Cell Signaling Pathways in Vertebrate Lens Regeneration

Henry, Jonathan J.; Thomas, Alvin G.; Hamilton, Paul W.; Moore, Lisa; Perry, Kimberly J.

doi:10.1007/82_2012_289

Cited by 19 publications

(17 citation statements)

References 100 publications

(128 reference statements)

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“…Certain vertebrates can completely regenerate a lens. In newts, for example, the new lens arises from the pigmented iris epithelium, via the de-differentiation and transdifferentiation of retinal epithelial cells, in a process called Wolffian lens regeneration (reviewed by Henry et al, 2013). In frogs, a new lens arises during larval stages from basal cells of the corneal epithelium, which are possibly uncommitted epithelial stem cells.…”

Section: Fgf Signaling In Lens Regenerationmentioning

confidence: 99%

Fibroblast growth factors: key players in regeneration and tissue repair

2017

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Tissue injury initiates a complex repair process, which in some organisms can lead to the complete regeneration of a tissue. In mammals, however, the repair of most organs is imperfect and results in scar formation. Both regeneration and repair are orchestrated by a highly coordinated interplay of different growth factors and cytokines. Among the key players are the fibroblast growth factors (FGFs), which control the migration, proliferation, differentiation and survival of different cell types. In addition, FGFs influence the expression of other factors involved in the regenerative response. Here, we summarize current knowledge on the roles of endogenous FGFs in regeneration and repair in different organisms and in different tissues and organs. Gaining a better understanding of these FGF activities is important for appropriate modulation of FGF signaling after injury to prevent impaired healing and to promote organ regeneration in humans.

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Section: Fgf Signaling In Lens Regenerationmentioning

confidence: 99%

Fibroblast growth factors: key players in regeneration and tissue repair

2017

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“…In vertebrates, one organ capable of complete regeneration is the lens of the eye. However, the capacity to replace this structure is restricted to certain species of frogs, one fish, and some newts and salamanders (Henry et al, 2013; Henry and Tsonis, 2010). Newts are able to regenerate a lens via transdifferentiation of the dorsal pigmented iris epithelium, in a process referred to as Wolffian regeneration (see Henry and Tsonis, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…The involvement of multiple pathways suggests that this process is regulated by a complex signaling network, and it is possible that other pathways may also be involved. One pathway that has been implicated as playing a role in cornea-lens regeneration in two independent screens for genes expressed during early regeneration is the Wnt signaling pathway (Day and Beck, 2011; Henry et al, 2013; Malloch et al, 2009). In the canonical Wnt/β-catenin signaling pathway, wnt ligands bind to corresponding frizzled receptors and associated co-receptors in order to inhibit the downstream β-catenin degradation complex (reviewed in Logan and Nusse, 2004; MacDonald et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Lens regeneration from the cornea requires suppression of Wnt/β-catenin signaling

