Peer Reviewed
Stem Cells for Retinal Disease
MICHAEL T. TRESE, MD & MICHAEL M. LAI, MD, PhD

Retinal physicians are looking to the future for therapies that might benefit patients who currently have little or no hope for improved or saved vision. In the United States and elsewhere around the world, microchip devices using nanoelectronics and space-age materials are being developed and tested in eyes with severe or complete vision loss.^1-3 In addition, combinations of both electronic and biologic solutions to these types of problems have been described by researchers
in the United States and Japan. Devices that interact with the retina, optic nerve, and visual cortex have
been proposed.^4-7

Figure 1. Mice homozygous for a mutation in the Rpe65 gene were transplanted with mouse embryonic stem cells expressing the yellow fluorescent protein (YFP). Immunofluorescence analysis of transplanted eyes showed differentiation of transplanted cells and their incorporation into multiple layers of the host retina. Cross sections of transplanted eyes were stained using a FITC-conjugated antibody against YFP. (40x)

Biologic solutions are perhaps more familiar to physicians than nanoelectronic solutions, and one of these is stem cells. Stem cells have been used in other ophthalmic problems such as severe corneal disease.⁸ Stem cells for retinal disease remain investigational, but with their multi-potential nature, they may offer hope for biological management for some of the diseases that have rendered our patients with reduced or no vision.

Stem cells may be capable of several functions given the current state of the art. One of the most appealing is the ability to rebuild complex tissues such as the subretinal space after it has had damage to photoreceptor outer segments and retinal pigment epithelium. This occurs in diseases such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), macular dystrophies, eyes with attached retinas following retinopathy of prematurity surgery, eyes damaged from blood in the subretinal space from familial exudative vitreoretinopathy, or perhaps even eyes with badly damaged subretinal space secondary to trauma. Stem cells may have the ability to rebuild the subretinal space that has been manipulated surgically such as with irrigation of blood or removal of a fibrovascular complex from any etiology.

POSSIBLE USES FOR STEM CELLS

Recently, animal studies have been performed showing tremendous promise in the use of stem cells to rebuild retinal vasculature and actual neural retinal thickness. This also brings hope to diseases such as RP or other diseases caused by vascular insult, including retinal vessel occlusive diseases.

What types of stem cells might be used in retinal therapies? Many researchers feel that embryonic stem cells may be the only choice. The ethical and political issues raised with embryonic stem cells are significant. However, in recent animal studies, the use of autologous hemopoietic stem cells has shown to be helpful in animal models with severe dystrophic retinal disease. It is possible that these stem cells may be injected into the vitreous cavity to achieve an effect as seen by Friedlander et al in their work on the rescue from retinal degeneration in a rodent model.⁹

Another application for stem cells may be in other pediatric retinal diseases such as congenital X-linked retinoschisis. Genetically corrected autologous stem cells may be able to be injected into the schisis cavities that have been flattened surgically to allow reestablishing of the neural connection between the inner and outer retinal leaflets.

CURRENT KNOWLEDGE

Figure 2. Mice homozygous for a mutation in the Rpe65 gene were treated with intravitreal injection of mouse embryonic stem cells expressing the yellow fluorescent protein (YFP). At 7 weeks post injection, a tumor derived from transplanted cells was seen growing near the injection site (arrow). (H&E, 4x)

What do we know about stem cells today? Data exist showing that stem cells can integrate into existing retinal tissue. As seen in Figure 1 in this rodent model, the immunohistochemically fluorescent stem cells are seen to migrate and incorporate to existing retinal tissue. This is 1 of the encouraging findings that suggest our ability to rebuild retinal structure using these multi-potential cells (Figure 1). Cells that have been tested to date include multi-potential embryonic stem cells as well as more differentiated retinal progenitor cells. These cells have mostly been injected into the vitreous cavity and not into the subretinal space. However, it has been described in the past that not all stem cell injections result in integration to existing retinal tissue, and it has been seen that retinal stem cells injected into the vitreous cavity can result in benign tumors of cells adjacent to retinal tissue (Figure 2). In addition, autologous hemopoietic stem cells have been shown to have a positive effect on retinal vasculature and neural sensory retinal thickness, as well as the ability to preserve ERG in treated animals. These animals otherwise will extinguish their ERG without these stem cell injections.⁹ Stem cells might require specific preparation and biochemical and cellular environments to produce the best stem cells for injection.

Other supporting evidence that stem or differentiated fetal retinal cell transplantation may be significant comes from Radtke et al, who transplanted fetal tissue to the subretinal space of eyes with retinitis pigmentosa and patients with AMD with the result of some eyes showing an improvement in function.¹⁰

FUTURE USES FOR STEM CELLS

More research must be performed to determine the specific types of stem cells that are of value for treating retinal disease and for which situations stem cells can be utilized. Expectations that introducing multi-potential embryonic stem cells into the eye may result in rebuilding of the retinal structure may be unfounded. However, appropriately adjusting the cell bolus injected either by adjusting its biochemical culture environment prior to injection, varying its anatomic placement, or cell selection or genetic structure may help us to manage previously untreatable diseases.

REFERENCES

1. Ahmad I. Stem cells: new opportunities to treat eye diseases. Invest Ophthalmol Vis Sci. 2001;42:2743-2748.

2. Anderson DJ. Stem cells and the pattern formation in the nervous system: the possible versus the actual. Neuron. 2001;30:19-35.

3. Perron M, Harris WA. Retinal stem cells in vertebrates. Bioessays. 2000;22:685-688.

4. Duret F, Brelen ME, Lambert V, et al. Object localization, discrimination, and grasping with the optic nerve prosthesis. Restor Neurol Neurosci. 2006:24:31-40.

5. Dobelle WH, Mlodejovsky MG, Girvin JP. Artificial vision for the blind: electrical stimulation of visual cortex offers hope for a functional prosthesis. Science. 1974;183:440-444.

6. Chow AY, Chow VY, Packo KH, Pollock JS, Peyman GA, Schuchard R. The artificial silicon retina microchip for treatment of vision loss from retinitis pigmentosa. Arch Ophthalmol. 2004;122:460-469.

7. Leng T, Wu P, Mehenti NZ, et al. Directed retinal nerve cell growth for use in a retinal prosthesis interface. Invest Ophthalmol Vis Sci. 2004;45:4132-4137.

8. Schwab IR, Isseroff RR. Bioengineered corneas: the promise and the challenge. N Engl J Med. 2000;343:136-138.

9. Otani A, Dorrell MI, Kinder K, et al. Rescue of retinal degeneration by intravitreally injected adult bone marrow-derived lineage-negative hematopoietic stem cells. J Clin Invest. 2004;114:765-774.

10. Radtke ND, Aramant RB, Seiler MJ, et al. Vision change after sheet transplant of fetal retina with retinal pigment epithelium to a patient with retinitis pigmentosa. Arch Ophthalmol. 2004;122:1159-1165.

Michael T. Trese, MD, is clinical professor of Biomedical Sciences at the Eye Research Institute, Oakland University in Rochester, Mich and clinical associate professor at Wayne State University School of Medicine in Detroit. He is chief of Pediatric and Adult Vitreoretinal Surgery at William Beaumont Hospital and is president of Associated Retinal Consultants, PC, Royal Oak, Mich. Michael M. Lai, MD, PhD, is a fellow at William Beaumont Hospital and Associated Retinal Consultants, PC. Neither author has a financial interest in any of the information contained in this article. Dr. Trese can be contacted at (248) 288-2280.