(Investigative Ophthalmology and Visual Science. 2001;42:2743-2748.)
© 2001
by The Association for Research in Vision and Ophthalmology, Inc.
Stem Cells: New Opportunities to Treat Eye Diseases
Iqbal Ahmad
From the Department of Ophthalmology, University of Nebraska Medical Center, Omaha, Nebraska.
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Introduction
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The recent identification and characterization of neural
progenitors with stem cell properties has opened new avenues that may
be useful for treating functional impairments caused by the death of
specific neural cell populations.1
2
Neuronal degeneration
is the cause of debilitating visual impairment associated with
prevalent ocular diseases, such as retinitis pigmentosa (RP),
age-related macular degeneration (AMD), retinal detachment, and
glaucoma. Neural stem cells may help to restore vision in patients who
have these diseases, by repopulating the damaged retina and/or by
rescuing retinal neurons from further degeneration. In addition,
understanding the molecular and cellular biology of neural stem cells
will shed light on developmental mechanisms that regulate their
maintenance, differentiation, and survival. Insights into these
developmental mechanisms are likely to provide additional therapeutic
approaches. This review provides an overview of the progress made in
the area of neural stem cell research with emphasis on the eye. First,
neural stem cells are defined and described. Second, their location and
characterization in the mammalian eye is outlined. Third, progress in
therapeutic usage of neural stem cell is discussed. And finally, the
current barriers to neural stem cell therapy are assessed in an attempt
to provide a balanced view of these exciting new opportunities in
treating degenerative eye diseases. This review does not include
corneal stem cells; the reader is referred to an excellent review by
Schwab and Isserhoff3
on the therapeutic uses of corneal
stem cells.
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Defining Neural Progenitors as Stem Cells
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The generation of cellular diversity in the brain is widely
believed to be a multistep process. The process is believed to involve
multipotent progenitors whose proliferative and differentiation
potentials are progressively restricted during development (Fig. 1)
. The progressive restriction of the developmental potential of neural
progenitors, regulated by intricate cell–cell interactions, ultimately
directs their differentiation into either neurons or glia. Neural
progenitors have been isolated from different regions of both embryonic
and adult brain, and their proliferation and maintenance in vitro
depend on the presence of high concentrations of mitogens, such as
epidermal growth factor (EGF) and/or basic fibroblast growth
(FGF2).1
2
4
The potential of these progenitors to give
rise to different cell types is demonstrated either by withdrawing
mitogens or by exposing them to differentiation-promoting factor(s).
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Figure 1. Schematic representation of relationships between stem cells,
progenitors, precursors, and differentiated neural cell types. Evidence
suggests that separate neuronal and glial progenitors may not be
present in the retina. The reverse broken lines
indicating that stem cell-progenitor precursors can be reprogrammed,
are based on recent observations of Clarke et al.37
and
Kondo and Raff.18
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Whereas the majority of embryonic and adult neural progenitors have
been demonstrated to be multipotential in terms of giving rise to three
basic central nervous system (CNS) cell types—neurons, astrocytes, and
oligodendrocytes—there is general disagreement about whether these
progenitors represent a true stem cell population. This controversy has
arisen, in part, because there is no consensus on the definition of
stem cells. In very general terms, stem cells can be defined as
tissue-specific ancestral cells that have the potential to give rise to
all differentiated cell types associated with that tissue and can
self-renew—that is, they have the ability to generate a large number
of identical multipotent progeny by clonal amplification. Other
properties attributed to stem cells such as asymmetrical division,
mitotic quiescence, and regenerative capacity are shared by some but
not all stem cells.5
Therefore, progenitors with the
capacity to self-renew and with the potential to give rise to neurons,
astrocytes, and oligodendrocytes, are generally regarded as stem
cell–like.2
5
Another reason for this cautious approach
in defining neural stem cells is that, unlike hematopoietic stem cells,
neural progenitors have not been tested for self-renewal in vivo. This
test requires serial transplantation of neural progenitors, which
involves the recovery of transplanted progenitors and re-expansion and
clonal analysis in vitro, followed by their retransplantation into
another brain. At present this is an extremely difficult, if not
impossible, proposal in the context of the brain. Hence, this review
takes a conservative approach and refers to these cells as neural stem
cells-progenitors.
