Transdifferentiation of Pigmented Epithelial Cells: A Source of Retinal Stem Cells?

Fischer, Andy J.; Reh, Thomas A.

doi:10.1159/000048710

Cited by 61 publications

(50 citation statements)

References 61 publications

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“…It was previously reported that CE-derived spheres express Nestin, a gene found in neural progenitor and stem cells (12). Our real-time RT-PCR analysis confirmed these previous findings (Fig.…”

Section: Resultssupporting

confidence: 92%

“…Thus, we propose that these cells can initiate transdifferentiation or reprogramming from pigmented CE cells rather than differentiate from RSCs or progenitors. This model is consistent with previous studies showing robust transdifferentiation between CE, retina, and retinal pigment epithelium in various species (10)(11)(12)(13)(14). To test this hypothesis, we maintained spheres on laminin-coated coverslips for 21 days, as described in refs.…”

Section: Resultssupporting

confidence: 83%

“…This would not be surprising considering that the neural retina, retinal pigment epithelium, and the CE are derived from the same embryonic tissue during eye morphogenesis. Indeed, key examples of transdifferentiation have been reported for retinal pigmented epithelium, neural retina, and ocular CE (10)(11)(12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

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Cells previously identified as retinal stem cells are pigmented ciliary epithelial cells

Cicero

Johnson

Reyntjens³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

200

178

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It was previously reported that the ciliary epithelium (CE) of the mammalian eye contains a rare population of cells that could produce clonogenic self-renewing pigmented spheres in culture. Based on their ability to up-regulate genes found in retinal neurons, it was concluded that these sphere-forming cells were retinal stem cells. This conclusion raised the possibility that CE-derived retinal stem cells could help to restore vision in the millions of people worldwide who suffer from blindness associated with retinal degeneration. We report here that human and mouse CE-derived spheres are made up of proliferating pigmented ciliary epithelial cells rather than retinal stem cells. All of the cells in the CE-derived spheres, including the proliferating cells, had molecular, cellular, and morphological features of differentiated pigmented CE cells. These differentiated cells ectopically expressed nestin when exposed to growth factors and low levels of pan-neuronal markers such as beta-III-tubulin. Although the cells aberrantly expressed neuronal markers, they retained their pigmented CE cell morphology and failed to differentiate into retinal neurons in vitro or in vivo. Our results provide an example of a differentiated cell type that can form clonogenic spheres in culture, self-renew, express progenitor cell markers, and initiate neuronal differentiation that is not a stem or progenitor cell. More importantly, our findings highlight the importance of shifting the focus away from studies on CE-derived spheres for cell-based therapies to restore vision in the degenerating retina and improving techniques for using ES cells or retinal precursor cells.O ver 40 million people worldwide are blind. Macular degeneration accounts for Ϸ8 million cases of blindness. Although the cause of macular degeneration is not known, 1 potential treatment is cell therapy. Stem cells hold great promise for regenerative medicine, and recently many efforts have been devoted to finding suitable candidates for retinal transplants. These candidates include photoreceptor progenitors (1) and embryonic stem cells (2, 3). Others have looked to the ciliary epithelium (CE) as a potential source of retinal stem cells (4, 5).In 2000, Tropepe and colleagues revealed that the CE of the mouse eye can be dissociated, maintained in culture at clonal density and stimulated to form clonogenic spheres (5). The CEderived spheres were pigmented, expressed nestin, and could be dissociated and replated to form spheres up to 8 times. When transferred to differentiation conditions in culture, cells from the CE-derived spheres up-regulated genes found in rod photoreceptors, bipolar neurons, and Müller glia (5). These findings were later extended to CE isolated from postmortem human eyes (4). Based on these and other data, it was suggested that the sphere-forming cells in the mammalian CE are retinal stem cells (RSCs) and, thus, hold promise for therapeutic replacement of retinal neurons lost to disease or degeneration.Given the potential impact of cell replacement ...

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 83%

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Cells previously identified as retinal stem cells are pigmented ciliary epithelial cells

Cicero

Johnson

Reyntjens³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

200

178

View full text Add to dashboard Cite

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“…Retinoblasts divide in the CMZ and as they are incorporated more centrally, they turn on genes that specify their particular retinal fates (Perron et al, 1998). Recent studies have shown that the most peripheral RPE at the rim of the optic cup has cells that continue to divide postnatally in chick (Fischer and Reh, 2001). This peripheral RPE, with the overlying choroid and underlying nonpigmented epithelium, generates the ciliary body and the iris near the anterior pole of the eye.…”

Section: Introductionmentioning

confidence: 99%

A novel function forHedgehogsignalling in retinal pigment epithelium differentiation

et al. 2003

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Sonic hedgehog is involved in eye field separation along the proximodistal axis. We show that Hh signalling continues to be important in defining aspects of the proximodistal axis as the optic vesicle and optic cup mature. We show that two other Hedgehog proteins, Banded hedgehog and Cephalic hedgehog, related to the mouse Indian hedgehog and Desert hedgehog, respectively, are strongly expressed in the central retinal pigment epithelium but excluded from the peripheral pigment epithelium surrounding the ciliary marginal zone. By contrast, downstream components of the Hedgehog signalling pathway, Gli2, Gli3 and X-Smoothened, are expressed in this narrow peripheral epithelium. We show that this zone contains cells that are in the proliferative state. This equivalent region in the adult mammalian eye, the pigmented ciliary epithelium, has been identified as a zone in which retinal stem cells reside. These data, combined with double labelling and the use of other retinal pigment epithelium markers, show that the retinal pigment epithelium of tadpole embryos has a molecularly distinct peripheral to central axis. In addition, Gli2, Gli3 and X-Smoothened are also expressed in the neural retina, in the most peripheral region of the ciliary marginal zone, where retinal stem cells are found in Xenopus, suggesting that they are good markers for retinal stem cells. To test the role of the Hedgehog pathway at different stages of retinogenesis, we activated the pathway by injecting a dominant-negative form of PKA or blocking it by treating embryos with cyclopamine. Embryos injected or treated at early stages display clear proximodistal defects in the retina. Interestingly, the main phenotype of embryos treated with cyclopamine at late stages is a severe defect in RPE differentiation. This study thus provides new insights into the role of Hedgehog signalling in the formation of the proximodistal axis of the eye and the differentiation of retinal pigment epithelium.

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“…It is possible that some of the proliferating cells transfected with viruses were derived from the pigmented epithelium. However, there is no evidence that mature pigmented cells underlying central regions of the postnatal chick retina are capable transdifferentiating like the pigmented cells of early-stage chick embryos (for reviews, see Reh and Fischer, 2001;Fischer and Reh, 2001b). 6.…”

Section: Discussionmentioning

confidence: 99%

NeuroD induces the expression of visinin and calretinin by proliferating cells derived from toxin‐damaged chicken retina

Fischer

Wang

Reh

2004

Developmental Dynamics

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Transdifferentiation of Pigmented Epithelial Cells: A Source of Retinal Stem Cells?

Cited by 61 publications

References 61 publications

Cells previously identified as retinal stem cells are pigmented ciliary epithelial cells

Cells previously identified as retinal stem cells are pigmented ciliary epithelial cells

A novel function forHedgehogsignalling in retinal pigment epithelium differentiation

NeuroD induces the expression of visinin and calretinin by proliferating cells derived from toxin‐damaged chicken retina

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