THE ANATOMICAL RECORD 297:137–160 (2014)
Retinal Stem Cells and Regeneration of
Vision System
1
HENRY K. YIP1,2,3*
Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong,
Pokfulam, Hong Kong Special Adminstrative Region, People’s Republic of China
2
Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of
Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Adminstrative
Region, People’s Republic of China
3
State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong,
Pokfulam, Hong Kong Special Adminstrative Region, People’s Republic of China
ABSTRACT
The vertebrate retina is a well-characterized model for studying neurogenesis. Retinal neurons and glia are generated in a conserved order from
a pool of mutlipotent progenitor cells. During retinal development, retinal
stem/progenitor cells (RPC) change their competency over time under the
influence of intrinsic (such as transcriptional factors) and extrinsic factors
(such as growth factors). In this review, we summarize the roles of these
factors, together with the understanding of the signaling pathways that
regulate eye development. The information about the interactions between
intrinsic and extrinsic factors for retinal cell fate specification is useful to
regenerate specific retinal neurons from RPCs. Recent studies have identified RPCs in the retina, which may have important implications in health
and disease. Despite the recent advances in stem cell biology, our understanding of many aspects of RPCs in the eye remains limited. PRCs are
present in the developing eye of all vertebrates and remain active in lower
vertebrates throughout life. In mammals, however, PRCs are quiescent
and exhibit very little activity and thus have low capacity for retinal regeneration. A number of different cellular sources of RPCs have been identified in the vertebrate retina. These include PRCs at the retinal margin,
pigmented cells in the ciliary body, iris, and retinal pigment epithelium,
and M€
uller cells within the retina. Because PRCs can be isolated and
expanded from immature and mature eyes, it is possible now to study these
cells in culture and after transplantation in the degenerated retinal tissue.
We also examine current knowledge of intrinsic RPCs, and human embryonic stems and induced pluripotent stem cells as potential sources for cell
transplant therapy to regenerate the diseased retina. Anat Rec, 297:137–
C 2013 Wiley Periodicals, Inc.
160, 2014. V
Key words: tissue engineering; stem cell; regeneration
Grant sponsor: The University of Hong Kong Seed Funding
Program for Basic Research; Grant numbers: 200611159203 and
201011159065; Grant sponsor: The University of Hong Kong
Small Project Funding; Grant number: 200807170103; Grant
sponsor: General Research Fund, Regional Grant Council of
Hong Kong; Grant number: 10208603.
*Correspondence to: Henry K. Yip, Department of Anatomy,
Li Ka Shing Faculty of Medicine, The University of Hong Kong,
C 2013 WILEY PERIODICALS, INC.
V
21 Sassoon Road, Pokfulam, Hong Kong SAR, China. Fax:
1852-28170857. E-mail: hkfyip@hku.hk
Received 13 September 2013; Accepted 13 September 2013.
DOI 10.1002/ar.22800
Published online 2 December 2013 in Wiley Online Library
(wileyonlinelibrary.com).
138
YIP
During development, the nervous system arises from
the neuroepithelium of the neural plate located along
the dorsal midline of the embryo and then folds into the
neural tube before undergoing various patterning events
and specification. Most cells in the emerging nervous
system during early embryonic development are multipotent and they can give rise to both neurons and glia.
The population and the neurogenic potential of neural
stem/progenitor cells (NPCs) decrease progressively with
age in higher vertebrates, for example, avian and mammal, so that NPCs become restricted to two neurogenic
areas in the adult mammalian brain: the subgranular
zone (SGZ) of the dentate gyrus in the hippocampus,
and subventricular zone (SVZ) lining the lateral ventricles (Miller and Gauthier-Fisher, 2009; Weinandy
et al., 2011) as well as in non-neurogenic regions such as
cerebral cortex (Gould et al., 1999; Magavi et al., 2000),
spinal cord (Xiao et al., 2010; Sabelstrom et al., 2013)
and in various structures of the eye (Ffrench-Constant
and Raff, 1986; Ahmad et al., 2000; Tropepe et al., 2000;
Haruta et al., 2001). NSCs in the SGZ generate granule
neurons and NSCs in the SVZ give rise to neurons and
glia in the developing telencephalon and to ensure a lifelong contribution of neural progenitors that migrate long
distance along the rostral migratory stream to reach
their final destination in the olfactory bulb, a major area
of adult neurogenesis (Costa et al., 2010). The SVZ in
the adult brain has the highest neurogenic rate, from
which NSCs are first isolated, and characterized (Reynolds and Weiss, 1992). These cells resemble a radial glia
during neurogenesis, after that they acquire an astroglial stem cell or ependymal identity (Mori et al., 2005).
This glial identity of NSCs is important since it has
been suggested that adult glial cells such as NG2 glia or
even astrocytes, may acquire stem cell properties of self
renew and multipotency following brain injury to participate in local tissue repair (Robel et al., 2011; Bonaguidi
et al., 2012). NPCs in the non-neurogenic regions remain
dormant and quiescent, but can be activated by exogenous factors, for example, after injury (Palmer et al.,
1995, 1999; Weiss et al., 1996; Magavi et al., 2000; Kernie et al., 2001; Ming and Song, 2005).
The regenerative potential of the vertebrate retinal
has been observed in a variety of species during either
their development or for some even during their adult
life. In mammals, the neuroretina and the retinal pigmented epithelium (RPE) show no evidence of regeneration in the adult as observed in fish and amphibian.
Although the eye continues to grow for some time after
birth in mammals and birds, this is largely due to the
stretching of the retina associated with the growth of
the sclera rather than addition of new cells to the retina
(Perron and Harris, 2000). Fish, amphibian, and birds
are among those with the ability to regenerate during
adulthood (Perron et al., 1998; Reh and Levine, 1998;
Fischer and Reh, 2000; Perron and Harris, 2000; Amato
et al., 2004; Klassen et al., 2004a,b; Moshiri et al. 2004;
Fischer and Omar, 2005). It has been well documented
that in the cold-blooded vertebrates, like fish and
amphibian, the retina continues to grow throughout
their lifetime by addition of new neurons at the peripheral rim of the retina at the ciliary margin (Reh and
Levine, 1998; Otteson and Hitchcock, 2003). In this
review, we provide an overview of retinal progenitor cells
(RPCs) identified in different regions of the vertebrate
eye, in particular, in the epithelia of the retina, ciliary
body, and iris, and the retinal radial glial cells. Before
we could use them for the possible treatment of retinal
diseases, it is important to understand their basic characteristic features. In addition, we discuss the intrinsic
properties of the RPCs and the key extrinsic signaling
molecules that regulate RPC behavior in proliferation
and differentiation. An integrating knowledge of the
molecular and genetic processes underlying the development of the retina is essential for understanding not
only normal developmental mechanisms, but also in
future therapeutic strategies aiming at restoring vision
loss. Recent advances in the field of stem cell research
have raised the feasibility of using stem cell-based therapies as a potential avenue for treatment of retinal diseases. Finally, this review will also focus on this
research in identifying suitable sources of pluripotent
stem/progenitor cells for cell replacement or transplantation therapies, including both human embryonic stem
cells (hESCs) and human induced pluripotent stem cells
(hiPSCs).
RPC IN THE DEVELOPING BRAIN
Intrinsic Properties of the RPCs in Retinal Cell
Specification
The retina of the vertebrate arises from an evagination of the diencepalon that constitutes the anterior neural tube during the early neurulation stage of the
embryo development. The continued evagination of the
optic primordia results in the formation of the optic
vesicles. The overlying surface ectoderm and the optic
vesicles undergo a coordinated invagination resulting in
the formation of the lens vesicle and the bilayered optic
cup. The inner layer of the optic cup, closest to the lens
vesicle, eventually forms the multilayered neural retina,
while the outer layer remains as a single epithelial layer
and gives arises to the retinal pigment epithelium
(RPE). The periphery of the optic cup, where the inner
layer and outer layer meet, become the ciliary epithelium (CE) and the iris (Beebe, 1986). The pigmented
part of the CE and the iris arises from the outer layer of
the optic cup, and it is continuous with the pigment epithelium of the retina. The nonpigment part of the CE
represents the extension of the neural layer of the retina, in which muscle and connective tissue developed.
Before the formation of eye field, expression of the
orthodenticle homolog transcription factor Otx2 is found
at the anterior end of the neural tube and later in the
optic vesicle and optic cup. Otx2 is essential to “initiate”
the anterior neural plate cells to form the embryonic eye
fields (Chuang and Raymond, 2002). The single eye field
across the midline region is separated into two distinct
lateral eye primodia, by a number of soluble factors such
as sonic hedgehog, Shh, (MacDonald et al., 1995; Li
et al., 1997) and bone morphogenetic proteins (BMPs) 4
and 5 (Golden et al., 1999) released by the underlying
prechordal mesoderm. The cells of the developing retinal
epithelium are analogous to the neural progenitors from
other neurogenic regions of the CNS and are mutlipotent
retinal stem/progenitors cells (RPCs). These cells express
a unique set of transcription factors called eye field transcription factors (EFTFS), which set them molecularly
apart from the surrounding cells at the anterior edge of
RSC AND REGENERATION OF VISION SYSTEM
the neural plate. The two earliest EFTFS expressed in
the eye field are both paired-like homeodomain genes,
Rax/Rx and Pax-6 (Hill and Hanson, 1992; Furukawa
et al., 1997a; Mathers et al., 1997) (Fig. 1). Homozygous
mutation of both Rax/Rx and Pax-6 result in anophthamia (no eye formation) observed across species in Xenopus, mice and rats (Matsuo et al., 1993; Grindley et al.,
1995; Mathers et al., 1997; Andreazzoli et al., 2003). The
Rx-deficient mice also have a reduction in the expression
of other EFTFS include Pax-6 and Six3, suggesting that
Rx may have an induction role on these genes. However,
Pax-6 knockout mice have normal Rx expression, indicating that Pax-6 is downstream of Rx (Zhang et al.,
2000). Overexpression of Rx and Pax-6 in Xenopus
results in the formation of ectopic retinal tissue (Mathers et al., 1997; Zuber and Harris, 2006). Pax-6 overexpression also induces ectopic expression of Rx,
suggesting that Pax-6 also has an induction role on Rx.