Hamilton

Henry

2016

Experimental Eye Research

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The frog, Xenopus laevis, possesses a high capacity to regenerate various larval tissues, including the lens, which is capable of complete regeneration from the cornea epithelium. However, the molecular signaling mechanisms of cornea-lens regeneration are not fully understood. Previous work has implicated the involvement of the Wnt signaling pathway, but molecular studies have been very limited. Iris-derived lens regeneration in the newt (Wolffian lens regeneration) has shown a necessity for active Wnt signaling in order to regenerate a new lens. Here we provide evidence that the Wnt signaling pathway plays a different role in the context of cornea-lens regeneration in Xenopus. We examined the expression of frizzled receptors and wnt ligands in the frog cornea epithelium. Numerous frizzled receptors (fzd1, fzd2, fzd3, fzd4, fzd6, fzd7, fzd8, and fzd10) and wnt ligands (wnt2b.a, wnt3a, wnt4, wnt5a, wnt5b, wnt6, wnt7b, wnt10a, wnt11, and wnt11b) are expressed in the cornea epithelium, demonstrating that this tissue is transcribing many of the ligands and receptors of the Wnt signaling pathway. When compared to flank epithelium, which is lens regeneration incompetent, only wnt11 and wnt11b are different (present only in the cornea epithelium), identifying them as potential regulators of cornea-lens regeneration. To detect changes in canonical Wnt/β-catenin signaling occurring within the cornea epithelium, axin2 expression was measured over the course of regeneration. axin2 is a well-established reporter of active Wnt/β-catenin signaling, and its expression shows a significant decrease at 24 hours post-lentectomy. This decrease recovers to normal endogenous levels by 48 hours. To test whether this signaling decrease was necessary for lens regeneration to occur, regenerating eyes were treated with either 6-bromoindirubin-3’-oxime (BIO) or 1-azakenpaullone – both activators of Wnt signaling – resulting in a significant reduction in the percentage of cases with successful regeneration. In contrast, inhibition of Wnt signaling using either the small molecule IWR-1, treatment with recombinant human Dickkopf-1 (rhDKK1) protein, or transgenic expression of Xenopus DKK1, did not significantly affect the percentage of successful regeneration. Together, these results suggest a model where Wnt/β-catenin signaling is active in the cornea epithelium and needs to be suppressed during early lens regeneration in order for these cornea cells to give rise to a new lentoid. While this finding differs from what has been described in the newt, it closely resembles the role of Wnt signaling during the initial formation of the lens placode from the surface ectoderm during early embryogenesis.

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“…40,41 TGFb-2 released from the lens is required for the expression of transcription factors PITX2 and FOXC1 in the NC-derived cornea and in the chamber-angle structures of the eye that controls IOP. 42 TGFb-2 enhances FOXC1 and induces PITX2 expression in cell cultures. Based on the above findings, it can be stated that the lens is considered to be the center for the development of corneal endothelium and stroma, and the signal molecules generated by them reach the targeted part possibly through the anterior chamber.…”

Section: Discussionmentioning

confidence: 99%

Directed Differentiation of Human Corneal Endothelial Cells From Human Embryonic Stem Cells by Using Cell-Conditioned Culture Media

Chen

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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Citation: Chen X, Wu L, Li Z, et al. Directed differentiation of human corneal endothelial cells from human embryonic stem cells by using cellconditioned culture media. Invest Ophthalmol Vis Sci. 2018;59:3028-3036. https://doi.org/10.1167/ iovs.17-23627 PURPOSE. A shortage of human corneal endothelial cells (HCEC) for transplant and current methods of differentiation induction require chemical compounds, which might cast further influences after differentiation induction. Therefore, we developed a simple and straightforward approach to endothelial cell differentiation from human embryonic stem cells (hESC).METHODS. HESC are used to differentiate into HCEC by employing a two-stage method, which involves the application of two different types of conditioned culture medium, human corneal stromal cell-conditioned medium (HCSC-CM) and lens epithelial cell (LEC) plus HCSC-CM (LEC-CMþHCEC-CM). In brief, hESCs were treated with different conditioned media to induce directed endothelial differentiation. RESULTS.In the presence of conditioned culture medium, embryonic stem cells differentiate first under the control of periocular mesenchymal precursors (POMPs). Consequently, the expression of several POMP markers was observed. Following this first stage differentiation, POMPs were further directed to differentiate into corneal endothelial cell (CEC)-like cells in the presence of the second-conditioned culture medium. The differentiation of POMPs into CEC-like cells is regulated by a TGFb-2/FOXC1 signaling pathway that is activated by the factors present in the conditioned culture medium.CONCLUSIONS. HCEC-like cells could be differentiated from hESC by simply using a two-step, preconditioned, medium-mediated approach, which could significantly minimize the workload to generate HCEC for potential clinical use. This research may provide an ideal cell source for corneal regenerative medicine and clinical treatment for corneal diseases in the future.

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Cell Signaling Pathways in Vertebrate Lens Regeneration

Cited by 19 publications

References 100 publications

Fibroblast growth factors: key players in regeneration and tissue repair

Fibroblast growth factors: key players in regeneration and tissue repair

Lens regeneration from the cornea requires suppression of Wnt/β-catenin signaling

Directed Differentiation of Human Corneal Endothelial Cells From Human Embryonic Stem Cells by Using Cell-Conditioned Culture Media

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