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Other eye cellsProduction of other ocular tissue
There are many types of cells in the retina - the delicate network of nerves in the eye that allow you to see. The two most important cells are the Retinal Pigment Epithelial cell and the photoreceptor. The latter actually captures the light that enters the eye and transforms it into an electrical signal. The RPE cell is critical in supporting and nourishing the photoreceptor cell and as such the two are interdependent and critical to sight. Most retinal disease in some way affect these two cell types and their loss is often the source of vision decline. As such the main aim of our stem cell projects is to be able to replace these two cell types in order to restore long term vision.
Since the 1990’s there have been many experiments transplanting retinal pieces or photoreceptors into rodents with photoreceptor degeneration. Rod photoreceptors isolated from either neonatal or adult rodents have been shown to integrate and survive for months in the outer retina of host rodents, whether in the normal retina or in the degenerating environment (Gouras et al., 1991a; Gouras et al., 1991b; Gouras et al., 1991c; Gouras et al., 1994). Once transplanted, these immature cells can appear to mature and produce outer segments (Gouras et al., 1992). An alternative strategy has been transplantation of whole sheets of retina, or retina with RPE into animals with retinal degeneration. This has been done with allografts of normal retina transplanted into rat (Aramant et al., 1999) and cat (Ivert et al., 1998), as well as xenografting of human fetal retina with RPE into rat retina (Aramant & Seiler, 2002). These approaches demonstrate that transplanted/grafted photoreceptors can survive at least in the short term with little evidence of immune rejection.
Only more recently has research begun to address the efficacy of transplanted photoreceptors in terms of functionally restoring light sensitivity. In an important study by Kwan et al., (1999) dissociated retinal cells (from mice 6-7 days old) were transplanted into the sub-retinal space of adult mice with retinal degeneration. Large areas of photoreceptors with outer segments were reconstituted in these mice and they integrated sufficiently with the host retina to drive a simple light dark discrimination test. Similarly multipotent retinal progenitor cells derived from GFP-expressing mice once grafted into the degenerating retina of adult mice develop into mature neurones expressing the photopigments (rhodopsin or cone opsins), which results in improvements in visual function (Klassen et al., 2004).
Most recently, Maclaren et al., (2006) have shown that post-mitotic rod donor cells taken from post natal day 1 mice successfully integrate into host retina, differentiate into rod photoreceptors, form synaptic connections and can subsequently improve the visual function (measured by both light evoked extracellular field potentials recorded from the ganglion cell layer and the pupillary light reflex) of retinally degenerate mice.
All the successful photoreceptor replacement studies thus far have involved the use of retinal cells from a donor animal, which is unlikely to be a useful strategy in treating human retinal disease. Additionally transplantation work has concentrated on restoring rod photoreceptors. Although they almost certainly provide trophic support (Mohand-Said et al., 1997; Mohand-Said et al., 1998; Mohand-Said et al., 2000) for the remaining cones, this approach however does not address the problem of restoring cone photoreceptor cell numbers, which is an important issue for restoring high acuity vision in humans.
Pioneering work is currently being undertaken to differentiate stem cells towards rod and cone photoreceptor phenotypes (Tabata et al., 2004; Ikeda et al., 2005; Lamba et al., 2006). We plan to expand and build on this work to differentiate functional cone photoreceptors from human ES or iPS cells. The efficacy of these cells for improving visual function will then be tested in models of retinal degeneration.Other potential methods
In rodent models of retinal degeneration preservation of rods and cones has also been accomplished by the introduction of growth factors into the eye. These factors have been delivered by three major routes (i) direct injection, (ii) gene therapy and (iii) by transplantation of cells expressing growth factors. However, these approaches do not address the problem of replacing lost photoreceptors.