Thus, these loss- and gain-of-function studies support
the idea that each of these transcription factors regulates the activity of each other or a number of other
EFTFS genes such as ET, Six3, Lhx2, T11, and Optx2
(Six6) (Zuber et al., 2003). It would appear that all the
EFTFS work together at the beginning of the developmental network of transcription factors to establishing
the initial commitment of anterior neural plate cells to a
retinal fate (Fig. 1).
Cell lineage analysis of the progeny of these actively
dividing RPCs shows that all the different types of retinal cells, including all six types of retinal neurons and
together with the radial M€
uller glial cells, arise from a
common pool of multipotent RPCs (Turner and Cepko,
1987; Holt et al., 1988; Wetts and Fraser, 1988; Turner
et al., 1990; Fekete et al., 1994; Cepko et al., 1996).
Birthdating experiments have demonstrated that retinal
cell types are generated by the RPCs in a relatively fixed
chronological order that is evolutionary conserved,
although the time scale of retinogenesis could vary
greatly between species (review see Altshuler et al.,
1991). These studies have determined that RGCs, cone
photoreceptors, amacrine cells, and horizontal cells are
generated during the first wave of neurogenesis in the
retina, followed, in a second wave, by rod photoreceptors, bipolar cells, and M€
uller glial cells, with considerable overlap in the appearance among these different
cell types (Holt et al., 1988; Wetts and Fraser, 1988;
Prada et al., 1991; Hu and Easter, 1999; Galli-Resta,
2002; Marquardt and Gruss, 2002; Das et al., 2003) (Fig.
1). Once various cell types are generated, they migrate
into the developing retina forming three cellular layers:
(i) the outer nuclear layer (ONL), which contains photoreceptors (rod and cone); (ii) the inner nuclear layer
(INL), which contains interneurons (horizontal, bipolar,
and amacrine cells) and M€
uller glial cells; and the inner
most layer (iii) the ganglion cell layer (GCL), which contains projecting neurons retinal ganglion cells (RGCs).
Retinogenesis in vertebrates begins in central retina and
spread toward the periphery, such that cells in the
periphery retina are the last to born and differentiate,
while those in central retina are older (Perron and Harris, 2000; Amato et al., 2004).
The vertebrate retina consists of seven major classes
of cells, and several of which can be further divided into
multiple distinct subtypes (Harris, 1997; Masland,
2001). It has been shown that retinal cell fate specifica-
139
tion and differentiation are controlled by temporally
varying intrinsic properties of RPCs and extrinsic signals from the environment (Cepko 1999). The basic
helix-loop-helix (bHLH) transcription factors are likely
candidates as intrinsic factors in regulating retinal cell
fate (Cepko, 1999) (Fig. 1). In Drosophila, proneural
genes of atonal (ato) and achaete-scute complex (AS-C)
are required for the selection of sense organ precursors
(Jan and Jan, 1993). Atonal is also the proneural gene
for photoreceptor neurons in the developing Drosophila
retina (Jarman et al., 1995; White and Jarman, 2000).
Many neurogenic bHLH genes such as the AS-C homolog Mash1 and ato homologs Math3, Ngn2, Math5, and
NeuroD are expressed by the RPCs in the developing
vertebrate retina and bias RPCs toward retinal cell fates
(Cepko et al., 1996; Brown et al., 1998). Loss- and gainof-function studies indicate that retinal cell fate determination is regulated by multiple bHLH transcription factors. Hes1 and Hes5 are chief regulators of proliferation
process during early retinal development to ensure a
continuous supply of RPCs for the successive production
of differentiated retinal cells during retinogenesis. In
Hes1 mutant murine embryos, cell proliferation in the
retina is severely impaired. In addition, precocious neurogenesis and disruption of laminar structures are
observed (Ishibashi et al., 1994; Takatsuka et al., 2004;
Lee et al., 2005). Double Hes1/Hes5 mutant animals
have more eye formation abnormalities, including
absence of optic vesicles (Hatakeyama et al., 2001), suggesting that Hes1 and Hes5 work cooperatively to maintain RPCs in an undifferentiated state. Furthermore,
Hes1 and Hes5 are downstream targets of Notch signaling (Ohtsuka et al., 1999). Notch signaling plays a critical role in maintaining stem cells in an undifferentiated
state (Gaiano et al., 2000) without affecting the competency of the RPCs over the course of development (Jadhav et al., 2006). In Xenopus, targeted expression of
Xath5, a Xenopus ortholog of Math5, promotes ganglion
cell differentiation (Kanekar et al., 1997). Math5, a
murine ortholog of the atonal, is involved in ganglion
cell specification (Brown et al., 2001; Wang et al., 2001)
through the activation of downstream Brn3b, a POU
domain transcription factor (Liu et al., 2001). In Math5
null mice, there is a significant decrease of ganglion cells
accompanied by an increase in amacrine cells and cone
photoreceptors (Brown et al., 2001), indicating that
Math5, in addition to direct cell fate specifications, also
involved in controlling the number of retinal cells and
may regulate successive stages of retinal cell differentiation (Marquardt and Gruss, 2002). In contrast, Math3
and NeuroD double-mutant retina displays selective loss
of amacrine cells, while ganglion cells are significantly
increased in number. In addition, Math5 expression is
upregulated in the absence of Math3 and NeuroD, suggesting that Math5 and Math3/NeuroD are acting antagonistically in regulating ganglion and amacrine cell fate
specification (Inoue et al., 2002). Mash1 and Math3
(Tomita et al., 2000), and the homeobox gene Chx10
(Hatakeyama et al., 2001) are required for bipolar cell
specification. In either Mash1- or Math3-mutant retinas,
no apparent defect in bipolar cell fate specification is
observed (Tomita et al., 1996). However, in Mash1 and
Math3 double-mutant, bipolar cells disappear and the
RPCs adopted the M€
uller glial cell fate (Tomita et al.,
2000). Taken together, these findings indicate that
140
YIP
retinal cell fate depends on the expression of multiple
bHLH genes and the downregulation of these genes
could be one of the mechanisms to initiate glial cell
fate determination. In addition, these studies also
revealed the intricate cross-regulation among bHLH
genes. Furthermore, a combination of the bHLH and
the homeobox genes are required for the specification
of bipolar cells. It is suggested that bHLH genes determine the neuronal cell fate, while the homebox gene
confer the positional identity to the RPCs in the INL
(Hatakeyama et al., 2001). The homeobox gene Crx and
Otx2 direct RPCs toward a photoreceptor cell fate.
Otx2 activates the replication of Crx gene and deletion
of Otx2 results in the conversion of photoreceptor cells
to amacrine-like cells (Chen et al., 1997; Furukawa
et al., 1997b; Nishida et al., 2003). Similarly, Crx-null
mutant retinas exhibit defects in the generation of photoreceptors (Furukawa et al., 1999). Recent studies
have shown that Nrl, a basic leucine zipper transcription factor, is required for the regulation of cell fate
determination between rod and cone photoreceptors
through the activation of an orphan nuclear receptor
Nr2e3 (Cheng et al., 2006). Deletion of Nrl resulted in
the loss of rod photoreceptors and Nr2e3 expression in
the mutant retinas (Mears et al., 2001). Nr2e3 was
shown to activate rod-specific genes, but works in concert with CrX, represses cone-specific genes (Cheng
et al., 2006; Chen et al., 2005; Peng et al., 2005). Horizontal cell specification is regulated by the core group
of Foxn4, Ptf1a and Prox1. In the absence of any of
these three genes, horizontal cell genesis is impaired
(Dyer et al., 2003; Li et al., 2004; Fujitani et al., 2006).
Hes1 and Hes5, which is a negative regulators of neurogenic bHLH genes such as Mash1 and Math3 (Akazawa et al., 1992; Ohtsuka et al., 1999), induce M€
uller
glial cell fate (Furukawa et al., 2000; Hojo et al., 2000).
In Hes5-null mice, there is a significant decrease in the
number of M€
uller glial cells due to insufficient expansion of RPCs that could differentiate into M€
uller glial
cells (Hojo et al., 2000; Deneen et al., 2006). Hes1 or
Hes5 misexpression induces M€
uller glial cell generation
in the postnatal retina. Notch (Dorsky et al., 1995;
Ohnuma et al., 1999; Furukawa et al., 2000) and the
homeobox gene rax (Furukawa et al., 2000) are also
reported to promote the formation of M€
uller glial. Rax
has been shown to promote proliferation of RPCs (Furukawa et al., 1997a,b; Mathers et al., 1997). Thus,
Hes1 and Hes5 as well as Notch and Rax have dual
functions in maintaining RPCs and promoting gliogenesis during retinal development. Interestingly, M€
uller
glial cells share many morphological characteristics of
neural/glial progenitors in many other regions of the
CNS. They have a simple bipolar morphology, with
extending processes contacting both the ventricular and
vitreal surfaces of the neuroepithelium. Furthermore,
these cells are competent to generate neurons and glia
(Fischer and Reh, 2001a,b; Dyer et al., 2003). It is conceivable that RPCs retain Hes1 and Hes5 expression in
the late stage of retinogenesis adopt the M€
uller glial
cell fate. While our understanding of the molecular
mechanisms of retinal cell fate specification has
advance dramatically in recent year, we probably just
have the crudest outline of the whole process describing
how the orchestrated expression of these intrinsic factors act to generate a functional retina. Nevertheless,
such knowledge is fundamental to an understanding
the role of RPCs in regenerating the retina.
