Retinal stem cells and regeneration of vision system.

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: [email protected] Received 13 September 2013; Accepted 13 September 2013. DOI 10.1002/ar.22800 Published online 2 December 2013 in Wiley Online Library (wileyonlinelibrary.com).

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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-

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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

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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


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-

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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

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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


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

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(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

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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


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

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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),


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

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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


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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.

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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.


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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