Inhibition of DNA Methylation and Methyl-CpG-Binding Protein 2 Suppresses RPE Transdifferentiation: Relevance to Proliferative Vitreoretinopathy

He, Shikun; Barrón, Ernesto; Ishikawa, Keijiro; Khanamiri, Hossein Nazari; Spee, Chris; Zhou, Peng; Kase, Satoru; Wang, Zhuoshi; Dustin, Laurie; Hinton, David R.

doi:10.1167/iovs.14-16258

Cited by 24 publications

(33 citation statements)

References 67 publications

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“…Cells were plated equally and cultivated in serum-free medium for 12 h before experiments. EMT of RPE cells was induced with recombinant TGF-b2 at a concentration of 10 ng/ml for 48 h, as previous reported (22)(23)(24). BMP7 concentrations ranged from 0 to 100 ng/ml for 48 h.…”

Section: Cell Cultures and Models In Vitrosupporting

confidence: 55%

BMP7 antagonizes proliferative vitreoretinopathy through retinal pigment epithelial fibrosis in vivo and in vitro

Yao

Zhang

et al. 2018

FASEB j.

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The major pathogenesis of proliferative vitreoretinopathy (PVR) is that retinal pigment epithelial (RPE) cells undergo epithelial‐mesenchymal transition (EMT) because of disordered growth factors, such as TGF‐β, in the vitreous humor. Bone morphogenetic proteins (BMPs) are pluripotent growth factors. In this study, we identified the antifibrotic activity of BMP7 in a PVR model both in vivo and in vitro. BMP7 expression was confirmed on the PVR proliferative membranes. BMP7 was down‐regulated in the PVR vitreous humor and TGF‐β–induced RPE cell EMT. In the in vivo studies, BMP7 injection attenuated PVR progression in the eyes of the rabbit model. Additionally, BMP7 treatment maintained RPE cell phenotypes and relieved TGF‐β2–induced EMT, migration, and gel contraction in vitro. BMP7 inhibited the TGF‐β2–induced up‐regulation of fibronectin and α–smooth muscle actin and the down‐regulation of E‐cadherin and zona occludens‐1 by balancing the TGF‐β2/Smad2/3 and BMP7/Smad1/5/9 pathways. These findings provide direct evidence of the ability of BMP7 in PVR inhibition and the potential of BMP7 for use in PVR therapeutic intervention.—Yao, H., Ge, T., Zhang, Y., Li, M., Yang, S., Li, H., Wang, F. BMP7 antagonizes proliferative vitreoretinopathy through retinal pigment epithelial fibrosis in vivo and in vitro. FASEB J. 33, 3212–3224 (2019). http://www.fasebj.org

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Section: Cell Cultures and Models In Vitrosupporting

confidence: 55%

BMP7 antagonizes proliferative vitreoretinopathy through retinal pigment epithelial fibrosis in vivo and in vitro

Yao

Zhang

et al. 2018

FASEB j.

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“…Previous studies indicated that TGF-b1 and TGF-b2 are capable of modulating the PVR environment in vitro (including initiating EMT and migration in RPE) and have both been widely used in related studies. 5,14,16,[22][23][24][25] Our previous study 16 confirmed that TGF-b1 and TGF-b2 elicited similar EMT-initiating effects, including the downregulation of the expression of E-cadherin and ZO-1. Considering the similar effects of TGF-b1 and TGF-b2 in RPE cells and the predominant use of TGF-b1 in our laboratory, only TGF-b1 was used in this study.…”

Section: Discussionsupporting

confidence: 63%

The Interplay Between E-Cadherin, Connexin 43, and Zona Occludens 1 in Retinal Pigment Epithelial Cells