Extrinsic Signaling Molecules in the Regulation
of RPC Proliferation and Differentiation
One of the remaining challenges is to elucidate the
mechanisms by which extrinsic environmental cues
impact on the intrinsic cell determinants in RPC fate
determination. Two important common events emerge
from the studies of RPC specification during retinal
development: (1) seven major types of retinal cells are
generated is a sequential and yet overlapping order that
is conserved among many species (Altshuler et al.,
1991); (2) vertebrate RPCs are multipotent at different
developmental stages and the progeny derived from individual RPC can assume a variety of cell fate (Turner
and Cepko, 1987; Holt et al., 1988; Wetts and Fraser,
1988; Turner et al., 1990; Fekete et al., 1994). The multipotency of the RPCs throughout retinogenesis indicates
that the local environment plays critical roles in cell fate
determinations. There are abundant evidence to support
that RPCs are not homogenous and do not stay static
during development (Lillien, 1998). Heterotopic transplantation studies have demonstrated that early and
late RPCs have different differentiation capacities when
placed in similar environment (Watanabe and Raff,
1990; Morrow et al., 1998; Belliveau and Cepko, 1999;
Belliveau et al., 2000) and they have different gene
expression profiles (Jasoni and Reh, 1996; Yang and
Cepko, 1996; Alexiades and Cepko, 1997; Perron et al.,
1998; Matter-Sadzinski et al., 2001). Thus, the intrinsic
determinants that define the properties of RPCs, including surface receptors, intracellular signaling pathways
and nuclear transcription factors, undergo adaptive
changes with the progression of developmental events in
the retina. It was proposed the RPCs advance through a
series of “competent state” during development, and
each “competent state” support specification of one or
more cell fates. The “competent state” is defined as the
intrinsic cell properties that determine the responsiveness of the RPCs to extrinsic cues and the potential of
the RPCs. Hence, cell fate specification is determined by
both the intrinsic properties of RPCs and the extrinsic
cues from the environment from the developing retina
(Cepko et al., 1996; Livesey and Cepko, 2001).
The development of the eye is known to involve many
different interactions and signaling events between the
intrinsic factors and extrinsic environment. Extrinsic
molecules help to specify and ensure a balanced production of the types of retinal cells, establishing the laminar
structures, defining dorsoventral and nasotemporal differences and establishing topographical connections
between the RGCs and the visual centers of the brain
(Fig. 1).
Hedgehog signaling pathways. Multiple signaling pathways have been demonstrated to regulate the
development of vertebrate eye. The family of vertebrate
hedgehog (Hh) proteins is important secreted signaling
molecules that have multiple roles in a variety of developmental processes including pattern formation, tissue
specification, neurogenesis, cell survival, and cell proliferation (Huh et al., 1999; Ingham and McMahon, 2001;
Zhang and Yang, 2001; Perron et al., 2003). Hh
RSC AND REGENERATION OF VISION SYSTEM
molecules are expressed in dynamic pattern by the anterior ventral midline tissues, RPE, and specific types of
postmitotic retinal neurons during vertebrate eye morphogenesis and retinogenesis. Hedgehog mediates signaling through two transmembrane receptors Patched
(Ptc) and Smoothened (Smo), and activated Smo is translocated to the nucleus and affects the transcription of
target genes (Murone et al., 1999). The cellular
responses to Hh signals are determined by the local Hh
concentration gradient and the intrinsic properties of
the cells within the Hh gradient. Studies in fish, Xenopus, chick, and murine have demonstrated that expression of Shh, a member of Hh family, in the ventral
midline of the CNS plays a critical role in vertebrate eye
pattern formation. Persistent Shh signals are required
for the temporal transition from the optic vesicle to optic
cup and after eye cup formation (Huh et al., 1999; Zhang
and Yang, 2001; Perron et al., 2003). Shh expression in
the anterior ventral midline of the neural plate, are
involved in the formation of separate eye fields. Mutations in the Shh gene in the murine results in a single
centrally positioned primitive eye vesicle (Chiang et al.,
1996). Similarly, disruption of Shh gene leads to the formation of cyclopic eye in human (Muenke and Beachy,
2000). Distinct Shh signal thresholds emanating along
the ventral midline control the expression of various
transcription factors and contribute to the pattern formation of the eye primordium along the proximodistal
axis. Shh signals activates the paired domain genes
Pax2 (Nornes et al., 1990) and Vax (Bertuzzi et al., 1999;
Hallonet et al., 1999; Schulte et al., 1999; Mui et al.,
2002; Take-uchi et al., 2003) in portions of the optic primordium proximal to the midline and specify the formation of optic stalk and ventral retinal fates, whereas
Pax6 (Walther and Gruss, 1991) and Rx/Rax (Furukawa
et al., 1997a,b; Mathers et al., 1997) expressed in the
primodium further distal to the midline that forms the
optic cup. In addition, Shh also regulates expression of
bHLH zipper gene MITF (Mochii et al., 1998) and the
homeodomain gene Otx2 (Martinez-Morales et al., 2001)
in the RPE. Furthermore, Shh signals are involved in
the dorsoventral compartmentation of the vertebrate eye
primodium (Chiang et al., 1996; Huh et al., 1999; Zhang
and Yang, 2001). In zebrafish, Shh secreted by the differentiated RGCs is necessary for the propagation of the
neurogenic wave from the center of the retina towards
the
undifferentiated
periphery
(Neumann
and
Nuesslein-Volhard, 2000). Beside initiating the entry of
RPCs from a proliferative state to a differentiated state
in the retina primordium, Shh produced by the differentiated RGCs have also been demonstrated to suppress
further production of RGCs from the early RPC pool in
the chick retina (Zhang and Yang, 2001). Furthermore,
Shh molecule suppresses both the number and the
length of neurites form retinal explants in the chick
(Trousse et al., 2001b). Interestingly, conditional deletion
of Shh in murine RGCs shows a loss of astrocyte precursors in the optic disc and defective RGC axon guidance
(Trousse et al., 2001b), as well as conversion of the RPCs
in the optic stalk to RPE cells (Dakubo et al., 2003).
Conditional ablation of Shh gene in RGCs also results in
lamination defects as indicated by the disorganized photoreceptor cell layer and the malformation of M€
uller glia
(Wang et al., 2001). In addition, members of the Hh family are also produced by RPE; for example, Indian hedge-
141
hog (Ihh) is expressed in both embryonic and mature rat
RPE (Levine et al., 1997), and Banded hedgehog and
Cephalic hedgehog, homologs to the mammalian Ihh and
desert hedgehog (Dhh), respectively, are found in the
embryonic Xenopus RPE (Perron et al., 2003). In rat and
murine retinal cultures, Shh stimulates RPC proliferation and enhances the generation of later born retinal
cell types (Jansen and Wallace, 1997; Levinie et al.,
1997). In zebrafish, RPE-derived Hh may be implicated
in promoting differentiation of photoreceptor cells (Stenkamp et al., 2000).
Transforming growth factor beta (TGF-b) signaling pathways. Transforming growth factor beta
(TGF-b) constitutes a large super family of pleiotropic
growth factors, participates in the development of the
nervous system, including neural induction, dorsoventral
patterning of the neural tube, cell fate determination
and differentiation, and neuronal survival. TGF-b superfamily members transduce signals through the Type I
(BMPR-1) and Type II (BMPR-II) transmembrane serine/threonine kinase receptors. The signals are transduced from the receptors by Smad transcription factors
to the nucleus to regulate gene transcription (Messague
and Kelly, 1986; Moustakas et al., 2001). Emerging evidence has been accumulating recently suggesting a role
of TGF-b family of members in retingogensis and eye
development. BMPs, members of the TGF-b family, are
essential for the development of nervous system. Several
BMP members are expressed during murine eye development (Dudley and Robertson, 1997; Du et al., 2010).
Gene deletion studies have shown that BMPs are critical
for early morphogenesis of the eye (Dudley et al., 1995;
Luo et al., 1995; Furuta and Hogan, 1998; Wawersik
et al., 1999). In the eye, specific BMPs contribute to multiple aspects of early retinal and lens development.
BMP4 specifies domain-specific gene expression and cell
identity in the dorsal retina and induces the surface
ectoderm overlying the optic cup to form lens tissue
(Furuta and Hogan, 1998; Belecky-Adams and Adler,
2001; Sasagawa et al., 2002; Beebe et al., 2004). Absence
of BMP7 in the surface ectoderm overlying the optic
vesicles in the BMP7 null mice frequently displays an
eyeless phenotype and retarded lens development (Dudley et al., 1995; Jena et al., 1997; Wawersik et al., 1999;
Lang, 2004), probably due to the disruption of interaction between the pre-lens ectoderm and the optic vesicle
during eye morphogenesis (Hyer et al., 2003). These
studies showed that target deletion of murine BMP4 and
BMP7 resulted in failure of lens placode formation, suggesting these molecules are essential in lens induction.
There is also evidence that BMPs and TGF-bs contribute
to the differentiation of lens fiber cells and lens fiber
elongation (Belecky-Adams et al., 2002; Faber et al.,
2002), the formation of ciliary body (Zhao et al.,
2002b,c), the differentiation of ventral optic cup structures (Adler and Belecky-Adams, 2002), programmed
cell death and axon guidance (Dunker et al., 2001;
Sakuta et al., 2001; Trousse et al., 2001a; Liu et al.,
2003; Franke et al., 2006), the formation of corneal epithelium and stroma (Sanford et al., 1997; Saika et al.,
2001) and the participation in the development of pigmented epithelium (Fuhrmann et al., 2000; Idelson
et al., 2009; Hongisto et al., 2012). In addition to the
142
YIP
signaling in ocular tissue specification and retinal pattern formation, TGF-b protein Activin promotes differentiation of RPCs into photoreceptor (Jaffe et al., 1994;
Davis et al., 2000) and BMP7 stimulates chick photoreceptor outer segment formation (Sehgal et al., 2006).
Recently, BMPs has been demonstrated to stimulate
RPCs and neuroblastoma cells to differentiate into neuronal linage whereas astrocyte differentiation was inhibited. In addition, it was shown that the effect BMPs is
mediated through the activation of inhibitor of DNAbinding (Id) target genes by the BMP/Smad signaling
pathway (Du et al., 2010; Du and Yip, 2010, 2011).
The Wnt signaling pathway. The canonical Wnt
signaling pathway is highly conserved among various species and is known to regulate multiple eye development
events, such as the formation of eye field, cell proliferation, differentiation, polarity, and movement during different stages of ocular development and growth. Wnt
proteins belong to a large family of secreted glycoproteins,
bind to the Frizzled (Fz) family of transmembrane receptors and co-receptor of the lipoprotein receptor-related
protein (LRP) and activate the canonical b-catenindependent Wnt (Wnt/b-catenin) pathways or the noncanonical b-catenin-independent Wnt signaling pathways.