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Neural Stem Cells-Progenitors in the Mammalian Eye
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Embryos
The ocular neuroepithelium is an excellent model for
characterization of neural stem cells-progenitors because of its
accessibility and limited cellular heterogeneity. Furthermore,
progenitors from ocular neuroepithelium are relatively well
characterized in context of the factors that regulate their
proliferative and differentiation potential.6
The
observation that EGF promotes proliferation of retinal progenitors at
the expense of differentiation7
and the discovery of
EGF-responsive striatal stem cells-progenitors8
have
provided an approach to isolate and characterize EGF-responsive retinal
progenitors in vitro.9
The approach includes culturing
embryonic retinal cells in serum-free medium containing high
concentrations of EGF. Under these conditions, a subset of cells
survives and, similar to striatal stem cells-progenitors, generates
floating spheres of cells termed neurospheres. The neurospheres consist
of proliferating cells that express the neuroectodermal stem cell
marker, nestin (Figs. 2A
2B
2C
). When EGF is withdrawn and the medium is supplemented with 1% fetal
bovine serum, cells in neurospheres downregulate the expression of
nestin, change their morphology, and differentiate into cells
expressing neuronal and glial-specific markers, suggesting that they
are multipotent. Multilineage differentiation of EGF-responsive retinal
progenitors is also supported by the presence of voltage-dependent
current profiles characteristic of neurons and glia.9
In
addition to their ability to differentiate into basic neural cell
types, these progenitors can also differentiate into retinal neurons
when cocultured with embryonic or neonatal retinal cells.
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Figure 2. Neural stem cells-progenitors in the mammalian eye. Neural progenitors
are present both in the embryonic retina (A– C)
and adult ciliary body (D– F). These cells can
be isolated and maintained in the culture in the presence of EGF and/or
FGF2. In the presence of mitogens, these cells generate neurospheres
containing proliferating cells (as shown by BrdU incorporation in
B and E) that express the neuroectodermal stem
cells marker, nestin (C, F).
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However, despite the demonstration of multipotentiality, these cells
cannot be defined as stem cells, because attempts to serially clone
them have not been successful—that is, they do not appear to
self-renew. The clonal generation of retinal progenitors has been
achieved only by culturing retinal progenitors obtained from embryos
expressing the antiapoptotic factor bcl2, in the presence of a mixture
of several growth factors.10
Even then, the proportion of
clones that contained more than two cells was only 14%. This suggests
two possibilities: The proliferating cells isolated from E17 embryos
are not stem cells, but rather are neural progenitors with a limited
self-renewal property, or these cells are indeed stem cells, but
conditions have not been identified that promote their self-renewal in
vitro.
Adult
The question of whether the adult derivatives of mammalian retinal
neuroepithelium–harbored cells with stem cell properties was recently
addressed. Two laboratories showed that the ciliary epithelium and not
the neural retina in the adult mammalian eye contains neural
progenitors.11
12
The hypothesis that neural stem
cells-progenitors are present in the adult ciliary epithelium was based
on a well-known observation that an analogous region in adult fish and
frogs, called the ciliary marginal zone (CMZ), harbors neural
progenitors.13
14
15
Neural progenitors have also been
identified in the CMZ of postnatal chickens.16
In addition
to progenitors in the CMZ, there is evidence that two separate
progenitor populations are present in the neural retina of adult fish
and that these progenitors participate in normal growth and/or
regeneration of the retina in response to lesion.17
In
vivo labeling analysis with bromodeoxyuridine (BrdU) shows that the
pigmented portion of ciliary body of adult rats contains cells with
proliferative potential.12
Indeed, when cultured in the
presence of EGF and/or FGF2, these cells proliferate and give rise to
neurospheres containing nestin-positive cells resembling those
generated by embryonic retinal progenitors (Figs. 2D
2E
2F)
. These cells
are multipotent and can differentiate along neuronal and glial lines.
Unlike embryonic retinal progenitors, these cells can self-renew,
because they clonally generate neurospheres. Therefore, they fulfill
the basic criteria of stem cells. These cells express the retinal
progenitor markers Chx10, Rx, and Pax6, which suggests that they
possess retina-specific properties and they can differentiate into
retinal cells when exposed to conducive environment.12
The
ability of these cells to self-renew, their plasticity, and their
potential to express retinal phenotypes suggests a possibility that
they represent a residual population of retinal stem cells. However,
because these cells are derived from pigmented ciliary epithelium,
there is likelihood that they acquire stem cell properties in vitro by
reprogramming or dedifferentiation. Similar mechanisms have been
invoked to explain the conversion of oligodendrocytic progenitors into
neural stem cells.18
Investigation of these possibilities
will be helped by prospective identification of neural stem cells,
instead of characterizing them in response to mitogens.
