Lens and retina regeneration: new perspectives from model organisms

Barbosa-Sabanero, Karla Y; Hoffmann, Andrea; Judge, Chelsey J.; Lightcap, Nicole; Tsonis, Panagiotis A.; Rio‐Tsonis, Katia Del

doi:10.1042/bj20120813

Cited by 91 publications

(68 citation statements)

References 161 publications

(254 reference statements)

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“…It is known from several organisms, that transdifferentiation occurs by the following steps: transient dedifferentiation, proliferation and differentiation into the new linage [1,51]. However, the time of dedifferentiation and proliferation is highly dependent on the type of damage and model of regeneration.…”

Section: Resultsmentioning

confidence: 99%

“…Several vertebrate species have the capacity to transdifferentiate the retinal pigmented epithelium (RPE) to retina (for reviews, see [1,2]). In the chick, the process of RPE transdifferentiation was first described based on histological observations [3].…”

Section: Introductionmentioning

confidence: 99%

“…However, the ectopic expression of pax6 is sufficient to induce RPE transdifferentiation in the intact developing chick eye up to E14 (Stage 35) [7]. In chick RPE cultures, overexpression of different pro-neural transcriptional factors such as sox2 , ash1 , ath5 , neuroD , neurogenin1 , neurogenin3 , cath5 and msx2 can promote the transdifferentiation of the RPE into neuronal cells (reviewed in [1]). By contrast, there are several factors associated with RPE specification, including Mitf , Otx2 , Wnt13 , BMP , Shh and Activin [6,8-15].…”

Section: Introductionmentioning

confidence: 99%

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Reprogramming of the chick retinal pigmented epithelium after retinal injury

et al. 2014

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BackgroundOne of the promises in regenerative medicine is to regenerate or replace damaged tissues. The embryonic chick can regenerate its retina by transdifferentiation of the retinal pigmented epithelium (RPE) and by activation of stem/progenitor cells present in the ciliary margin. These two ways of regeneration occur concomitantly when an external source of fibroblast growth factor 2 (FGF2) is present after injury (retinectomy). During the process of transdifferentiation, the RPE loses its pigmentation and is reprogrammed to become neuroepithelium, which differentiates to reconstitute the different cell types of the neural retina. Somatic mammalian cells can be reprogrammed to become induced pluripotent stem cells by ectopic expression of pluripotency-inducing factors such as Oct4, Sox2, Klf4, c-Myc and in some cases Nanog and Lin-28. However, there is limited information concerning the expression of these factors during natural regenerative processes. Organisms that are able to regenerate their organs could share similar mechanisms and factors with the reprogramming process of somatic cells. Herein, we investigate the expression of pluripotency-inducing factors in the RPE after retinectomy (injury) and during transdifferentiation in the presence of FGF2.ResultsWe present evidence that upon injury, the quiescent (p27Kip1+/BrdU-) RPE cells transiently dedifferentiate and express sox2, c-myc and klf4 along with eye field transcriptional factors and display a differential up-regulation of alternative splice variants of pax6. However, this transient process of dedifferentiation is not sustained unless FGF2 is present. We have identified lin-28 as a downstream target of FGF2 during the process of retina regeneration. Moreover, we show that overexpression of lin-28 after retinectomy was sufficient to induce transdifferentiation of the RPE in the absence of FGF2.ConclusionThese findings delineate in detail the molecular changes that take place in the RPE during the process of transdifferentiation in the embryonic chick, and specifically identify Lin-28 as an important factor in this process. We propose a novel model in which injury signals initiate RPE dedifferentiation, while FGF2 up-regulates Lin-28, allowing for RPE transdifferentiation to proceed.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reprogramming of the chick retinal pigmented epithelium after retinal injury

et al. 2014

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“…To date, adult lens regeneration has been observed only in newts including the species Notophthalmus viridescens, Triturus viridescens and Cynops pyrrhogaster (Reyer, 1954;Yamada, 1967Yamada, , 1977. Lens regeneration in adult newts is a well-understood process of natural transdifferentiation (Eguchi, 1988;Barbosa-Sabanero et al, 2012). Following lentectomy, pigmented epithelial cells (PECs) from the dorsal iris first dedifferentiate to precursor cells, then form a new lens ventricle, re-enter the cell cycle and subsequently differentiate into new lineages to restore the lost lens (Fig.…”

