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Stem Cell Retinal Replacement
Therapy
By Jeffrey Stern, Ph.D., M.D., Michael Radosevich, M.D., Ph.D. and Sally Temple, Ph.D.
ver the past decade stem cells have
captured public interest by generating
hope for untreatable illness. Support has
grown such that stem cells are now a major focus
of biomedical industry. The field is at a critical
stage where progress to create an effective
treatment is within sight. This opportunity to
prove stem cells’ promise underlies a shift that is
underway to direct research toward efforts most
likely to produce practical medical benefit. Retinal
disease is one, among many, targets well suited
for this next stage of development in the stem cell
field.
from living patients as well as cadaveric donors (Jeffrey Stern,
unpublished data).
Early formed, dormant RPE cells have a close relationship with
early embryonic cells and it is not surprising, in this context, that
embryonic stem cells (ESCs) spontaneously differentiate into RPE
(ESC-RPESCs).13, 14 ESCs also can be differentiated into neural fates
(ESC-NSCs) that are another potential source for retinal replacement
therapy.15, 16
Neural stem cells (NSCs) can be derived from committed central
nervous tissue such as the embryonic or adult forebrain.17, 18 NSCs can
be expanded extensively and retain limited plasticity19 making them
less prone to form tumors than ESCs.
Bone marrow stem cells (BMSCs) also have restricted potential.
Although BMSCs are not closely related to neural lineages, they can
be driven to produce neuron-like progeny20, 21 including cells that
share retinal cell markers.22 More robustly, BMSCs produce more
closely related blood vessels23 and may be useful to replace vasculature
lost in retinal diseases as diverse as retinitis pigmentosa (RP) and
diabetes.
O
Advantages of retina for stem cell therapy are accessibility for
placement of cells, for monitoring transplanted cells, for
measurement of functional change and for ablation should
inappropriate growth occur. Early retinal transplantation experiments
have been encouraging, showing visual improvements that are limited
by problems now amenable to stem cell-based solutions.
Retinal Transplantation
The first viable transplants of mammalian retina showed that
fetal retina transplanted into adult rat eyes remained viable for
months.24 Subsequently, transplants using embryonic sheets or
aggregates were found to develop many normal retinal characteristics
but with limited integration into the host.25, 26, 27, 28, 29, 30 Younger source
tissue improved integration31 and improved integration occurred
when the host retina was injured.32, 33 Transplanted fetal retina
improved vision in animal models34, 35, 36 and in a few patients with RP
or AMD where visual recovery was transient lasting only 3-13
months.37 These pioneering studies showed that retinal
transplantation is technically feasible and provided tantalizing
evidence for a new paradigm to address otherwise untreatable,
devastating blindness.
Retinal progenitor cells (RPCs), considered the active cell type in
fetal retina transplants, were purified from green fluorescent protein
(GFP) transgenic mice and transplanted into the degenerating retina
of mature mice. These developed into mature neurons including
presumptive photoreceptors expressing rhodopsin, opsin, and
recoverin. The host retinas showed rescue of cells in the outer nuclear
layer as well as widespread integration of donor cells into the inner
retina. Recipient mice demonstrated an improved response to light
when compared with the control mice.38 Unfortunately, transplanted
RPCs did not integrate well into the outer nuclear layer where
photoreceptor cells normally reside. In order to improve transplant
success, combinations of implanted progenitor cells and growth
Stem Cells Sources for Retinal Replacement
The neural retina (‘retina’) initiates vision and is supported by
the underlying retinal pigment epithelium (RPE). The retina and
adjacent RPE both arise from neural ectoderm. In lower species RPE
regenerates retina but in mammals, RPE-mediated regeneration is
inhibited and renewal occurs to a very limited extent via stem cells
located at the peripheral retinal margin.1
Mammalian retinal stem cells (RSCs) have been isolated from
the ciliary margin.2, 3, 4, 5 RSCs expand through several passages and
differentiate into the major retinal cell types including photoreceptor,
bipolar, horizontal, amacrine, ganglion and glial Mueller cells.
Ciliary epithelial stem cells6, 7 photoreceptor precursors8 and Mueller
stem cells9 have also been described.
Another potential source for stem cell replacement therapy is the
RPE. The RPE is one of the first neural cell types to undergo
differentiation.10 RPE differentiates at about 6 weeks of gestation in
humans and then remains dormant throughout life. Quiescent RPE
cells can be activated to proliferate after injury11 or by culture.12 RPE
cultured under embryonic stem cell (ESC) proliferative conditions
self-renew suggesting the presence of RPE stem cells (RPESCs).