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Therapeutic Uses of Neural Stem Cells-Progenitors
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Neural stem cells-progenitors can be used in two different but
complementary ways to treat degenerative diseases. Although these
approaches have not yet been used in ocular diseases, studies in a
number of animal models of neurodegeneration suggest that they may be
helpful in treating degenerative changes in the retina. In addition, in
vitro models of retinal differentiation consisting of ocular neural
stem cells-progenitors, in combination with DNA microarrays, may
provide a powerful means of identifying differentiation and
survival-promoting genes that can serve as potential targets to treat
retinal degeneration (Fig. 3)
.
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Figure 3. The possible uses of neural stem cells in the treatment of ocular
degenerative diseases. Cultured neural stem cells-progenitors can be
transplanted to repopulate degenerating retina
(off-color photoreceptors) by differentiating into
photoreceptors (blue photoreceptors). Intrinsic neural
stem cells-progenitors, such as those in the ciliary body, can be
activated to proliferate, migrate to the site of degeneration, and
differentiate into missing photoreceptors. Cultured neural stem
cells-progenitors can also be genetically engineered to synthesize and
secrete neuroprotective factors and can be used to rescue degenerating
photoreceptors (off-color photoreceptors). In addition
to promoting survival, the genetically modified cells can differentiate
into photoreceptors (blue photoreceptor) and reconstruct
the degenerating retina. The cultured neural stem cells-progenitors
from ocular tissues offer a model of retinal development in vitro.
These cells can be used to screen drugs and neuroprotective factors
that promote survival of retinal cells and can also be used to identify
differentiation and survival genes, by using DNA microarray technology.
Bent arrows, secretion of neuroprotective
factors.
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Cell-Replacement Therapy
Cell-replacement therapy exploits the plasticity of stem
cells-progenitors to replace cells and repair tissues damaged by
disease or injury. There are two approaches to cell replacement
therapy: replacement of damaged cells with cultured stem
cells-progenitors and regeneration or replacement of damaged cells with
endogenous stem cells-progenitors.
The concept that neural stem cells-progenitors can be used to
repopulate damaged brain areas is supported by the remarkable survival
and differentiation potential of these cells when used in heterotopic
transplantation. For example, hippocampal neural stem cells-progenitors
transplanted in the rostral migratory zone not only survive but also
migrate to the olfactory bulb where they differentiate into
site-specific neurons.19
These properties of neural stem
cells-progenitors may be useful for brain repair, based on early
evidence emerging from transplantation studies performed in animal
models of neurodegeneration. For example, transplanted neural
progenitors have been shown to substitute efficiently for dysfunctional
oligodendrocytes by myelinating axons in animal models of myelin
dysfunction.20
21
Similarly, it has been demonstrated that
a subset of neural progenitors differentiate into cells with
dopaminergic properties and cause modest behavioral recovery when
grafted into the striatum of an animal model of Parkinson’s
disease.22
Similar cell replacement therapy may work to reverse photoreceptor
degeneration in ocular diseases if at least two prerequisites are met.
First, the transplanted neural stem cells-progenitors must
differentiate into photoreceptors. Second, the differentiated cells
must establish contact with the second-order neurons. The first
positive evidence of the viability of this approach was reported by
Takahashi et al.23
and Young et al.,24
who
observed that adult hippocampal stem cells-progenitors, when
transplanted in the vitreous of neonatal or adult eyes, survive and
incorporate into the laminar structure of the host retina. Results in a
more recent study25
have suggested that some of the
incorporated adult hippocampal stem cells-progenitors can establish
synaptic contact with the host’s retinal cells. However, in each of
these studies, despite the transplanted cells’ incorporation within
the host’s retina and their morphologic similarities to various
retinal cell types, they failed to express any retina-specific markers.
At least, two explanations are available for this failure. First,
hippocampal neural stem cells may be intrinsically different from
retinal stem cells and may not have the plasticity to differentiate
into retina-specific neurons. This intrinsic difference between
region-specific neural stem cells is probably due to pattern formation
in the developing nervous system.2
Alternatively,
hippocampal stem cells are plastic, but the host retina may not have
the necessary cues to induce their differentiation into retinal
neurons.