The noncanonical Wnt signaling pathways include the
Wnt/planar cell polarity (PCP) and the Wnt/Calcium
pathway. In the Wnt/b-catenin pathway, binding of Wnt
to Fzs leads to the activation of intracellular protein
Disheveled (Dsh), which results in the inhibition of GSK3b. This blocks phosphorylation and degradation of bcatenin resulting in its translocation into the nucleus and
the formation of b-catenin and the TCF/LEF complex that
initiates target gene transcription (Huelsken and Behrens, 2002; Wharton, 2003). In the Wnt/PCP pathway,
Dsh activates Rho/Rac small GTPase and JNK in the subsequent regulation of cytoskeletal organization and gene
expression (Tree et al., 2002; Zallen, 2007; Simons and
Mlodzik, 2008). Activation of Wnt/Calcium pathway leads
to a transient increase in the concentration of intracellular molecules, such as inositol 1,4,5-triphosphate (IP3)
and 1,2 diacylglycerol (DAG). IP3 interacts with the calcium channels on the membrane of endoplasmic reticulum (ER) causing it to release calcium ions. The released
calcium together with the cytosolic expressed calmodulin
activates calcium calmodulin-dependent protein kinase II
(CaMKII). The DAG along with the ER-released calcium
activates Protein kinase C (PKC). Both CaMKII and PKC
then activate nuclear factors NF-AT and other transcription factors like NFjB and CREB (Sheldahl et al., 1999;
K€
uhl et al., 2000; Hogan et al., 2003; De, 2011).
The dynamic expression pattern of various components of the Wnt/Fz signaling at different stages of eye
development suggested that Wnt/Fz signaling is involved
in coordinating numerous critical processes during ocular tissue development. A graded Wnt signaling in the
anterior neural plate allows specification of forebrain
subdomains (Yamaguchi, 2001; Nordstrom et al., 2002;
Satoh et al., 2004). Inhibitory molecules, such as EFTFs
(Six3), secreted frizzled related protein 1 (SFRP1) and
transcription factor-3 (TCF-3), expressed in the anterior
neural plate allow the development of the forebrain,
including the eye field, by suppressing the Wnt/b-catenin pathway (Kim et al., 2000; Houart et al., 2002;
Lagutin et al., 2003; Esteve et al., 2004). Several studies
provided evidence to support the role of noncanonical
Wnt signaling in the formation and the maintenance of
eye field, mediated by the morphogenetic movements of
RPCs into the eye field (Cavodeassi et al., 2005; Lee
et al., 2006) and the activation of eye field-specific genes
Pax6 and Rx (Rasmussen et al., 2001; Maurus et al.,
2005). In the chick and murine, TCF/LEF binding sites,
which shows activation of Wnt/b-catenin signaling, is
detected in the dorsal optic vesicle (Maretto et al., 2003;
Smith et al., 2005; Cho and Cepko, 2006). Deletion of
Wnt/b-catenin co-receptor LRP6 leads to the downregulaton of TCF/LEF expression and the loss of the dorsal
marker Tbx5, indicating that Wnt/b-catenin pathway
might be involved in the dorsoventral patterning in the
optic vesicles (Maretto et al., 2003). In frog, Wnt/b-catenin pathway is implicated in the regulation of RPC proliferation and neurogenesis in the developing retina
(Ladher et al., 2000; Galy et al., 2002; Van Raay et al.,
2005). In contrast, loss of function of b-catenin in the
murine retina does not affect proliferation or differentiation of RPCs, suggesting that Wnt/b-catenin pathway is
not required in mammalian retingogenesis (Ouchi et al.,
2005; Fu et al., 2006). However, Wnt/b-catenin signaling
pathway may play a role in retinal regeneration, since it
enhances stem cell-like properties of M€
uller glial cells in
adult mammalian eye (Das et al., 2006; Osakada et al.,
2007). In murine retinal explants, ectopic expression of
b-catenin inhibits neurite outgrowth, indicating that
Wnt/b-catenin pathway might also be involved in the
regulation of axonal guidance of projecting neurons,
RGCs, in the retina (Ouchi et al., 2005; Rodriguez et al.,
2005). Furthermore, Wnt signaling could also participate
in the medial-lateral retinotectal topographic mapping
in the murine (Schmitt et al., 2006). Interestingly, in
contrast, noncanonical Wnt signaling promotes RGC
axon outgrowth in chick and frog mediated by the interaction of Wnt antagonists SFRP1 and Fzd2 and the activation of pertussis toxin-sensitive Ga protein (Rodriguez
et al., 2005). It has been suggested that Wnt/b-catenin
in addition to FGF and TGF-b could participate in the
formation of ciliary body and iris (Zhao et al., 2002b,c;
Dias da Silva, 2007; Liu et al., 2007). In addition, Wnt/
b-catenin signaling may also function to keep PRCs in
the adult ciliary margin in an undifferentiated state so
as to maintain a continuous stem cell pool (Inoue et al.,
2006). Reports have demonstrated that suppression of
Wnt/b-catenin signaling is required in the lens ectoderm
to initiate lens formation, but is necessary during the
later stage of the lens morphogenesis for the proper
development of the lens epithelium and differentiation of
lens fibers (Smith et al., 2005; Kreslova et al., 2007).
Inhibition of Wnt/b-catenin pathway is also found to be
essential for the differentiation of cornea in the murine
(Mukhopadhyay et al., 2006). Finally, studies have demonstrated that Wnt/b-catenin signaling pathway controls
both the regression of hyaloids vessels and the development retinal vasculature, although by a different mechanism (Xu et al., 2004; Lobov et al., 2005; Masckauchan
et al., 2007; Rao et al., 2007).
Fibroblast growth factor (FGF) signaling
pathways. The FGF is a large family of neurtrophic
signaling molecules that are characterized by their
RSC AND REGENERATION OF VISION SYSTEM
ability to bind heparin and heparin sulfate proteoglycans
(HSPG) as cofactors for the activation of FGF tyrosine
kinase receptors (FGFR1–4) (Venkataraman et al., 1999;
Schlessinger, 2000). The interactions of the growth factors, proteoglycan, and FGFR mediate FGF dimerization
and activate multiple signal pathways, including those
involving Ras, mitogen-activated protein kinase
(MAPKS), extracellular signal-regulated kinases (ERKs),
phosolipase-gamma (PLC-Ç), Jun N-terminal kinase
(JNK), and protein kinase-C (PKC). FGFR activation
induces tyrosine phosphorylation of FGFR substrate-2
(FRS2) in a complex with growth factor receptor bound
protein-2 (GRB2) and Src Homology 2 Phosphatase-2
(SHP2), which promotes RAS activation and in turn activates the Raf1/MEK/MAPK pathway leading to change
in gene transcription (Turner and Grose, 2010). Acidic
FGF (aFGF or FGF-1) and basic FGF (bFGF or FGF-2)
are the two prototypical members of the FGF family
named because of their different isoelectric points.
FGF signaling has long been recognized for its neural
induction role in the developing embryo (Storey et al.,
1998; Stern, 2006) as well as for its role as the key mitogen for self-renewal of NSCs in vitro and in vivo (Gritti
et al., 1996; Reuss and von Bohlen und Halback, 2003;
Sirko et al., 2010). Indeed, FGF-2 in combination with
EGF is universally used to expand NSCs in the neurosphere assay. At least 10 of the 23 FGF ligands have
been described to be expressed in the brain. FGFR1 is
expressed as early as E8.5–9.5 in murine telencephalon
and persists in the ventricular zone and dentate gyrus
later on (Tropepe et al., 1999; Beer et al., 2000). Expression of FGFR2 and 3 have also been reported and seem
to be highly expressed by glial cells, mostly in the subependymal zone and SGZ but also around brain lesions
following trauma (Reuss and von Bohlen und Halback,
2003; Chadashvili and Peterson, 2006). The expression
of FGFRs and their ligands appears to be very dynamic
and their effects may depend on specific stages during
development and adult life (Ford-Perriss et al., 2001;
Temple, 2001; Fortin et al., 2005). Interestingly, bFGF
has been found to be closely associated with HSPGs in
NSC proliferation in vivo and may also in the regulation
of NSCs self-renewal in vitro (Kerever et al., 2007; Sirko
et al., 2010). Moreover, increased FGF signaling in the
radial glia along the ventricular zone in zebrafish does
not correlate with proliferative activity but rather correlates with the radial glia nature of ventricular cells
(Topp et al., 2008).
In the eye development, several FGFs are implicated
in playing a role in separating the neuroepithelium of
the optic vesicle into the neuroretinal and the RPE
domains. bFGF is highly expressed in the surface ectoderm overlying the optic vesicle in the chick (Pittack
et al., 1997). Presence of FGFs in optic vesicle culture
causes the pigmented epithelial cells to undergo neuronal differentiation resulting in the formation of a
double-layered neural retina. Conversely, when the
optic vesicles are cultured in FGF neutralizing antibodies neural differentiation in the retina is blocked but
the RPE is not affected (Pittack et al., 1997). Surgical
removal of the surface ectoderm results in a mixture of
mingled neural and pigmented cells in the optic vesicle.
Addition of FGF after ectoderm removal partially
restore the segregated neural and RPE domains, with
the neural domain being formed near to the FGF source
143
(Hyer et al., 2003). The results of these studies suggest
that FGFs are required for neural retina specification
and FGFs released from the overlying surface ectoderm
provide the positional cues that induce the neuroepithelium of optic vesicle to develop into an inner neural retina and an outer RPE. The specification of neural
retina and pigmented epithelium of the optic vesicle is
in part mediated by the inhibition of FGFs on specific
genes required for RPE determination. The expression
of specific bHLH-zipper transcription factor MITF is
initially found ubiquitously in the undifferentiated
murine optic vesicle and later become restricted to the
pigmented epithelium (Nguyen and Arnheiter, 2000).