RPESCs cultured under ESC differentiation conditions differentiate
into a wide variety of progeny including retina, RPE, neurons, bone,
muscle and other cell types (presented by Sally Temple at the 2008
International Stem Cell Research Meeting). RPESCs can be obtained
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factor treatments have been tested. For example, coating the retinal
sheets with microspheres containing brain derived neurotrophic
factor (BDNF) was found to improve the functional efficacy of RPC
grafts.39
Although NSCs are found in all regions of the embryonic
nervous system, most work on transplantation has focused on
forebrain-derived NSCs. GFP-expressing NSCs survived and
displayed morphologies characteristic of retinal neurons with
integration after transplantation into mouse retina. As seen with
RPCs, however, NSCs integrated into inappropriate retinal layers and
the age of the host had a key role in determining NSC fate.40 This
confirmed prior studies showing that NSCs survive in the subretinal
space, migrate to integrate into the retina, and differentiate into
retinal cell phenotypes41 when transplanted into young or injured
host retina.42, 43 ESC-NSCs transplanted into healthy adult monkey,
however, showed less migration and integration, forming a
monolayer of stable NSCs.44 Integration may not be needed to treat
retinal degeneration as NSCs without integration rescued
photoreceptor cell loss in a rat model.45
Like NSCs, RSCs transplanted into the subretinal space of
young mice survive, migrate, integrate, and differentiate into retinal
cell types, especially photoreceptor cells.46 In adults, however,
transplanted RSCs preferentially express ganglion cell or glial markers
rather than differentiating into photoreceptor cells.47 These findings
suggest that RSC differentiation depends on the pre-transplantation
state of both the source RSCs and the host retina. Thus, RSCs have
the potential to mediate retinal repair but control of differentiation is
needed before clinical application. The restricted fates and lineage
choices of these specialized stem cells may facilitate control. Indeed,
retinal progenitor cells isolated at the stage they normally generate
photoreceptors were found to generate photoreceptors in vivo upon
transplantation.48
BMSCs transplanted into the retina replace vasculature49 lost in
diseases such as diabetes or retinopathy of prematurity. Significant
revascularization of retina can be directly observed, making retinal
transplantation a model system for studying stem cell-mediated
revascularization. In addition, enhanced survival of retinal neurons
was attributed to neurotrophic effects of improved circulation in
these ischemic animal models. Other reports indicate that BMSCs
produce retinal-like progeny after transplantation into the subretinal
space50, 51 indicating that, with additional phenotype direction, cell
replacement may be possible.
Transplanted ESC-NSCs incorporate into retina where the
retinal microenvironment drives differentiation preferentially into
photoreceptor cell fates, and importantly functional rescue of the
animal model was observed.52, 53, 54 Teratomas were not observed with
ESC-NSCs although tumors were frequent with related neurally
selected ESCs.55 Directing ESCs toward retinal NSCs prior to
transplantation improved integration and photoreceptor cell progeny
and tumor formation was not observed for 6 weeks.56
Like ESC-NSCs, ESC-RPEs injected into retinal degeneration
models differentiate and integrate appropriately into the host retina,
and rescue or restore function.57, 58 Tumor formation by human ESCRPEs was not observed for more than 220 days in rats.59 ESC-RPEs
repopulated the RPE layer to rescue photoreceptor cell loss in this rat
model. There has been wide, recent press coverage about FDA
applications for commercial development of ESC-RPEs cells by
Pfizer, Inc and Advanced Cell Therapuetics, Inc.
RSCs, NSCs, ESC-RPEs, ESC-NSCs, and BMSCs all
demonstrate photoreceptor cell rescue in animal models. This early
success raises hope that the ‘right’ cell(s) for durable improvement of
patients with common blinding conditions is near, yet challenges
remain.
Remaining Challenges
A key hurdle for retinal replacement therapy is to obtain
effective, stable stem cell sources that functionally integrate into
diseased retina. Pluripotent stem cells, primed to generate diversity,
offer a wide repertoire of candidate cells. ESCs generate RPE or
retinal fates which are suitable for replacement therapy. Their
inherent plasticity, however, raises the possibility of inappropriate
progeny, including tumors, as a safety concern.
Tumor formation is long known to be an important
consideration when transplanting pluripotent cells.60, 61, 62 Tumor
formation by ESCs transplanted into the vitreous is slowed when the
pluripotent cells are differentiated into ESC-NSCs prior to
transplantation,63 indicating reduced tumor formation with more
differentiated stem cell types. Tumors are not produced after retinal
transplantation of human ESCs predifferentiated into NSCs,64 RPE,65
or retinal progenitor types.66 Methods to further reduce pluripotent
cell tumorigenicity such as sorting for more differentiated types prior
to transplantation67 have met great success. The stability of purified,
differentiated pluripotent cell progeny after transplantation in
humans is not reported.
The large numbers of cells needed for commercial distribution
can be produced by ESCs, iPSCs, NSCs, BMSCs or RPESCs. Selfrenewal is an imperfect concept, however, and generating large
numbers of cells can destabilize lineages as seen, for example, after
overexpansion caused degradation of ‘government-approved’ ESC
lines. Multiple passaging of highly plastic, ESC-derived cells may
also, presumably, destabilize lineage, affecting the safety and
reliability of transplants.