A more promising approach is to use ocular stem cells-progenitors that
are known to have the capacity to generate retinal neurons. Neural stem
cells-progenitors isolated from either embryonic retina or the adult
ciliary body possess retina-specific properties and can differentiate
preferentially into cells expressing photoreceptor-specific markers
when cocultured with neonatal retinal cells.9
12
As
expected, when cultured retinal stem cells-progenitors were
transplanted into the subretinal space of normal rat, the grafted cells
not only survived but expressed photoreceptor-specific markers
suggesting their differentiation into cells of photoreceptor
lineage26
(Fig. 4)
. These findings suggest that these cells may be able to replace
degenerating photoreceptors in animal models of ocular degenerative
diseases. However, this approach also has limitations. Although the
expression of photoreceptor-specific markers by the grafted cells is
encouraging, these cells do not show migration and integration into
host retina comparable to that observed in the hippocampal stem
cells-progenitors. Therefore, conditions must be defined that promote
both the structural and functional integration of retinal stem
cells-progenitors within the retinal circuitry. One of the likely cues
that mobilizes the transplanted cells to migrate and integrate into
host tissue is injury. For example, the widespread migration and
incorporation of adult hippocampal neural stem cells-progenitors was
observed only in the adult retina that were either
diseased24
or traumatized.25
This premise
therefore suggests that degenerating retina may offer a more conducive
environment for differentiation as well as efficient integration of
transplanted retinal stem cells-progenitors.27
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Figure 4. Differentiation of cultured retinal stem cells-progenitors in the
subretinal space. Retinal stem cells-progenitors isolated from
embryonic retina were cultured for a week in the presence of
EGF. Proliferating cells were stained with vital dye, CFDA, and
transplanted into the subretinal space of PN10 rats. Two weeks after
transplantation grafted cells (A, B) were found to express
photoreceptor-specific markers, opsin (C).
(D) Merged images. Arrows, grafted cells; RPE,
retinal pigment epithelium; OS, outer segment; ONL, outer nuclear
layer.
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The identification of stem cells in the adult brain, spinal cord, and
eye has opened tantalizing possibilities of regeneration by mobilizing
endogenous stem cell populations to respond to disease and injury.
Regeneration in response to lesion has been studied in the retina of
adult goldfish. It has been observed that cone photoreceptors ablated
by argon laser can be selectively regenerated from a pool of
proliferating progenitors resident in the retina.28
The
identification of a quiescent population of neural stem
cells-progenitors in the adult ciliary body also opens an interesting
possibility that these cells can be mobilized in vivo and recruited to
replace degenerated retinal cells. The concept of healing the brain or
eye from within was lent further credence by an elegant
experiment29
in which a subset of pyramidal neurons in rat
cortex was damaged by chromophore-induced apoptosis. These cells
project to the thalamus and form the circuitry involved in cortical
function. Neural stem cells-progenitors resident either in the cortex
or in the subventricular zone were activated in response to the lesion
and were recruited to replace some of the degenerated pyramidal
neurons. In addition, the newly differentiated pyramidal neurons
extended processes to the thalamus, suggesting that these cells
partially restored the damaged circuitry. Evidence suggests that neural
stem cells-progenitors may not be the only source of neural
regeneration. Cells of glial lineage may also participate in the
regeneration process in response to disease or injury by providing an
alternative source of neural progenitors. This notion is supported by
observations that glial precursors can be reprogrammed to become
multipotential neural progenitors18
and that neural
regeneration in injured adult goldfish28
and postnatal
chicken retina30
may be supported by Müller glia.
Ex Vivo Gene Therapy
The ability to maintain and manipulate stem cells-progenitors in
culture suggests that genetically engineered neural stem cells can be
used to target gene products to sites of degeneration. These gene
products can include survival-promoting factors to rescue degenerating
neurons, factors that can act in an autocrine manner to promote
survival and differentiation of grafted cells into site-specific
neurons or to deliver neurotransmitter(s) to permit functional
recovery. Proof of principle of ex vivo gene therapy has been provided
by a study in which intrastitial transplantation of stem cells
genetically modified to secrete nerve growth factor (NGF) provided
protection to a vulnerable population of striatal neurons from
excitotoxic degeneration in an animal model of Huntington’s
disease.31
Similarly, ex vivo gene therapy could be used effectively as a
neuroprotective strategy to prevent retinal cell loss in RP, AMD, and
glaucoma and in diseases that cause retinal detachment. This notion is
supported by observations emerging from several laboratories that
growth factors and neurotrophins such as FGF2,32
NGF,33
ciliary neurotrophic factor (CNTF),34
and brain derived neurotrophic factor (BDNF)35
can
significantly slow the process of cell death in animal models of
retinal degeneration. Because growth factors and neurotrophins usually
have short half-lives, sustained delivery of these factors is needed to
promote long-term rescue from cell death in the retina. Ex vivo gene
therapy using neural stem cells-progenitors engineered to synthesize a
growth factor or a combination of growth factors can not only ensure
sustained delivery of neuroprotectants, but may also reconstruct
damaged retina. However, caution is warranted in the use of this
approach with some growth factors. For example, the oncogenic potential
of FGF2 should be a concern if this growth factor is chosen for ex vivo
gene therapy to promote photoreceptor survival.
