Basic fibroblast growth factor induces retinal regeneration in vivo

Park, Carol M.; Hollenberg, Martin J.

doi:10.1016/0012-1606(89)90089-4

Cited by 276 publications

(141 citation statements)

References 11 publications

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“…In addition, this 'RPE-to-NR' conversion, triggered only by a change in extracellular signals, can occur even after the onset of Mitf expression (bona fide RPE marker) and the repression of Chx10 expression (bona fide NR marker). These observations are consistent with previous studies in vivo showed a profound plasticity between the NR and RPE fates during development 41,42,54 . Interestingly, the temporal window of competence for RPE-NR reversal may be limited in our hESC culture; preliminary experiments have indicated that a longer treatment of GSK3 and FGFR inhibitors (for example, days 18-27 or 18-30, instead of days 18-24) makes RPE less responsive to reversal signals in NR-differentiation medium.…”

Section: Discussionsupporting

confidence: 94%

“…Our previous hESC study 32 showed that RPE differentiation could be induced from hESC-derived retinal epithelium by treating with canonical Wnt signals from day 18 (RPE-inducing roles of Wnt signals in vivo are also reported and discussed in refs [37][38][39][40]. Conversely, FGF signals have been shown to promote NR differentiation and suppress RPE differentiation 41,42 . Based on these effects (summarized in Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…2 (refs 30,59). Furthermore, specification into NR and RPE is promoted and suppressed by FGF signals, respectively, which are produced by NR 41 . These multiplex regulations of mutual inhibition and autoactivation lead to a 'bistable' system, in which a small difference in endogenous signals could make a pivotal specification of retinal epithelium (or its local domains) into either NR or RPE.…”

Section: Discussionmentioning

confidence: 99%

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Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue

et al. 2015

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In the developing neural retina (NR), multipotent stem cells within the ciliary margin (CM) contribute to de novo retinal tissue growth. We recently reported the ability of human embryonic stem cells (hESCs) to self-organize stratified NR using a three-dimensional culture technique. Here we report the emergence of CM-like stem cell niches within human retinal tissue. First, we developed a culture method for selective NR differentiation by timed BMP4 treatment. We then found that inhibiting GSK3 and FGFR induced the transition from NR tissue to retinal pigment epithelium (RPE), and that removing this inhibition facilitated the reversion of this RPE-like tissue back to the NR fate. This step-wise induction-reversal method generated tissue aggregates with RPE at the margin of central-peripherally polarized NR. We demonstrate that the NR-RPE boundary tissue further self-organizes a niche for CM stem cells that functions to expand the NR peripherally by de novo progenitor generation.

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Section: Discussionsupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue

et al. 2015

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“…In most vertebrates, these retinal stem cells remain quiescent and do not respond to injury. However, cells in the anterior margin of the embryonic chick eye respond to injury during a limited time of retina development, providing an opportunity to study the induction process of these stem/progenitor cells (13-15).The embryonic chick has been shown to regenerate a complete retina in Ϸ7 days as long as a retinectomy is performed on or around embryonic day 4 (E4) and a source of FGF is added (14,16,17). In the presence of ectopic FGF2, regeneration takes place by transdifferentiation of the retinal pigmented epithelium (RPE) and the activation of retinal stem/progenitor cells (RS/ RPCs) present in the anterior region of the eye known as the ciliary margin (CM), which ultimately houses the ciliary body and ciliary marginal zone (14, 16).…”

