinal approach to RPE transplantation following pars plana vitrectomy is impossible. In contrast, the rabbit eye (c) is only slightly smaller than a human adult eye, and there is sufficient space within the vitreous cavity to allow pars plana vitrectomy and induction of a subretinal bleb. While the rabbit lens is larger than a human lens, intraoperative lens touch can be avoided with careful surgery. The rabbit eye is therefore an excellent model for RPE transplantation techniques.