In addition to their usefulness in rescuing neurodegenerative changes,
it is likely that neural stem cells-progenitors can offer an approach
to treatment of neoplastic changes in the eye, such as retinoblastoma.
The concept of stem cell therapy to treat neoplastic changes in the
brain is supported by a recent study that showed that transplantation
of cortical progenitors, engineered to secrete interleukin-4, can cause
a progressive reduction of rat brain glioblastoma and promote the
survival of tumor-bearing animals.36
Barriers to the Therapeutic Use of Stem Cells-Progenitors
Although the studies described herein support the therapeutic
application of neural stem cells-progenitors, there are outstanding
issues and concerns that currently constitute barriers to the practical
and successful use of neural stem cells in the clinical realm. First is
the issue of availability of neural stem cells-progenitors in
sufficient quantity for therapeutic purposes. This is a significant
roadblock because, contrary to expectations, neural stem
cells-progenitors have not been cultured in "unlimited" quantities.
Identification of conditions that will allow the generation of
multipotential progenitors over multiple passages would solve this
problem. The use of embryonic stem (ES) cells is another potential
solution, because it is generally believed that embryonic cells have a
greater proliferative potential than adult stem cells. However, the use
of ES cells requires caution, because they tend to differentiate
spontaneously and in some instances have displayed oncogenic potential.
Second, the issue of the effects of extended exposure to mitogens is
important from the viewpoint of maintaining the inherent
characteristics of primitive stem cells-progenitors from one generation
to the next. It is important to know whether cells that are exposed to
high concentrations of mitogens over several generations undergo
genetic changes and therefore acquire potentials different from their
parents. This requires the identification of a panel of markers of
neural stem cells-progenitors so that the primitive characteristics of
these cells can be followed over several generations. Third, knowledge
of the fidelity, efficiency, and consistency of the differentiation of
grafted stem cells-progenitors into tissue-specific cell types is
critical in predicting the functional outcome of cell replacement
therapy. Although, there is evidence that transplanted cells can
differentiate into site-specific cells,1
20
26
27
details
regarding the proportions of grafted cells that remain undifferentiated
or that differentiate into some other cell types remain incomplete.
This information is particularly critical for cell replacement therapy
in highly ordered and laminated sensory structures such as the retina,
where the presence of undesirable glia or neurons may exacerbate rather
than solve problems. Lastly, the issue of the therapeutic potential of
stem cells-progenitors derived from embryonic versus adult brain, is
not only important from the viewpoint of stem cell biology, but also
because of ethical concerns associated with the origin and use of fetal
tissues. Although adult neural stem cells-progenitors have shown
significant plasticity in the variety of cell types they can
generate,1
whether they have potential similar to
embryonic neural stem cells-progenitors in their utility as
transplantation reagents is unknown.
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Summary
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Emerging evidence suggests that multipotential stem
cells-progenitors, isolated from the brain, spinal cord, and eye hold
considerable promise to elucidate fundamental issues of brain
development and treat neurodegenerative diseases. Therapeutic
applications of neural stem cells have special appeal for the treatment
of otherwise intractable degenerative diseases of the eye. However, the
field of neural stem cell research is relatively nascent. Many issues
related to the therapeutic use of neural stem cells-progenitors have
not yet been addressed. Strategies must be developed to identify and
enrich neural stem cells-progenitors in a practical way. In addition,
identification of optimal conditions for their maintenance, storage and
differentiation into desirable cell types for cell-replacement therapy
is critical. Therefore, the true potential of these cells in brain
repair can only be realized with more information about mechanisms that
regulate their proliferation and differentiation and by development of
techniques that allow their prospective identification and enrichment.
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Acknowledgements
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The author thanks Pamela Raymond, Colin Barnstable, Carl Cameras,
Angie Rizzino, Anne Kessinger, and Graham Sharp for critical reading of
the manuscript and for insights and suggestions; Dave Chacko and Wally
Thoreson for constructive criticisms; and Justin Madson for
graphics.
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Footnotes
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Supported by the Foundation Fighting Blindness, Research to Prevent
Blindness, and the Nebraska Research Initiative.
Submitted for publication March 28, 2001; revised June 14, 2001;
accepted July 18, 2001.
Commercial relationships policy: N.
Corresponding author: Iqbal Ahmad, Department of Ophthalmology,
University of Nebraska Medical Center, 98-7691 Nebraska Medical Center,
Omaha, NE 68198-7691. iahmad{at}unmc.edu
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Introduction
Defining Neural Progenitors as...