mentioning

confidence: 99%

BMP signaling mediates stem/progenitor cell-induced retina regeneration

Haynes¹,

Gutierrez²,

Aycinena³

et al. 2007

Proceedings of the National Academy of Sciences

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We identified a mechanism whereby retina regeneration in the embryonic chick can be induced by the contribution of stem/ progenitor cells. We show that bone morphogenetic protein (BMP) signaling is sufficient and necessary to induce retina regeneration and that its action can be divided into two phases. By 3 days after postretinectomy (d PR), the BMP pathway directs proliferation and regeneration through the activation of Smad (canonical BMP pathway) and the up-regulation of FGF signaling by the MAPK pathway. By 7d PR, it induces apoptosis by activating p38 (a noncanonical BMP pathway) and down-regulating FGF signaling (by both MAPK and AKT pathways). Apoptosis at this later stage can be prevented, and BMP-induced regeneration can be further induced by inhibition of p38. These results unravel a mechanism for stem/ progenitor cell-mediated retina regeneration, where BMP activation establishes a cross-talk with the FGF pathway and selectively activates the canonical and noncanonical BMP pathways. Retina stem/progenitor cells exist in other species, including humans. Thus, our findings provide insights on how retinal stem cells can be activated for possible regenerative therapies.p38 ͉ FGF B one morphogenetic proteins (BMPs) are secreted signaling proteins that elicit their effect by binding to a heterodimer receptor complex composed of a BMP type I receptor (BMPRIA or BMPRIB) and a BMP type II receptor (BMPRII) (1). The BMP pathway can activate the canonical downstream effector, Smad, or a noncanonical downstream effector, transforming growth factor-␤-activated kinase (TAK1) (1). Several endogenous inhibitors, including noggin, chordin, follistatin, and gremlin, can regulate the ability of BMP to activate these pathways (2).In the developing retina, BMP2, BMP4, and BMP7, as well as the BMP receptors, are expressed in the chick (3) and mouse (4-6) and have been found to play a role in establishing the dorsal/ventral patterning of the retina. They also regulate the differentiation and survival of retinal neurons (7-11). Because of the BMP pathway's importance during retina development and in stem cell biology, we wanted to examine its role in inducing and regulating retina regeneration.A population of retinal stem cells is maintained after retinal development in the anterior margin of the eye in many vertebrates, including humans (12, 13). In most vertebrates, these retinal stem cells remain quiescent and do not respond to injury. However, cells in the anterior margin of the embryonic chick eye respond to injury during a limited time of retina development, providing an opportunity to study the induction process of these stem/progenitor cells (13-15).The embryonic chick has been shown to regenerate a complete retina in Ϸ7 days as long as a retinectomy is performed on or around embryonic day 4 (E4) and a source of FGF is added (14,16,17). In the presence of ectopic FGF2, regeneration takes place by transdifferentiation of the retinal pigmented epithelium (RPE) and the activation of retinal stem/progenitor cells (RS/ R...

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“…These layers are orientated with a revered polarity, the outer nuclear layer facing the vitreous side (Coulombre & Coulombre, 1965;Park & Hollenberg, 1989). Thus, the transdifferentiated retina contains many different types of cells.…”

Section: Introductionmentioning

confidence: 99%

Differential induction of gene expression by basic fibroblast growth factor and neuroD in cultured retinal pigment epithelial cells

Yan

Wang

2000

Vis Neurosci

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Embryonic chick retinal pigment epithelial (RPE) cells can undergo transdifferentiation upon appropriate stimulation. For example, basic fibroblast growth factor (bFGF) induces intact RPE tissue younger than embryonic day 4.5 (E4.5) to transdifferentiate into a neural retina. NeuroD, a gene encoding a basic helix-loop-helix transcription factor, triggers de novo production of cells that resemble young photoreceptor cells morphologically and express general neuron markers (HNK-1/ N-CAM and MAP2) and a photoreceptor-specific marker (visinin) from cell cultures of dissociated E6 RPE (Yan & Wang, 1998). The present study examined whether bFGF will lead to the same transdifferentiation phenomenon as neuroD when applied to dissociated, cultured E6 RPE cells, and whether interplay exists between the two factors under the culture conditions. Dissociated E6 RPE cells were cultured in the presence or absence of bFGF, and with or without the addition of retrovirus expressing neuroD. Gene expression was analyzed with immunocytochemistry and in situ hybridization. Unlike neuroD, bFGF did not induce the expression of visinin, or HNK-1/N-CAM and MAP2. However, bFGF elicited the expression of RA4 immunogenicity; yet, many of these RA4-positive cells lacked a neuronal morphology. Addition of bFGF to neuroD-expressing cultures did not alter the number of visinin-expressing cells; misexpression of neuroD in bFGF-treated cultures did not change the number of RA4-positive cells, suggesting the absence of interference or synergistic interaction between the two factors. Our data indicated that bFGF and neuroD induced the expression of different genes in cultured RPE cells.

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Basic fibroblast growth factor induces retinal regeneration in vivo

Cited by 276 publications

References 11 publications

Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue

Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue

BMP signaling mediates stem/progenitor cell-induced retina regeneration

Differential induction of gene expression by basic fibroblast growth factor and neuroD in cultured retinal pigment epithelial cells

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