Retinal Transplantation
Antonio López Bolaños
The possibility of rebuilding a damaged retina has been the aim of multiple researchers. Because of improved technology and the molecular biology, it is now possible to manage many diseases that were previously untreatable. However, retinal degenerations, such as retinitis pigmentosa and age-related macular degeneration (AMD), among others, continue to be devastating causes of progressive vision loss and blindness. These diseases primarily affect the photoreceptors or the retinal pigment epithelium (RPE). There are currently no effective treatments available to prevent the loss of photoreceptors in most of these disorders.
A variety of approaches to preserve or restore vision are under investigation. Treatment strategies for retinal degeneration are aimed at either preventing photoreceptor loss or restoring vision by replacing the lost photoreceptors and/or the RPE. Retinal transplantation is based on the hypothesis that the degenerated retina can be repaired by introducing normal RPE and photoreceptor cells that may develop appropriate connections with the still functional part of the host retina.
Retinal transplantation was first performed in 1946 by Tansley (1), who demonstrated features of retinal differentiation in embryonic ocular tissue transplanted into the brains of young rats. In 1959, Royo and Quay (2) reported the first intraocular retinal transplantation procedure and demonstrated that fetal mice retina could survive in the anterior chamber of the maternal parent. In 1980, del Cerro et al. (3) transplanted full-thickness strips of retina into the anterior chamber of a mouse and demonstrated survival of both allografts and xenografts. Turner and Blair (4) transplanted neonatal rat retina into the subretinal space via a transscleral approach and demonstrated survival and differentiation of the graft into retinal layers.
Dissociated retinal microaggregates and retinal cell suspensions were subsequently tried by a numerous investigators (5,6,7). These preparations were easily manipulated and introduced into the subretinal space with a minimal amount of trauma. After transplantation, however, microaggregate suspensions are often organized into rudimentarily differentiated rosettes rather than well-organized layers (8,9).
Several sources of cells have been tested for their ability to replace photoreceptors. Fetal or embryonic retinal progenitors can be grown in vitro (10) and used for transplantation. Neurospheres can be grown from the adult pigmented ciliary epithelium, and these cells can also be transplanted to the retina (11). Neural stem cells derived from the hippocampus show a remarkable ability to integrate into the retinal layers and form morphologically normal-appearing retinal neurons (12). The best evidence for functional photoreceptors comes from the study of MacLaren et al. (13), in which freshly dissociated, postmitotic rod photoreceptors were transplanted to the subretinal space; however, the number of cells cannot be increased in vitro due to their postmitotic state.
Embryonic stem cells (ESCs) might also be a source for replacement of photoreceptors. Their indefinite selfrenewal and pluripotency make them an ideal source (13).
Lamb et al. in 2009 transplanted human ESC-derived photoreceptors. After transplantation of the cells into the subretinal space of a mice model of Leber’s congenital amaurosis, the cells differentiated into functional photoreceptors and restored light responses to the animals. These results demonstrate that ESCs can, in principle, be used for photoreceptor replacement therapies.
In principle, successful transplantation requires graft survival and integration with the host. Graft survival
depends on a number of factors, both immunologic and nonimmunologic. Immune privilege in the eye is the result of (a) the blood-ocular barrier, which minimizes contact of allografts with the cells and molecules of the immune system, thus blunting the immune response to alloantigens; (b) deficient lymphatic drainage of the eye; (c) an unusual distribution and functional properties of bone marrow-derived antigen-presenting cells; and (d) an ocular microenvironment rich in soluble or cell membrane-associated immunomodulatory factors.
depends on a number of factors, both immunologic and nonimmunologic. Immune privilege in the eye is the result of (a) the blood-ocular barrier, which minimizes contact of allografts with the cells and molecules of the immune system, thus blunting the immune response to alloantigens; (b) deficient lymphatic drainage of the eye; (c) an unusual distribution and functional properties of bone marrow-derived antigen-presenting cells; and (d) an ocular microenvironment rich in soluble or cell membrane-associated immunomodulatory factors.
Synapse formation between retinal grafts and the host retina is much more complex (14).
The prospective transplant interconnections with the host retina need to be improved and enhanced, which is expected to occur in future experiments outlined below. Retinal interneurons in the transplant may interfere with the synaptic connectivity of transplant photoreceptors with the host retina. Connectivity could be supported by factors that reduce glial reactivity and trauma to the retina because the formation of glial scars is another barrier to integration. Treatment with trophic factors or gene delivery into donor cells also needs to be explored. This requires carefully controlled experiments to account for the normal up-regulation of trophic factors that are seen after injury (15).