Furthermore, in MITF mutant mice, parts of the future
pigmented epithelium are converted to a laminated
neural retina. Implantation of FGF-coated beads in the
presumptive RPE region leads to a downregulation of
MITF and the formation of neural retina. Conversely,
after the removal of the surface ectoderm, expression of
MITF is retained, neuroretinal-specific CHX10 expression is lost and the epithelium is converted to a pigmented monolayer. These effects can be reversed by the
application of FGF. Similar results has been found in
chick retina, overexpression of MITF causes hyperpigmentation and inhibits FGF-induced dedifferentiation
and transdifferentiation of RPE into neural retina
(Mochii et al., 1998). In addition to the FGF derived
from the surface ectoderm, FGF9 expression is also
found in the distal optic vesicle, which gives rise to the
neural retina. Ectopic or misexpression of FGF9 expression induces the conversion of RPE into neural retina
(Zhao and Overbeck, 1999; Zhao, 2001). In the FGF9
knockout mice, RPE extends into the outer neural
retina, suggesting a role of FGF9 in defining the boundary between the RPE and retina. In addition, in these
FGF9 deficient mice, the lens fiber cells are underdeveloped; indicating that FGF9 may involve in the
differentiation of lens fiber cells. Moreover, the transdifferentiation of the RPE into neural retina requires the
activation of RAS and MAPK/ERK signaling pathway
(Zhao et al., 2001; Galy et al., 2002).
FGFs are not only involved in the RPE and retina
specification, but also are implicated in retinal cell fate
determination. Blocking of FGF signaling with a FGFR
inhibitor retards the wave of RGC differentiation in
chick retinal explants, whereas exogenous FGF1 but not
FGF8 induces ectopic development of RGCs in the
peripheral retina, suggesting that FGFs play a role in
RGC differentiation and progression of wave of RGC differentiation (McCabe et al., 1999). Interestingly, in Xenopus, inhibition of FGF signaling with a dominant
negative FGFR causes a loss of photoreceptor and amacrine cells, with an increase of M€
uller glia (McFarlane
et al., 1998). However, overexpression of FGF2 in Xenopus RPCs increases the number of RGCs and decreases
the number of M€
uller glia. Although the proportion of
photoreceptors is unchanged, there is a two-fold increase
in rod photoreceptor cells compared with cone photoreceptors (Patel and McFarlane, 2000). Similar results
were obtained when FGF2 was added to embryonic rat
retinal explants cultures, accelerated the RGC differentiation of the uncommitted RPC, whereas anti-FGF antibodies delay their appearance (Zhao and Barnstable,
1996). In the same study, it was also reported that even
though differentiation of photoreceptors were not
144
YIP
affected, the rosette formation of rod photoreceptor is
suppressed. In addition to the role of FGF2 in the timing
of RGC differentiation, other studies have also shown
that FGF2 can regulate the proliferation of RPCs, and
shift the bias of retinal cell differentiation (Hicks and
Courtois, 1992; Lillien and Cepko, 1992). Furthermore,
FGFs are expressed in conjunction with Hhs in various
regions of the developing CNS, including optic vesicles
and retina (Crossley et al., 2001). In fish, Hh requires
FGF signaling to activate the Hh target gene Spalt in
the proximal eye vesicle at the eye and mid-hindbrain
boundary (Carl and Wittbrodt, 1999). FGFs and Hhs
have similar roles in dorsoventral patterning of the eye,
and in retinal cell fate specification and neurogenic
wave progression. Thus, it is possible that FGFs and
Hhs may act together or complement each other in these
important events during eye development.
The Nature and Origin of Intrinsic Retinal
Stem/Progenitor Cells
Retinal stem/progenitor cells in the ciliary
marginal zone (CMZ). In fish and amphibians, retinal growth is coordinated with the overall increase in
body size and retinogenesis occurs continuously throughout life. The addition of new neurons is generated from
two sources (Fig. 1). First, highly proliferative multipotent RPCs are found in the CMZ along the peripheral of
the retina (Straznicky and Gaze, 1971; Johns, 1977) and
the newly differentiated retinal cells are functionally
integrated into the existing circuits between the retina
and the iris epithelium (Otteson and Hitchcock, 2003).
Second, new rod photoreceptors are added to the central
retina in order to maintain visual acuity in the expanding retina. These rod photoreceptors are generated from
the rod progenitor cells in the ONL (Otteson and Hitchcock, 2003). It was originally thought that rod progenitors can generate multiple retinal cell types in response
to injury (Raymond et al., 1988). However, recent studies
suggest that new neurons in the regenerating retina are
derived from a population of slow-dividing stem cells in
the INL (Wu et al., 2001; Yurco and Cameron, 2005;
Fausett and Goldman, 2006). Furthermore, these proliferative cells of the INL express markers of PRCs such
as Pax6, Vsx1, Notch-3, and N-cadherin (Levine et al.,
1994; Hitchcock et al., 1996; Sullivan et al., 1997; Wu
et al., 2001), and have been suggested to be the true
PRCs that in intact retina give rise to the progenitor
cells for retinal regeneration, including rod progenitor
cells in the ONL. Interestingly, M€
uller glia whose cell
bodies are also located in the INL, proliferate after retinal injury and have not been ruled out as a source of
RPCs in fish (Braisted et al., 1994; Wu et al., 2001;
Yurco and Cameron, 2005; Fausett and Goldman, 2006).
However, these putative RPCs in the INL have not been
isolated and propagated in vitro making the examination
of their stem cell potential difficult. Nevertheless, it is
possible that the INL-derived stem cells, rod progenitor
cells and M€
uller glia can all serve as sources of regenerating retinal cells and the final cell fate decisions
depends on the type and extent of damage.
The ability of the retina of fish to regenerate within
several days to weeks after subjected to various types of
injury has been well documented (see reviews in Fadool,
2003; Otteson and Hitchcock, 2003). However, it should
be noticed that the functionality of the newly regenerated neurons and reintegration of these neurons into
existing circuitry has not been fully examined. In fact, it
has been demonstrated that after injury, regenerated
fish retinal tissue fails to reform a proper cone photoreceptor mosaic pattern (Vihtelic and Hyde, 2000; Stenkamp et al., 2001; Raymond et al., 2006). In amphibians,
CMZ stem cells are also implicated for cellular regeneration after retinal injury (Keefe, 1973; Reh, 1987; Reh
and Nagy, 1987; Perron et al., 1998). Moreover, it has
demonstrated that loss of specific type of retinal neurons
after neurotoxic injury promotes the production of that
particular neuronal cell types (Reh and Tully, 1986; Reh,
1987). In contrast to fish, the size and the regenerative
potential of the CMZ in the amphibian retina reduce
drastically after metamorphosis (Moshiri et al., 2004). In
birds, retinogenesis is completed and all neurons are
generated by hatching (Prada et al., 1991). Postnatal
growth of the avian retina is due to the tissue stretching
of the growing sclera and not as a result of addition of
new neurons (Amato et al., 2004). A CMZ-like germinal
zone at the peripheral margin of the retina was nevertheless identified in the chick (Fischer and Reh, 2000)
and quail (Kubota et al., 2002). Although the cells at the
retinal margin of post-hatched chicks have the capacity
to divide, express PRC genes, such as Pax6 and Chx10,
and generate neurons, the neurogenic potential of these
cells are fairly restricted compared with the cells in the
CMZ of the fish and amphibian. In contrast to the fish
and amphibian CMZ that can generate all retinal cell
types, CMZ in the chick regenerate only amacrine and
bipolar cells, but not photoreceptor and ganglion cells
and only in small quantity (Fischer and Reh, 2000).
However, this restriction can be overcome by exogenous
growth factor stimulation, suggesting that extrinsic and
not intrinsic factors limit the neurogenic potential of the
CMZ-derived RPCs in the chick (Fischer and Reh, 2000).
Furthermore, in contrast to fish and amphibian, avian
CMZ-derived RPCs do not response to retinal damages
and contribute to retinal regeneration (Fischer and Reh,
2000).
The CMZ is either greatly reduced or absence in mammalian eye. Several studies that searched for a comparable region in the mice, rats, and macaques indicated
that there is no CMZ in mammalian retina (Ahmad
et al., 2000; Kubota et al., 2002; Moshiri et al., 2004).
However, the ciliary body in the adult murine eye contains a population of quiescent cell that can be expanded
in vitro (Ahmad et al., 2000; Tropepe et al. 2000). The
ciliary body is derived from neuroepithelium and located
behind the iris at the distal margin of the neuroretina.
The CE is composed of two layers. The inner layer is
transparent and unpigmented, and is continuous from
the neural tissue of the retina. The outer layer is highly
pigmented, continuous with the RPE. This doublelayered epithelium of the ciliary body is often regarded
to be continuous with the retina and a rudiment of the
embryological retina. Cell labeling studies with chronic
injections of BrdU revealed that a rare population (0.2%)
of proliferative cells is found in the pigment layer of the
ciliary body in adult rats (Ahmad et al., 2000). A population of nestin-expressing cells in the adult mice ciliary
body responds to RGC injury by increase in proliferation
and upregulation of homeodoamin protein Chx10 and
recoverin, which is normally expressed in photoreceptors
RSC AND REGENERATION OF VISION SYSTEM
and bipolar cells (Nickerson et al., 2007). Dissociated
cells of the ciliary body from adult mice proliferate in
vitro, forming pigmented neurospheres that can be
expanded to secondary neurospheres in subsequent passages (Tropepe et al., 2000). Furthermore, exogenous
FGF and pigment epithelium-derived factor (PEPF) can
enhance the formation and proliferation of pigmented
neurospheres (Tropepe et al., 2000; De Marzo et al.,
2010). These pigmented neurosphere cells (PNCs)
express RPC marker Chx10 and EFTFs such as Pax6,
Six3, and Rx (Ahmad et al., 2000; Tropepe, et al., 2000;
Lord-Grignon et al., 2006), and can be induced to differentiate along neuronal and glial lineages (Ahmad et al.,
2000). Wnt3a, a canonical Wnt ligand, stimulates the
proliferation and multipotency of PNCs (Inoue et al.,
2006). Moreover, PNCs can express specific markers and
differentiate into different retinal cell types, including
rod photoreceptors, bipolar neurons, RGCs, and M€
uller
glia (Ahmad et al., 2000; Tropepe et al., 2000). Although
porcine CE-derived cells express b–III-tubulin and NeuN in vitro, they fail to express specific retinal markers
(MacNeil et al., 2007). Recently, it was suggested that
the efficient differentiation of CE-derived cells to acquire
RPE-like phenotypes depends on the conditions of differentiation protocols and cellular environment in vivo;
suggesting that pre-differentiated or re-programmed porcine CE-derived cells may have better potential for retinal repair (Guduric-Fuchs et al., 2011). Several groups
have reported that pigmented cells isolated from the
adult human CE can transdifferentiate to retinal
progenitor-like cells (Ahmad et al., 2000; Fischer and
Reh, 2003; MacNeil et al., 2007). Cells with RPE features have also been differentiated from postmorteum
human eyes and can be induced to differentiate into photoreceptors after transplanted into adult mice eyes
(Coles et al., 2004). Thus, these studies indicate that
RPCs in the pigmented ciliary body display stem cell
properties and have the capacity to generate different
retinal neurons in vitro. However, it is important to
point out the fact that these PRCs in the CE are rare,
fully differentiated, and pigmented epithelial cells which
are different from the naive, undifferentiated and unpigmented stem cells found in the CMZ of lower vertebrates
or in the neurogenic regions of adult mammalian brain.
