Reprogramming of the chick retinal pigmented epithelium after retinal injury

Luz-Madrigal, Agustín; Grajales-Esquivel, Erika; McCorkle, Alexander; DiLorenzo, Ashley; Barbosa-Sabanero, Karla Y; Tsonis, Panagiotis A.; Rio‐Tsonis, Katia Del

doi:10.1186/1741-7007-12-28

Cited by 59 publications

(96 citation statements)

References 81 publications

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“…The most notable difference between the gut and the RNC is the absence of SoxB1 expression during early stages of intestinal regeneration, whereas it remains expressed at the normal level in the injured radial nerve. This observation suggests that cell dedifferentiation in the gut mesothelium does not require expression of SoxB1 , which is puzzling, as Sox2, the homolog of H. glaberrima SoxB1, is not merely expressed in various vertebrate regeneration models (Christen et al, 2010; Luz-Madrigal et al, 2014; Maki et al, 2009; Perry et al, 2013), but is absolutely required for regeneration (Christen et al, 2010). The functional significance of SoxB1 down-regulation in the regenerating sea cucumber intestine is unknown and can only be determined in future experiments involving forced ectopic over-expression.…”

Section: Discussionmentioning

confidence: 99%

Expression of pluripotency factors in echinoderm regeneration

2014

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Cell dedifferentiation is an integral component of post-traumatic regeneration in echinoderms. Since dedifferentiated cells become multipotent, we asked if this spontaneous broadening of developmental potential is associated with the action of the same pluripotency factors (known as Yamanaka factors) that were used to induce pluripotency in specialized mammalian cells. In this study, we investigate expression of orthologs of the four Yamanaka factors in regeneration of two different organs, the radial nerve cord and the digestive tube, in the sea cucumber Holothuria glaberrima. All four pluripotency factors are expressed in uninjured animals, although their expression domains do not always overlap. In regeneration, the expression levels of the four genes were not regulated in a coordinated way, but, instead, showed different dynamics for individual genes and also were different between the radial nerve and the gut. SoxB1, the ortholog of the mammalian Sox2, was drastically downregulated in the regenerating intestine, suggesting that this factor is not required for dedifferentiation/regeneration in this organ. On the other hand, during the early post-injury stage, Myc, the sea cucumber ortholog of c-Myc, was significantly upregulated in both the intestine and the radial nerve cord, and is, therefore, hypothesized to play a central role in dedifferentiation/regeneration of various tissue types.

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Section: Discussionmentioning

confidence: 99%

Expression of pluripotency factors in echinoderm regeneration

2014

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“…Changes in redox status were documented by measuring levels of immunofluorescence when using an antibody against 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) which covalently binds to oxidized adducts in proteins. Previous work in our laboratory determined that activation of transcription factors necessary for induction of regeneration occurs in response to injury by 6 hours (h) post-retinectomy (PR) (Luz-Madrigal et al, 2014). Therefore, we investigated changes in the redox status within the CM at both 6h PR and 24h PR to be certain measurements were within the window of induction.…”

Section: Resultsmentioning

confidence: 99%

A biochemical basis for induction of retina regeneration by antioxidants

Echeverri-Ruíz

Haynes

Landers

et al. 2018

Developmental Biology

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The use of antioxidants in tissue regeneration has been studied, but their mechanism of action is not well understood. Here, we analyze the role of the antioxidant N-acetylcysteine (NAC) in retina regeneration. Embryonic chicks are able to regenerate their retina after its complete removal from retinal stem/progenitor cells present in the ciliary margin (CM) of the eye only if a source of exogenous factors, such as FGF2, is present. This study shows that NAC modifies the redox status of the CM, initiates self-renewal of the stem/progenitor cells, and induces regeneration in the absence of FGF2. NAC works as an antioxidant by scavenging free radicals either independently or through the synthesis of glutathione (GSH), and/or by reducing oxidized proteins through a thiol disulfide exchange activity. We dissected the mechanism used by NAC to induce regeneration through the use of inhibitors of GSH synthesis and the use of other antioxidants with different biochemical structures and modes of action, and found that NAC induces regeneration through its thiol disulfide exchange activity. Thus, our results provide, for the first time, a biochemical basis for induction of retina regeneration. Furthermore, NAC induction was independent of FGF receptor signaling, but dependent on the MAPK (pErk1/2) pathway.