Section: Amphibiansmentioning

confidence: 99%

Regeneration across Metazoan Phylogeny: Lessons from Model Organisms

Yang

Zhong

2015

Journal of Genetics and Genomics

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“…When NR is damaged, the adult newt can regenerate an entire functional NR by reprogramming the RPE. In contrast, mammalian RPE (mouse) cells often reprogram and undergo an epithelial-mesenchymal transition resulting in scar formation [1,2]. Since both the mouse and the newt can reprogram their RPE cells in the face of retina damage, we compared the similarities and differences of the RPE between the regenerative newt model and non-regenerative mouse model.…”

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confidence: 99%

One Simple and Reproducible Sample Prep Protocol Used to Compare the Surface Topography (SEM) of the Mouse and Newt RPE and the Bruch's Membrane

et al. 2017

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Retinal pigmented epithelium (RPE) supports the neural retina (NR), and responds to NR injury. When NR is damaged, the adult newt can regenerate an entire functional NR by reprogramming the RPE. In contrast, mammalian RPE (mouse) cells often reprogram and undergo an epithelial-mesenchymal transition resulting in scar formation [1,2]. Since both the mouse and the newt can reprogram their RPE cells in the face of retina damage, we compared the similarities and differences of the RPE between the regenerative newt model and non-regenerative mouse model. However, current SEM protocols were designed for the whole eyecup, which easily undergos morphological and structural deformation ( fig.1A,B) during critical point drying (CPD) [3]. Here, we combined light microscopy (LM) cryosectioning and modified SEM techniques to generate one simple and reproducible protocol, which we use to compare the surface topography of the mouse and the newt RPE and underlying Bruch's membrane.Whole eyes with the optic nerve were detached from the ocular muscles of adult newts and mice. The anterior eye with the iris and lens were separated from the posterior eyecup based on published protocols in mice [4]. The posterior eyecups were fixed in 2.5% glutaraldehyde and 2% formaldehyde in 0.05M cacodylate buffer for 4 hours at 4 0 C. After extended washes, the samples went through a gradual sucrose gradient from 7.5% to 80% at 12hrs each in 4 0 C before being cryo-embedded in Optimal Cutting Temperature (OCT) medium on dry ice. 25µm cryostat sample sections were collected on gelatin-coated 12mm cover glass. Sections were post-fixed in the above fixative for an additional 12hrs at 4 0 C. After extended washes with the same buffer, samples were fixed in 1%OsO4 for 1 hour on ice. After ddH2O washes, the samples were en bloc stained with 1%uranyl acetate overnight at room temperature (RT). After washes, the samples were dehydrated through a gradient of ethanol (EtOH) from 50%-70% on ice, and from 80% to 100% at RT for 60min each. The samples were further dehydrated in 100% EtOH overnight twice. They were then CPD with 1hr CO2/EtOH exchange time. The samples were viewed under the Zeiss Supra 35 VP FEG-SEM after coated with 20nm of gold.This protocol resulted in minimal morphological and structural deformation (figs.1A & B vs C & D) during processing and sectioning which permitted reliable measurements of retinal thickness in both newt and mouse eyes. The data of the cryo-sectioned adult C57BL/6 mouse and Notophthalmus viridescens newt eyecups showed that the thickness of the mouse NR is 228µm, which is significantly thinner than the newt at 500µm (fig.1C&D). Additionally, under higher mag (35,000x), three intact layers: (1) RPE) (2) BrM) and (3) choroid were identified in each model. Moreover, the samples revealed elongated and oblated melanosome-like structures preserved as solid bodies. The thickness of the BrM in the two models was between 3.0-4.0µm ( fig.2), which is consistent with recent findings [5][6][7]. Further interspecies comparisons of ...

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Lens and retina regeneration: new perspectives from model organisms

Cited by 91 publications

References 161 publications

Reprogramming of the chick retinal pigmented epithelium after retinal injury

Reprogramming of the chick retinal pigmented epithelium after retinal injury

Regeneration across Metazoan Phylogeny: Lessons from Model Organisms

One Simple and Reproducible Sample Prep Protocol Used to Compare the Surface Topography (SEM) of the Mouse and Newt RPE and the Bruch's Membrane

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