Review
Regenerative medicine for retinal diseases: activating endogenous repair mechanisms

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The retina is subject to degenerative diseases that often lead to significant visual impairment. Non-mammalian vertebrates have the remarkable ability to replace neurons lost through damage. Fish, and to a limited extent birds, replace lost neurons by the dedifferentiation of Müller glia to a progenitor state followed by the replication of these neuronal progenitor cells. Over the past five years, studies have investigated whether regeneration can be stimulated in the mouse and rat retina. Several groups have reported that at least some types of neurons can be regenerated in the mammalian retina in vivo or in vitro, and that the regeneration of neurons can be stimulated using growth factors, transcription factors or subtoxic levels of excitatory amino acids. These recent results suggest that some part of the regenerative program that occurs in non-mammalian vertebrates remains in the mammalian retina, and could provide a basis to develop new strategies for retinal repair in patients with retinal degenerations.

Introduction

The retina is a complex neural circuit responsible for transducing light into a pattern of electrical impulses that informs the brain about the visual world. The retina has a common architecture across non- and mammalian species with six classes of neurons, including two types of light sensitive or photoreceptor cells: cones (daytime color vision) and rods (low light sensors). Photoreceptor signals are processed through three types of interneurons: horizontal cells, bipolar cells and amacrine cells. The cell bodies of these neurons, along with Müller glia (Box 1), are located in the inner nuclear layer (INL). In the outer plexiform layer (OPL), the synaptic terminals of rods and cones connect with horizontal cells and bipolar cells. These two cell types modify the incoming signals and then relay them to the dendrites of the amacrine and ganglion cells via synapses in the inner plexiform layer (IPL). The amacrine cells further process the incoming signals (e.g. motion detection), whereas the ganglion cells relay the visual information to the brain via their axons in the optic nerve (Figure 1a).

Like other areas of the nervous system, the retina is subject to many acquired and inherited neuronal degenerative diseases. Because the retina provides the input for all visual sensory information to the brain, the loss of cells results in visual impairment and potentially complete blindness. Many retinal degenerative diseases affect only a subset of the retinal cells, although, frequently in more advanced disease, the loss and reorganization of the entire retina can occur 1, 2. In humans, there seems to be little or no recovery of lost cells. By contrast, non-mammalian vertebrates, such as amphibians and fish, have robust regenerative responses to injury, which can lead to the near complete restoration of the neurons lost through injury. Studies of the response to injury over many years have led to strategies for potentially stimulating these processes in the mammalian retina.

Here, we review recent progress in our understanding of regeneration in non-mammalian vertebrates and how this has impacted recent attempts to promote regeneration in mammals, particularly mice and rats. Furthermore, based on current knowledge and questions in the field of regenerative medicine, we discuss new avenues for the application of embryonic stem cells and induced pluripotent cells in the development of cell-based therapies for retinal diseases.

One area that we will not review, however, is the retinal stem cell zone at the anterior margin of the retina, the so-called ciliary margin zone (CMZ) or circumferential germinal zone (CGZ) that exists in fish, amphibians and birds and allows a new retina to be added as the eye grows along with the rest of the animal throughout its entire life (Figure 1b). This region does not play a significant role in the regeneration of the majority of retina in any species [3], although it is stimulated to produce retinal neurons by damage of the central or peripheral retina. In addition, the fact that this zone exists in non-mammalian vertebrates has led many to search for it in mammals, including humans, and there have been many claims that retinal stem cells exist and can be propagated in vitro [4]. However, these results are controversial [5] and, as this region is not crucial for most retinal regeneration in vertebrates, we confine our focus to those sources demonstrated to play more essential roles in this process. Nevertheless, there is interesting biology in the CMZ, and the reader is referred to other reviews on this interesting area of the retina 6, 7.

Section snippets

Basic biology of retinal regeneration

In amphibians, particularly urodeles (salamanders), there is an extensive literature extending over 100 years demonstrating that new retinas can be generated from the adjacent pigmented epithelial layer. If the retina is removed surgically or destroyed by transient interruption of the blood supply, the pigmented epithelial cells respond by re-entering the mitotic cell cycle (Figure 1b), losing their pigmentation and forming a new layer 8, 9. The cells of this new inner layer continue to

Retinal regeneration in mammals

In the mammalian retina, the regenerative response of the Müller glia to injury is even more limited than in the bird. In response to injury in the mouse or rat retina, the Müller glia become reactive and hypertrophic [31], but few re-enter the mitotic cell cycle. Several groups have studied the response of the rat retina to damage (in models similar to that which produces the regenerative response in fish and posthatch chicks) and found that at least a subpopulation of Müller glia can be

Future medical applications

Retinal cells degenerate in a variety of different diseases; some of the leading causes of retinal degeneration are diabetic retinopathy, glaucoma and age-related macular degeneration. However, there are many other inherited and acquired conditions that lead to visual impairment from the loss of retinal cells. What are the prospects that the stimulation of the regeneration of retinal neurons from Müller glia is likely to be of clinical benefit? From the work outlined in the preceding sections,

Concluding remarks

There is increasing evidence that the mammalian retina has a limited capacity for neuronal regeneration. Although there are still several key questions that need to be addressed, particularly those concerning the functional integration of the new cells, at least some of the components of the Müller response to injury are remarkably similar in teleosts, posthatch chicks and rodents. In all cases, some of the Müller glial cells re-enter the mitotic cell cycle, express key components of the

Acknowledgements

We acknowledge many helpful discussions with the members of the Reh lab, particularly Team Regenerate. We also thank Dr Joe Brzezinski for helpful criticisms of the manuscript and Dr Olivia Bermingham-McDonogh for her constant, constructive criticisms.

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