Retinal transplantation and approaches to develop retinal prostheses are presently the only potential treatments once photoreceptors are lost. Growth factor and gene therapy can only work to delay retinal diseases, not replace lost photoreceptors. In the future, one can conceive of stimulating stem cells in the adult eye to regenerate the lost photoreceptors or the bioengineering of a retina from stem cells (15).
RETINAL PIGMENT EPITHELIAL TRANSPLANT
Aging pathophysiology of the RPE and Bruch’s membrane
Retinal pigment epithelial dysfunction is believed to be the main cause of many debilitating retinal diseases of which AMD is the most common. In this disease, the retinal pigment epithelial dysfunction leads to photoreceptor damage causing severe vision loss. The RPE and Bruch’s membrane (BM) suffer cumulative damage over lifetime, which is thought to induce AMD in susceptible individuals.
There is a continuous “physiologic” increase in lipofuscin within the RPE cells, evident between 20 and 70 years of age. The concentration is higher in the posterior pole. In AMD, lipofuscin accumulates in the lysosomes of RPE and is associated with several adverse effects on RPE function and survival (16). In the aging human eye, apoptosis of RPE cells was found to be four times higher in the macular center than in the rest of the retina (17). Lipofuscin is also known to be a photoinducible generator of reactive oxygen species. RPE phagocytosis of photoreceptor outer segments is associated with oxidative stress, and H202 is probably the reactive oxygen intermediate involved (18).
The RPE seems to play an important role in sustaining the microenvironment and protecting it from various noxious insults. In vivo protection of photoreceptors from light damage by pigment epithelium-derived growth factor (PEDF) has been reported by Cao et al. (19). PEDF also inhibits retinal and choroidal neovascularization (CNV) (20). It has been suggested that RPE cells may control the growth of new vessels from the choroid because of the membrane protein Fas ligand, which is highly expressed on the RPE (21).
The RPE maintains retinal function as the metabolic gatekeeper between photoreceptors and the choriocapillaris. The RPE and BM suffer cumulative damage over lifetime. BM plays a crucial role in the pathogenesis of AMD. It is believed that BM forms a physical barrier against the invasion of new vessels into the retina (22). With its strategic location between the retina and the choroidal circulation, BM is involved in the exchange of numerous biomolecules, oxygen, nutrients, and waste products between the RPE and choriocapillaris. It plays a crucial role in cell-to-cell communication, cellular differentiation, proliferation, migration, and tissue remodeling (23).
BM thickness greatly varies among individuals and has been shown to double in size throughout life, from an average 2 µm in the first decade of life to 4.7 µm 80 years later. This thickening is caused by the deposition of waste products of the RPE, such as oxidized lipids and proteins. Over time, granular, membranous, filamentous, and vesicular material accumulates into the different layers of BM (24,25,26,27). This accumulation eventually leads to the formation of focal or diffuse sub-RPE deposits in BM, best known as drusen. The accumulation of biomolecules in BM causes changes in hydrostatic pressure and permeability, resulting in hypoxia and lack of nutrient exchange. This leads to the release of cytokines and growth factors, including vascular endothelial growth factor (VEGF), from the RPE cells (28).
RPE Transplantation
RPE transplantation is conceptually easier because the RPE is only a monolayer of cells between the systemic circulation and the photoreceptors. It works by being next to the outer segments of the photoreceptors, separated by a narrow extracellular space, uniquely enriched with specialized proteins. Although all of the functional roles of the RPE have not been elucidated yet, most of the major ones have. We know that without an RPE layer, the photoreceptors as well as the choriocapillaris degenerate. Transplanted RPE corrects this defect and prevents the photoreceptor cells from degenerating.
In the past 20 years, a huge amount of research has been conducted in the area of transplantation of RPE. This technique aims to restore the subretinal anatomy and reestablish the critical interaction between the RPE and the photoreceptor, which is fundamental to sight.
The success of RPE transplantation depends largely on the origin of introduced RPE cells: autologous transplants taken from the patient’s own eye and allogenic
The success of RPE transplantation depends largely on the origin of introduced RPE cells: autologous transplants taken from the patient’s own eye and allogenic
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