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
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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)
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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
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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) |
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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.
Retinal Physician, Issue: May 2006