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“…In contrast, several non-mammalian vertebrates, including the chick, have the potential to regenerate their entire retina from endogenous cell populations after retinal damage Luz-Madrigal et al, 2019 4 [4,5]. The embryonic chick can regenerate its retina at embryonic day (E) 4-4.5 (stages 23-25; [6,7]) by reprogramming cells of the retinal pigment epithelium (RPE) into retina progenitor cells that eventually differentiate into the major retinal cell types [8][9][10][11]. We previously demonstrated that during the Phase I of RPE reprogramming, within 6 hours after surgical removal of the retina (retinectomy), the quiescent cells of the RPE transiently reprogram (these cells are referred to as transient reprogrammed RPE, t-rRPE), and express pluripotency inducing factors including sox2, c-myc, klf4, and eye field transcription factors (EFTF), while simultaneously down-regulating RPE specific markers [11].…”

Section: Introductionmentioning

confidence: 99%

DNA demethylation is a driver for chick retina regeneration

Luz-Madrigal

Grajales-Esquivel

Tangeman

et al. 2019

Preprint

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ABSTRACTBackgroundA promising avenue toward human retina regeneration lies in identifying the factors that promote cellular reprogramming to retinal neurons in organisms able to undergo retina regeneration. The embryonic chick can regenerate a complete neural retina, after retinectomy, via retinal pigment epithelium (RPE) reprogramming in the presence of FGF2. Cellular reprogramming resets the epigenetic landscape to drive shifts in transcriptional programs and cell identity. Here, we systematically analyzed the reprogramming competent chick RPE prior to injury, and during different stages of reprogramming. We examined the dynamic changes in the levels and distribution of histone marks and DNA modifications, as well as conducted a comprehensive analysis of the DNA methylome during this process.ResultsIn addition to changes in the expression of genes associated with epigenetic modifications during RPE reprogramming, we observed dynamic changes in histone marks and intermediates of the process of DNA demethylation. At early times after injury, H3K27me3 and 5mC repression marks decreased while 5caC and the H3K4me3 activation mark increased, suggesting genome-wide changes in the bivalent chromatin, impaired DNA methylation, and active DNA demethylation in the chromatin reconfiguration of reprogramming RPE. Comprehensive analysis of the methylome by whole-genome bisulfite sequencing (WGBS) confirmed extensive rearrangements of DNA methylation patterns including differentially methylated regions (DMRs) found at promoters of genes associated with chromatin organization and fibroblast growth factor production. In contrast, genes associated with early RPE reprogramming are hypomethylated in the intact RPE and remain hypomethylated during the process. During the generation of a neuroepithelium (NE) at later stages of reprogramming, decreased levels of H3K27me3, 5mC, and 5hmC coincide with elevated levels of H3K27Ac and 5caC, indicating an active demethylation process and genome-wide changes in the active regulatory landscape. Finally, we identify Tet methylcytosine dioxygenase 3 (TET3) as an important factor for DNA demethylation and retina regeneration in the embryonic chick, capable of reprogramming RPE in the absence of exogenous FGF2.ConclusionOur results demonstrated that injury signals early in RPE reprogramming trigger genome-wide dynamic changes in chromatin, including bivalent chromatin and DNA methylation. In the presence of FGF2 these dynamic modifications are further sustained in the commitment to form a new retina. We identify DNA demethylation as a key process driving the process of RPE reprogramming and identified TET3 as a factor able to reprogram RPE in absence of FGF2. Our findings reveal active DNA demethylation as an important process that may be applied to remove the epigenetic barriers in order to regenerate retina in mammals.

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Reprogramming of the chick retinal pigmented epithelium after retinal injury

Cited by 59 publications

References 81 publications

Expression of pluripotency factors in echinoderm regeneration

Expression of pluripotency factors in echinoderm regeneration

A biochemical basis for induction of retina regeneration by antioxidants

DNA demethylation is a driver for chick retina regeneration

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