Furthermore, the capacity of these CE-derived adult
RPCs to proliferate and self-renew gradually decrease
with sequent passages and expansion (Coles et al., 2004;
Xu et al., 2007) and eventually lose the ability to differentiate into photoreceptors (Gualdoni et al., 2010).
Indeed, doubts have been raised recently over the identity and retinogenic potential of the RPCs in the CE
(Cicero et al., 2009; Gualdoni et al., 2010).
Retinal stem/progenitor cells in the RPE. RPE
arises from neuroectoderm which it shares with neural
retina in early development and plays multifunctional
roles in support of the vertebrate eye (Bok, 1993; Boulton and Dayhaw-Barker, 2001). The embryonic RPE is
capable of transdifferentiation into a neural retina in
many vertebrate species; including mammal (Zhao et al.,
1995; Layer PG, 1998; Cayouette et al., 2001; Jensen
et al., 2001; Del Rio-Tsonis and Tsonis, 2003), perhaps
because they are developed from a common origin. During the transdifferentiation process, the pigment epithe-
145
lial cells lose their pigmentation, proliferate, and begin
to express markers of RPCs (Okada, 1980). The dedifferentiated epithelial cells then proceed to generate new
retinal neurons and glia in a similar manner that resembles normal retinogenesis (Reh et al, 1987; Sakaguchi
et al., 2003).
Interestingly, it has been demonstrated that RPE in
amphibians, but not in fish, has the ability to transdifferentiatite into neurons and glia (Ikegami et al., 2002;
Susaki and Chiba, 2007). In addition, the ability of adult
RPE to transdifferentiate into retinal neurons and to
regenerate the entire retina is retained only in urodela
(newts and salamanders) (Fig. 1) and not in anura
(frogs; Raymond and Hitchcock, 1997; Reh and Fischer,
2001; Hitchcock et al., 2004; Klassen et al., 2004a).
Despite evidence of neuronal transdifferentiation of RPE
cells in adult rodent and human has been demonstrated
in cultures (Vinores et al., 1995; Chen et al., 2003; Amemiya et al., 2004; Engelhardt et al., 2005), the potential
of these cells as RPCs has not been clearly documented
in vivo. Adult rat mammalian peripheral RPE although
retains its ability to proliferate, albeit at a much slower
rate, appears to lose the ability to transdifferentiate into
diverse retinal cell types (Al-Hussaini et al., 2008).
Retinal stem/progenitor cells in the iris
pigment epithelium (IPE). IPE develops from the
inner layer of the optic cup shares a common embryonic
origin as the neural retina. The iris tissue has long been
known for its remarkable ability to regenerate lens in
newt, chick, and human under culture conditions (Eguchi 1971, 1986; Tsonis et al., 2001; Kosaka et al., 2004).
Epithelial cells of the iris from amphibians (Eguchi,
1986), birds (Sun et al., 2006), and rodents (Haruta
et al., 2001; Asami et al., 2007) exhibit stem cell-like
properties in vitro. Nestin-positive RPCs are located in
the pigmented inner layer of the iris epithelium adjacent
to the eye chamber (Yamaguchi et al., 2000; Asami
et al., 2007). When the iris tissue of adult rats was cultured in retinal cell differentiation medium with bFGF,
some of the iris-derived cells express differentiated neuronal marker, neurofilament 200, but not rhodopsin, a
specific marker for rod photoreceptors. However, ectopic
expression of Crx, a hemeobox gene critical for photoreceptor differentiation and is specifically expressed in the
photoreceptors in the mature retina, in the adult rat
iris-derived cells resulted in the expression of rhodopsin
and adoption of a photoreceptor-specific phenotype (Haruta et al., 2001; Akagi et al., 2005). A combination of
Crx and NeuroD was needed for the generation of irisderived photoreceptor cells in primate. Moreover, these
photoreceptor-like cells display electrophysiological characteristics of rod photoreceptors and are capable to integrate and survive in the cocultured embryonic retinal
explants (Akagi et al., 2005). More recently, it was demonstrated that a combination of CRx, Rx, and NeuroD
converts IPE cells into light responsive photoreceptorlike cells in human (Seko et al., 2012). Furthermore,
pure isolated IPE cells from postnatal chick and adult
rats cultured in the presence of bFGF form neurospheres, which express RPC markers Pax6, Chx10, and
vimentin (Sun et al., 2006; Asami et al., 2007). When
IPE-derived neurosphere cells were cultured on laminincoated dishes with bFGF, a subset initiated the
146
YIP
expression of TuJ1, GFAP, and O4. Some neurosphere
cells expressed retinal-specific neuronal markers, such
as rhodopsin (rod photoreceptor), iodopsin (cone photoreceptor), PKC (bipolar cell), and HPC-1 (amarcrine), suggesting that IPE-derived cells have the potential to
generate retinal-specific neurons in vitro (Sun et al.,
2006). IPE cells co-cultured with embryonic RPCs participate in the formation of spheroids and express rod photoreceptor marker rhodopsin only in the ONL and
M€
uller cell marker vimentin only in the INL (Sun et al.,
2006). The results indicate that IPE-derived cells could
respond to lamina-specific cues for differentiation and
integration similar to RPCs (Rothermel et al., 1997).
When IPE cells were grafted into the space between
RPE and the photoreceptor layer, IPE cells were incorporated in the subretinal space and differentiated into rod
photoreceptors. In the rat IPE, the inner and outer
layers of the IPE differentially expressed nestin in a
manner corresponding to their shared origins with the
neural retina and the pigmented epithelial layers,
respectively. The nestin-expressing cells are located only
in the inner IPE layer. These cells proliferate and differentiated into retina-specific cells in response to bFGF,
whereas cells that do not express nestin do not proliferate and have restricted neuronal potency and only
express pan-neural markers (Asami et al., 2007). The
results from these experiments suggest that heterogeneous populations of RPCs displaying different developmental potential exist postnatally in the IPE, and some
of them are able to differentiate into multiple retinal cell
types without gene transfer. However, just like the RPCs
derived from the ciliary pigment epithelium, recent
study has demonstrated that although human iris cells
proliferate and express low levels of RPC or neuronal
markers, many of them retained properties of differentiated epithelial cells and lack central properties of neural
stem cells to differentiate into retinal neurons (Cicero
et al., 2009; Moe et al., 2009; Gualdoni et al., 2010; Bhatia et al., 2011; Froen et al., 2011). Thus, functional
studies are essential to determine the potency of irisderived cells to differentiate into fully operative photoreceptors before it can be considered as a potential source
of cell-based therapy for retinal degenerative diseases.
Retinal stem/progenitor-like M€
uller cells in
the retina. M€
uller cells are the major glial cells in
the retina comprising about 5% of all retinal cells. During retinal histogenesis, M€
uller cells are generated last
(Marquardt and Gruss, 2002; Cayouette et al., 2006).
M€
uller cells are astrocyte-like radial glial cells with cell
bodies located in the INL and processes that span across
the retina from the vitreal surface to RPE. M€
uller glia
ensheath all retinal neurons and thus cells play crucial
roles in supporting the neurons and their functions.
From early stages of development, they are essential in
maintaining the homeostasis of the retinal tissue, providing structural support, participating neuronal signaling processes, contributing to the formation of bloodretina-barrier and regulating blood flow (Bringmann
et al., 2006, 2009; Reichenback et al., 2007). Similar to
astrocytes, M€
uller cells express GFAP and glutamate
sythetase. M€
uller cells become activated following injury
and form a protective barrier between the healthy and
damaged tissues. Reactive M€
uller glia response to injury
by increase in proliferation, and upregulation of GFAP
and neurotrophic factors expression. Reactive glia also
participate in wound healing, stabilizing damaged tissue, attracting inflammatory cells, and promoting neuronal survival. Moreover, reactive glia can also induce
apopotitic cell death (Bringmann et al., 2006).
M€
uller cells also display neurogenic properties in the
vertebrate retina. In the fish retina, M€
uller glia dedifferentiate and generate rod progenitor cells that give
rise to rods throughout life (Bernardos et al., 2007).