Bao

Yang

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Cell-cell contact in retinal pigment epithelium (RPE) involves adherent junctions, gap junctions, and tight junctions, which are primarily composed by E-cadherin, zona occludens 1 (ZO-1), and connexin 43, respectively. Here, we aimed to explore the relationship and interplay between these junction-associated proteins. METHODS. E-cadherin, connexin 43, and ZO-1 expression in human primary RPE in the early phase after TGF-b1 stimulation was detected. The knockdown of E-cadherin, ZO-1, and connexin 43 was performed to characterize the regulatory network involving these three proteins. Dye transfer and FITC-dextran permeability assays were conducted to observe the epithelial functional alterations. Transmission electron microscopy (TEM) was used to observe the ultrastructure of the cell-cell junctions in mouse RPE. The immunofluorescence staining and coimmunoprecipitation were performed to observe the colocalization and the physical association of E-cadherin, ZO-1, and connexin 43. RESULTS. Among these three components, E-cadherin appeared to be the first protein that was downregulated after TGF-b1 treatment. The ultrastructures of adherent junctions, gap junctions, and tight junctions could be observed in mouse RPE by TEM. E-cadherin, ZO-1, and connexin 43 were colocalized and physically bound to each other. The knockdown of one of these three proteins led to downregulation of the other two proteins and compromised epithelial function. CONCLUSIONS. E-cadherin, ZO-1, and connexin 43 were physically associated with each other and were mutually regulated. To enhance the understanding of cell-cell contacts, a holistic view is needed. Our results provide new insights in RPE disorders such as proliferative vitreoretinopathy.

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“…Previous in vitro studies and a small number of in vivo studies have demonstrated the ability of pharmacological inhibitors of DNA methylation, histone deacetylation, and histone methylation to suppress in vivo and culture-induced HSC transdifferentiation as well as development of fibrosis 12, 14, 43, 44, 45, 46, 47. The potential for epigenetic approaches to be exploited for suppressing fibrosis is also supported by in vivo investigations with mice lacking the master epigenetic regulator MeCP2, which is attenuated for fibrosis across multiple tissues, including liver, lung, heart, and retina 14, 48, 49, 50, 51, 52. The work we have described in this present study significantly advances these previous investigations by showing that in vivo administration of the epigenetic drug DZNep halts the progression of pre-established experimental liver fibrosis despite sustained liver damage.…”

Section: Discussionmentioning

confidence: 99%

A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis: Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A

et al. 2017

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The progression of fibrosis in chronic liver disease is dependent upon hepatic stellate cells (HSCs) transdifferentiating to a myofibroblast-like phenotype. This pivotal process is controlled by enzymes that regulate histone methylation and chromatin structure, which may be targets for developing anti-fibrotics. There is limited pre-clinical experimental support for the potential to therapeutically manipulate epigenetic regulators in fibrosis. In order to learn if epigenetic treatment can halt the progression of pre-established liver fibrosis, we treated mice with the histone methyltransferase inhibitor 3-deazaneplanocin A (DZNep) in a naked form or by selectively targeting HSC-derived myofibroblasts via an antibody-liposome-DZNep targeting vehicle. We discovered that DZNep treatment inhibited multiple histone methylation modifications, indicative of a broader specificity than previously reported. This broad epigenetic repression was associated with the suppression of fibrosis progression as assessed both histologically and biochemically. The anti-fibrotic effect of DZNep was reproduced when the drug was selectively targeted to HSC-derived myofibroblasts. Therefore, the in vivo modulation of HSC histone methylation is sufficient to halt progression of fibrosis in the context of continuous liver damage. This discovery and our novel HSC-targeting vehicle, which avoids the unwanted effects of epigenetic drugs on parenchymal liver cells, represents an important proof-of-concept for epigenetic treatment of liver fibrosis.

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Inhibition of DNA Methylation and Methyl-CpG-Binding Protein 2 Suppresses RPE Transdifferentiation: Relevance to Proliferative Vitreoretinopathy

Cited by 24 publications

References 67 publications

BMP7 antagonizes proliferative vitreoretinopathy through retinal pigment epithelial fibrosis in vivo and in vitro

BMP7 antagonizes proliferative vitreoretinopathy through retinal pigment epithelial fibrosis in vivo and in vitro

The Interplay Between E-Cadherin, Connexin 43, and Zona Occludens 1 in Retinal Pigment Epithelial Cells

A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis: Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A

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