RSCs, NSCs, BMSCs and RPESC have restricted lineage
potential that makes mis-differentiation or tumor formation less
likely. There is a trade-off, however, as restricted fate associated with
less plasticity can also be associated with less proliferative potential.
The ideal balance between restricted potency with improved control
of differentiation and pluripotency with increased plasticity and
proliferative capacity may depend on the strategy used to deliver the
transplantation therapy. Retinal replacement in an individual, for
example, requires fewer cells favoring limited potency whereas
commercial production for wide distribution to many recipients
requires extensive proliferation favoring, amongst stem cells,
pluripotency.
Immune rejection may prevent retinal replacement therapy from
achieving lasting results. Although immune rejection was not
significant in a human study where patients with RP and AMD were
treated by implanting neural retinal progenitor cell layers along with
retinal pigment epithelium,68 concern remains that some immune
rejection may emerge. Although ESC-derived cells have reduced
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immunogenicity69 and the retina immune privilege, rejection may
persist when mature progeny are exposed to a blood-retina barrier
weakened by disease or injury. Immune rejection can, in theory, be
circumvented by transforming a patient’s somatic cells into induced
pluripotent stem cells (iPSCs).70 iPSCs have been differentiated into
RPE-like cells71 but not transplanted into retina. For many stem cell
replacement strategies, systemic immune suppression is considered
necessary for long-term success.
Autologous transplantation to circumvent immune rejection has
proven success using BMSCs to treat hematopoietic diseases and a
similar strategy is also possible for retinal disease. Autologous
RPESCs from an individual have been expanded (unpublished data
of the authors) but not transplanted. Surgical risks for harvesting RPE
and reimplanting RPESC would be significant but likely acceptable
to many patients. It may also be possible to harvest BMSCs and
differentiate these into retinal progenitors72 for autologous transplant.
Such use of BMSCs would require two procedures as with autologous
RPESCs but with significantly more manipulation of cells into
progeny appropriate for implantation.
Technical challenges remain for retinal replacement therapy to
reach the bedside. The polarity of transplanted RPE cells may require
alignment and treatment of Bruch’s membrane may be needed to
promote the survival of transplanted cells.73 Modification of
transplanted cells may be needed to resist an underlying disease
process. Combined skills from stem cell biology and clinical retina are
needed to solve these technical hurdles.
Conclusion
The era of stem cells has renewed hope for restoring vision in
patients with diseases such as macular degeneration and retinitis
pigmentosa. Retinal transplantation improves vision but the
improvement is fleeting because transplanted cells do not fully
integrate or reject. These limitations can be overcome by stem cell
biology and clinical retina working together. Research should take
advantage of current strong public support, to progress methodically
and safely toward the practical results that are needed to sustain
support. With this, successful retinal replacement therapy can benefit
all stem cell research by delivering public value at a time of increasing
demand on the promise of stem cells.
Jeffrey Stern, Ph.D., M.D.
Dr. Jeffrey Stern is a native New Yorker.
He studied Biophysics at Brandeis
University for his Ph.D. with postdoctoral
studies in the Laboratory of Neurobiology
at Rockefeller University. He then
obtained an M.D. at the University of
Miami, completed a residency in Ophthalmology at Albany
Medical College followed by a fellowship in Retina-Vitreous at
Mount Sinai in NYC. Dr. Stern practices at Capital Region Retina
in Albany, NY. With his wife, Sally Temple, he founded the New
York Neural Stem Cell Institute where he focuses on translational
research.
Michael Radosevich, M.D., Ph.D.
Dr. Michael Radosevich received his B.S.
from the University of WisconsinMadison, his M.D. from the Johns
Hopkins University School of Medicine,
and his Ph.D. from Harvard University
in the field of ocular immunology. His
surgical internship was completed at
Stanford University School of Medicine, his Ophthalmology
residency was at the Doheny Eye Institute/University of Southern
California and his vitreoretinal fellowship was completed at the
University of Iowa. Dr. Radosevich practices at Capital Region
Retina in Albany, NY. He recently joined the New York Neural
Stem Cell Institute to focus on stem cell applications related to
macular degeneration, ocular tumors and proliferative
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Sally Temple, Ph.D.
Sally Temple is originally from the north
of England. She trained at Cambridge
University, then did her graduate work at
University College London with Martin
Raff. Sally now lives in the beautiful
upstate New York area. Her lab studies
central nervous system (CNS) stem and
progenitor cells and their role in generating the amazing neural cell
diversity during development. In August 2007 she cofounded the
non-profit New York Neural Stem Cell Institute with Jeff Stern,
focused on stem cell research for CNS ap
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