These stem cells can regenerate all retinal cell types,
including cone photoreceptors, in response to damage
(Easter and Hitchcock, 2000; Fausett and Goldman,
2006; Hitchcock and Raymond, 2004; Ramachandran
et al., 2010). Following injury, M€
uller cells reenter the
cell cycle, dedifferentiate, and become RPCs that generate neurons (Raymond and Hitchcock, 2000; Yurco and
Cameron, 2005; Fausett and Goldmann, 2006; Fimbel
et al., 2007) (Fig. 1). In addition, in response to ablation
of cone photoreceptor, it was shown that the subsequent
regeneration is biased towards in replacement of the
cognate cone photoreceptor cell type (Fraser et al.,
2013). Unlike the M€
uller cells in birds and mammals
uller glia in normal fish are GFAP1.
which are GFAP2, M€
Since GFAP is expressed by the NSCs in the neurogenic
regions in mammals, this could be an indication of the
“neurogenic” nature of the fish M€
uller glia compared to
birds and mammals. In the avian retina, when extensive
amacrine cell death was induced by intraocular injections of neurotoxin NMDA, M€
uller cells become activated, proliferated, and dedifferentiated (Fischer and
Reh, 2001a,b). Although the majority of the cells remain
undifferentiated or persisted as M€
uller glia, and continue to express RPC markers Chx10 and Pax6 (Fischer
and Reh, 2003), a small number of the M€
uller cells
transdifferentiated into retinal neurons, particularly
into amacrine and bipolar cells (Fischer and Reh,
2001a,b). Furthermore, there is a cell-type-specific
replacement of neurons that have been selectively
injured. Generation of Brn31 RGCs, in the presence of
bFGF and insulin, was observed after treatment of colchicine or kainate both selectively causes RGC cell
death. In addition, bFGF and insulin can also stimulate
M€
uller cells to transdifferentiate (Fischer and Reh,
2002). M€
uller glial cells of the mature mammalian retina
express genes that are specific for M€
uller glia and genes
that are also expressed in RPCs (Livesey et al., 2004;
Roesch et al., 2008). In culture, M€
uller cells generated
neurospheres and transdifferentiated into all three types
of glial cells in the CNS as well as retinal neurons (Das
et al., 2006; Monnin et al., 2007; Nickerson et al., 2008;
Takeda et al., 2008; Wan et al., 2008). M€
uller cells
remain dormant in normal adult rat retina, however, in
response to injury, they proliferate, become activated,
(Dyer and Cepko, 2000; Karl et al., 2008), change their
gene expression, for example, upregulation of GFAP,
Sox2, cyclinD, and nestin, and convert to retinal stem
cells or other retinal cell types (Bernardos et al., 2007).
Moreover, extrinsic and intrinsic cues promoted and controlled the differentiation of these cells to specific retinal
neurons (Kim et al., 1998; Lewis and Fisher, 2003; Ooto
et al., 2004; Kohno et al., 2006; Osakada et al., 2007;
Wohl et al., 2009; Xue et al., 2010). Addition growth factor treatment promoted the transdifferentiation of
M€
uller glia into retinal neurons (Karl et al., 2008),
RSC AND REGENERATION OF VISION SYSTEM
147
Fig. 1. Retinal stem cells (RSCs) at the periphery of the eye (CMZ
progenitor cells) and from the neuroepithelium spanning the width of
the developing retina (central progenitor cells) give rise to proliferating
retinal progenitor cells (RPCs). The cycling (intrinsic property) retinal
stem/progenitor cells are able to response to local environment
(extrinsic cues) to promote their transition from proliferation to differentiation. Generation of retinal cell types follows a temporal sequential
€ller cells are generated last.
order: RGCs are generated first, and Mu
Retinal cell fate commitment and specification are regulated by combinations of transcription factors (as shown). In retinal regeneration
€ller cells dedifferentiating and then give rise to differafter damage, Mu
ent retinal cell types mirrors the RSCs in the CMZ and central retina in
patterns of gene expression and cellular organization. RPE in response
to injury cues is capable of transdifferentiation into neuronal and glial
cell-phenotypes, inducing neural retinal regeneration. CMZ: ciliary marginal zone; NFL, nerve fiber layer; GCL: ganglion cell layer; IPL: inner
plexiform layer; INL, inner nuclear layer; OPL: outer plexiform layer;
ONL: outer nuclear layer; OS: outer segment of photoreceptors; RPE:
retinal pigment epithelium.
whereas growth factor treatment alone rarely activates
M€
uller cells (Close et al., 2006; Karl et al., 2008). In
human retina, a population of M€
uller glia with NSC
characteristics has been identified and they can be
induced to grow and differentiate into retinal neurons in
vitro (Limb et al., 2002; Lawrence et al., 2007; Bull
et al., 2008; Lamba et al., 2009a; Bhatia et al., 2010,
2011; Giannelli et al., 2011; Singhal et al., 2012), suggesting that these cells may be a promising source of
cells for cell-based therapies to treat retinal degenerative
diseases (Fig. 1).
tive pathway. One possible strategy for treatment of
these blinding diseases is to replace cells that are lost
via transplantation. One of challenges in this approach
is to identify and characterize sources of cells for transplantation. Several cell populations may be regarded as
potential sources for retinal transplantation, they
include NPCs derived from central nervous system
(CNS), adult stem cells such as mesenchymal stem cells,
embryonic stem cells (ESCs) and induced pluripotent
stem cells (iPSCs) (Fig. 2).
Retinal Stem Cell in Regenerative Medicine
Regeneration of retinal cells from retinal progenitor cells. Retinal progenitor cells (RPCs) derived
Treatments to repair the human retina following
degenerative diseases remain a challenge. Unlike species
of lower vertebrates, the human retina lacks a regenera-
from fetal or neonatal retinas comprise a population of
immature cells that is responsible for generation of all
retinal cells during development (Reh, 2006). RPCs have
148
YIP
been successfully isolated from several mammalian species, including rodents (Chacko, et al., 2000; Yang et al.,
2002; Akimoto et al., 2006), pigs (Klassen et al., 2007),
and human (Yang et al., 2002). By manipulating time
and environment in vitro, immature RPCs can be
expanded extensively in culture and express photoreceptor markers (Merhi-Soussi et al., 2006). Transplantation
of RPCs from the developing retina into dystrophic
mature retina promotes survival of host tissue, along
with integration into the neural retina and recovery of
light-mediated behavior (Klassen et al., 2004b; MacLaren et al., 2006; Aftab et al., 2009). However, these early
studies of photoreceptor transplantation have only met
with minimal success due to the limited ability of the
cells to invade and integrate into the recipient retina.
The environment of the degenerating retina is hostile to
the transplanted cells and has adverse effects on the
ability of the cells to migrate from the transplantation
site into the host retina (Kinouchi et al., 2003; Ma et al.,
2011). Not until recently, several publications have
shown high levels of integration of transplanted photoreceptor precursors in advanced degenerated retina. Using
transplantation of newborn rod precursors grafting in a
murine model of severe human retinitis pigmentosa,
Singh et al. (in press) provides evidence for replacement
of polarized ONL with light-sensitive outer segments,
reconnecting with host retinal circuit leading to visual
function recovery. In addition, it has been shown that
the outcome of rod-photoreceptor precursor transplantation depends on different types and stages of degeneration (Pearson et al., 2012). Thus, effective rodphotoreceptor transplantation can be achieved by tailored manipulations of the host environment and appropriate therapeutic time windows (Barber et al., 2013).
However, since the protocol involves harvesting RPCs
from fetal eyes poses an ethical issue for clinical applications, it cannot be translated to human patients.
Regeneration of retinal cells from adult stem
cells. Adult stem cells, which have been identified in a
variety of tissues, such as in the epidermis, cornea,
intestinal, peripheral blood, and bone marrow, are multipotent with a limited capacity of self-renewal and differentiation to certain cell types (Fig. 2). Thus, adult stem
cells can be obtained from the patients and used as autologus grafts without rejection. Recently, it has been demonstrated that hematopoietic stem cells of the bone
marrow can be differentiated into various lineage cells
including neural cells and astrocytes in vitro (SanchezRamos et al., 2000; Woodbury et al., 2000) and in vivo
(Eglitis and Mezey, 1997; Kopen et al., 1999; Brazelton
et al., 2000; Mezey et al., 2000). Interestingly, hematopoietic stem cells have also been reported in animal
models to have neuroprotective effects on retinal diseases (Harris et al., 2009; Marchetti et al., 2010). Adult
bone marrow-derived nonhematopoietic lineage stem
cells incorporate into the degenerating blood vessels following intravitreal injections in neonatal mice and rescue cone photoreceptor in murine models of RP (Otani
et al., 2004). Some of these bone marrow mesenchymal
stem cells migrated into the retina, differentiated into
microglia and promote vascular repair in the ischemicinduced retinopthy (Ritter et al., 2006). In addition,
RPE-induced bone marrow stem cells mobilized into
peripheral blood can home to focal damaged RPE tissue
in the subretinal space and express RPE-specific cell
markers (Li et al., 2007). Recent study demonstrates
that a rare population of very small embryonic/epiblastlike stem cells (VSEL) in the murine retina can also differentiate into RPE-like cells (Zuba-Surma et al., 2008;
Liu et al., 2009). Adult bone marrow stem cells transplanted into the adult degenerative (Kicic et al., 2003) or
mechanical injury rat eye (Tomita et al., 2002; Inoue
et al., 2007) slowed down retinal cell degeneration and
integrated into the retina and differentiated into photoreceptor cells. However, it has been demonstrated that
neuroprotective properties of the bone marrow stem cells
may be attributed to the secretion of neurotrophic factors (Crigler et al., 2006) and/or anti-inflammatory modulators (Pluchino et al., 2005) by these cells, instead of
direct functional retinal cell replacement (LevkovitchVerbin, 2010). Furthermore, although autologous transplantation of adult stem cells has the advantage of
reducing the risk of rejection and eliminating ethical
issues, the scarcity of these cells and the restriction in
their functional retinal differentiation have limited the
application of adult stem cells in stem cell therapies for
retinal diseases.
Regeneration of retinal cells from ESCs and
iPSCs. The current state of cell replacement-therapy
for the treatment of retinal diseases focus on the development of protocols on the direct differentiation of
hESCs or hiPSCs to RPCs and a photoreceptor cell phenotypes. ESCs are derived from the inner cell mass of
the embryonic blastocyst, with self-renewal capabilities
and the ability to differentiate into cell types derived
from all three embryonic germ layers (Thomson et al.,
1998; Reubinoff et al., 2000; Cowan et al., 2004). In vitro
differentiation of mouse and human ESCs into different
functional retinal cell types (Fig. 2), in particular RPE
cells and/or photoreceptors, has been demonstrated by
numerous stepwise protocols (Zhao et al., 2002a,b; Ikeda
et al., 2005; Lamba et al., 2006; Carr et al., 2009a; Idelson et al., 2009; Osakada et al., 2008, 2009a,b). Studies
have shown that transplantation of mouse, primate, and
human ESC-derived retinal cells, including RPE cells, in
rodent retinal degeneration models protected host photoreceptors, integrated into the recipient retina, differentiated into functional photoreceptors and restored visual
function (Haruta et al., 2004; Meyer et al., 2005; Lund
et al., 2006; Meyer et al., 2004, 2006; Vugler et al., 2008;
Idelson et al., 2009; Lamba et al., 2009b; Park et al.,
2011; Vaajasaari et al., 2011). Thus, transplantation of
photoreceptors with or without RPE cells derived from
the hESCs offers huge potential for cell replacement
therapy in treating retinal degenerative diseases (Jin
et al., 2009). Clinical trials in the United States using
human ESC-derived RPE to treat Stargardt’s disease
and AMD were approved by the FDA (Schwartz et al.,
2012). Furthermore, mouse ESCs can be induced to generate an eye-like structures made up of lens cells, retinal
cells and RPE cells (Hirano et al., 2003) and subsequently it has been shown that cells from these eye-like
structures can be differentiated into RGCs when transplanted into the vitreous body of an injured adult mouse
retina (Aoki et al., 2008). Most recently, in a pioneering
study by Eiraku et al., mouse ESCs aggregates can
RSC AND REGENERATION OF VISION SYSTEM
149
Fig. 2. Sources of replacement cells to provide treatments for people who suffer from retinal diseases:
(A) ESCs from the inner cell mass of the blastocyst; (B) adult stem cells from the bone marrow, brain, and
the eye; and (C) the iPSCs and induced retinal neurons (iRNs) derived from human fibroblasts. NSC: neu€ller glial cells. Dash line with
ral stem cells; RPCs: retinal progenitor cells; C: cone photoreceptor; M: Mu
question mark: suggested differentiation.
organize into stratified optic-cup in a three-dimensional
(3D) culture system (Eiraku et al., 2011; Eiraku and
Sasai, 2012a,b). Furthermore, the entire process of this
spontaneous optic-cup morphogenesis follows the typical
spatial and temporal histogenic sequence occurring during retinal development in vivo (Eiraku et al., 2011). In
the past few years, several groups have attempted to
reconstitute 3D retinal tissue in vitro using human
ESCs (Dutt and Cao, 2009; Nistor et al., 2010). The
ESCs aggregate and form sheets of differentiated retinal
cell types, but fail to organize into a typical laminated
3D retinal structure. In 2011, Meyer et al. made an
important breakthrough by demonstrating that a 3D
optic vesicle-like structure can be obtained using human
ESCs and iPSCs (Meyer et al., 2011) by the induction of
eye-field markers such as Rx and Pax6 (Meyer et al.,
2009). However, even with a high degree of neuroretinal
differentiation, RPE was rarely developed in the optic
vesicle-like structures without Activin A supplementation that mimic certain aspects of embryonic RPE devel-
opment. Although ESC-derived RPE has been shown to
have some success with transplantation and thus support the feasibility of using the human ESCs for cellbased retinal regenerative therapy, the potential of using
ESCs in cell replacement therapy for treatment of retinal diseases is limited by important ethical issues and
the risk of immune rejection. In addition, na€ıve ESCs
have been associated with tetratoma formation after
transplantation (Arnhold et al., 2004; Cowan et al.,
2004) and the efficiency of generation of functional RPE
cells is too low and the timing is too slow for the narrow
window of effective therapy.
An alternate source of cells for stem cell transplantation in retinal regeneration is iPSCs (Fig. 2). iPSCs are
ESC-like pluripotent cells that are reprogrammed in
vitro from terminally differentiate somatic cell without
using embryonic tissue (Takahashi and Yamanaka, 2006;
Takahashi et al., 2007; Wernig et al., 2007; Yu et al.,
2007; Nakagawa et al., 2008) and have the potential to
differentiate into all cell types of the adult organism.
150
YIP
Thus, iPSCs, unlike ESCs, have been identified as an
unlimited source of replacement tissue for use in human
retinal cellular therapies without ethical implications. In
addition, transplantation of autologus grafts from
patient’s own iPSC-derived cells could avoid the need of
long-term immunosuppression of graft rejection. Recent
studies have shown that human iPSCs could be genetically reprogrammed using either three or four transcription factors (Oct4/Sox2/Klf4 or Oct4/Sox2/Klf4/c-Myc,
respectively) and induced to differentiate into retinal
cells by small molecules, including RGCs and photoreceptors (Osakada et al., 2009a,b; Hara et al., 2012).
iPSCs have the same potential as the ESCs to mimics
retinal development in situ (Meyer et al., 2009). In addition, similar to human ESCs, human iPSCs can spontaneously differentiate into RPE cells (Buchholz et al.,
2009; Carr et al., 2009b; Meyer et al., 2009) and the differentiation process can be greatly facilitated by addition
of compounds such as Dkk1 and Lefty-A that are
involved in the developmental signaling pathways of
RPE (Hirami et al., 2009; Osakada et al., 2009b). It is
reported that transplantation of iPSC-derived RPE
exerts protective effects and restores visual functions in
retinal dystrophic rats (Buchholz et al., 2009; Carr
et al., 2009b; Tucker et al., 2011). Thus, retinal cells
such as iPSC-derived RPE generated from patients with
retinal degenerative diseases are of particular interest
because these cells reveal a disease-specific functional
defect that can be corrected either by pharmacological
treatment or by following gene target repair (Meyer
et al., 2011). Recently studies have shown that iPSCs
from swine eye which shares a close similarity to the
human eye can differentiate into photoreceptors in vitro,
and these cells can be transplanted and integrated in
damaged swine retina, thus provides an appropriate system for the evaluation of potential therapeutic strategies
for eye degenerative diseases, including RP and AMD
(Hendrickson and Hicks, 2002; Guduric-Fuchs et al.,
2009; Zhou et al., 2011). However, major safety concerns
of using clinical application of iPSCs include the potential risk of malignant formation results from the oncogenic properties of the transcription factors used in the
reprogramming protocols and the random genomic integration of these factors after retroviral transduction.
Extensive studies have been undertaken to establish
new reprogramming protocols that use nonintegrating
gene delivery methods (Yu et al., 2009) or that replace
the application of exogenous reprogramming factors by
treatment with proteins (Kim et al., 2009) or small molecules (Li et al., 2009).
CONCLUDING REMARKS
Eye formation requires the coordination of complex
interactions from multiple cellular sources to create the
cell behaviors that progressively shape the developing
eye. Research into understanding the mechanisms that
regulate stem cells in progenitor cell fate determination
and their subsequent differentiation during eye development is still far from complete. Nevertheless, significant
progress has been made towards the identification of various extrinsic cues and intrinsic determinants involved in
RPC specification. The mechanisms of development and
differentiation of eye are remarkably similar in all vertebrates. During retinogenesis, proliferating RPCs and
newly generated cells are confined at the peripheral margin of the retina. In fish and amphibians, this region is
maintained after embryonic development and this specialized region referred to as the CMZ. The retina of many
fish and amphibians continue to grow throughout their
life. The increase in retinal size is due to in part to the
addition of new neurons, at the CMZ. In birds, neurogenesis at the CMZ decreases dramatically than that observed
in fish and amphibians. Furthermore, in rodents the retinal margin does not exhibit mitotic activities after the
first week of postnatal life. It is interesting to note that
there might be a direct correlation of the evolutionary
importance of the ability of retina to regenerate with the
presence of RPCs and their potential to generate retinal
neurons. Regeneration of retina is frequently observed
fish and amphibians. In fish, the major source of new neurons is the stem cells of the marginal zone and the rod
progenitors in the INL and ONL in association with
M€
uller glia cells. Neurogenesis in adult fish visual system
has provided valuable insights into the regulatory mechanisms and potential of adult neural stem cells, and the
basic molecular and cellular processes underlying neurogenesis and cell specification. Adult mammalian retina
has long been known to be devoid of stem cells and has
lost the ability to regenerate after damage.
Nevertheless, several groups have reported that pigmented cells isolated from the adult human CE can
transdifferentiate to retinal progenitor-like cells and
M€
uller glia cells can display characteristics of NPCs,
thus identified both cell populations as potential candidate for stem-cell based therapies to regenerate visual
function. It seems logical that it is preferable to mobilize
endogenous RPCs to drive the repair process in the retina. However, the challenge of using endogenous RPCs
for self repair will be to identify appropriate cellular
sources and molecules, including pharmacological
agents, that can expand the endogenous cell pool and
reactivate the regenerative processes similar to those
described for the lower vertebrates in the mammalian
retina. Recent advances in stem cell research have
raised the possibility to use hESCs and HiPSCs to repair
or regenerate damaged mammalian retina. Cell transplantation is the most direct approach towards replacing
damaged retinal cells and restoration of lost visual function. To achieve a breakthrough in cell replacement
therapies in retinal degenerative diseases would require
isolation and molecular characterization of human RPCs
for specific neuronal replacement in the actively degenerating adult retina and that these new cells survive
without immune suppression as well as displaying evidence of integration into host circuitry. Information on
the phenotypic potential and immunogenicity of the
donor cells would most likely benefit from future clinical
application of these cells. Findings in the understanding
the role of coordinated transcription factor expression in
fate specification should have predicative significance in
phenotypic potential and improve our ability to control
stem cell differentiation. However, the mammalian retina is a highly complex organized structure whose putative neurogenic potential we just begin to understand.
Thus, even if methods for successful cell replacement of
new neurons are established, there is no guarantee that
regenerating axons from these newly replaced cells
would grow towards the correct targets and be functional integrated into existing neural circuits.
RSC AND REGENERATION OF VISION SYSTEM
Furthermore, the inhibitory environment in the injured
adult mammalian CNS caused by myelin-associated glycoproteins and extracellular matrix molecules such as
chondroitin sulphate proteoglycans would strongly
inhibit axonal, and therefore, cellular regeneration. In
addition, inhibitory molecules secreted by activated
microgla and astrocytes in response to injury, further
exacerbate this hostile environment. Therefore, to have a
successful migration, integration, and synaptic formation
of grafted or endogenous RPCs, the inhibitory environment in the degenerating tissue has to be overcome by
pharmacological approaches. Regenerative medicine for
retinal degenerative diseases must take a combinatory
approach involving exogenous reprogramming or gene
transfer of RPCs, together with modulation of the
changes of environmental cues required for the regenerative processes within the appropriate time frame. While
much needed to be demonstrated, particularly recovery of
visual function, this challenging and multifaceted
approach to RPC transplantation provide an exciting new
strategy for the treatment of retinal disease and offers
the hope that effective treatments may be within reach in
the near future.
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