BMP7 antagonizes proliferative vitreoretinopathy through retinal pigment epithelial fibrosis
            <i>in vivo</i>
            and
            <i>in vitro</i>

Yao, Haipei; Ge, Tandi; Zhang, Yao; Li, Min; Yang, Shuai; Li, Hui; Wang, Fang

doi:10.1096/fj.201800858rr

Cited by 37 publications

(27 citation statements)

References 38 publications

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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: 61%

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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Section: Discussionsupporting

confidence: 61%

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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“…TGF-β induces EMT of RPE cells via two pathways: the classical SMAD-dependent pathway and the SMAD-independent pathway ( Fig. 2 ) ( Cai et al, 2018 ; He et al, 2017 ; Heffer et al, 2019 ; Ishikawa et al, 2015 ; Takahashi, Haga & Tanihara, 2015 ; Yao et al, 2019 ; Zhang et al, 2017 ; Zhang et al, 2018b ; Zhou et al, 2017 ). In the SMAD dependent pathway, TGF-β binds to cell surface receptor complexes, and activates type I TGF-β receptors, which phosphorylate SMAD2 and SMAD3.…”

Section: Survey Methodologymentioning

confidence: 99%

Polarity and epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy

Zou

Shan

et al. 2020

PeerJ

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Under physiological conditions, retinal pigment epithelium (RPE) is a cellular monolayer composed of mitotically quiescent cells. Tight junctions and adherens junctions maintain the polarity of RPE cells, and are required for cellular functions. In proliferative vitreoretinopathy (PVR), upon retinal tear, RPE cells lose cell-cell contact, undergo epithelial-mesenchymal transition (EMT), and ultimately transform into myofibroblasts, leading to the formation of fibrocellular membranes on both surfaces of the detached retina and on the posterior hyaloids, which causes tractional retinal detachment. In PVR, RPE cells are crucial contributors, and multiple signaling pathways, including the SMAD-dependent pathway, Rho pathway, MAPK pathways, Jagged/Notch pathway, and the Wnt/β-catenin pathway are activated. These pathways mediate the EMT of RPE cells, which play a key role in the pathogenesis of PVR. This review summarizes the current body of knowledge on the polarized phenotype of RPE, the role of cell-cell contact, and the molecular mechanisms underlying the RPE EMT in PVR, emphasizing key insights into potential approaches to prevent PVR.

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“…A prior study showed that an RAR-γ agonist inhibits the development of subretinal fibrosis in mice by inhibiting the TGF-β pathway (Kimura et al, 2015). Bone morphogenetic proteins (BMPs) are pluripotent growth factors which have anti-fibrotic activity (Yao et al, 2019). Injections of BMP7 in a rabbit PVR model maintained RPE cell phenotypes and prevented TGF-β2-induced EMT, migration and gel contraction (Yao et al, 2019).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

“…Bone morphogenetic proteins (BMPs) are pluripotent growth factors which have anti-fibrotic activity (Yao et al, 2019). Injections of BMP7 in a rabbit PVR model maintained RPE cell phenotypes and prevented TGF-β2-induced EMT, migration and gel contraction (Yao et al, 2019). Anti-inflammatory agents, including Bortezomib, a proteasome inhibitor that regulates the NF-κB pathway, and resveratrol, a polyphenol phytoalexin and heavy chain-hyaluronan/pentraxin3, inhibit EMT in RPE cells and prevent PVR development by downregulating the TGF-β pathway (Ishikawa et al, 2015;He et al, 2017;Moon et al, 2017).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Role of Epithelial-Mesenchymal Transition in Retinal Pigment Epithelium Dysfunction

Zhou

Geathers

Grillo

et al. 2020

Front. Cell Dev. Biol.

134

101

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Retinal pigment epithelial (RPE) cells maintain the health and functional integrity of both photoreceptors and the choroidal vasculature. Loss of RPE differentiation has long been known to play a critical role in numerous retinal diseases, including inherited rodcone degenerations, inherited macular degeneration, age-related macular degeneration, and proliferative vitreoretinopathy. Recent studies in post-mortem eyes have found upregulation of critical epithelial-mesenchymal transition (EMT) drivers such as TGFβ, Wnt, and Hippo. As RPE cells become less differentiated, they begin to exhibit the defining characteristics of mesenchymal cells, namely, the capacity to migrate and proliferate. A number of preclinical studies, including animal and cell culture experiments, also have shown that RPE cells undergo EMT. Taken together, these data suggest that RPE cells retain the reprogramming capacity to move along a continuum between polarized epithelial cells and mesenchymal cells. We propose that movement along this continuum toward a mesenchymal phenotype be defined as RPE Dysfunction. Potential mechanisms include impaired tight junctions, accumulation of misfolded proteins and dysregulation of several key pathways and molecules, such as TGF-β pathway, Wnt pathway, nicotinamide, microRNA 204/211 and extracellular vesicles. This review synthesizes the evidence implicating EMT of RPE cells in post-mortem eyes, animal studies, primary RPE, iPSC-RPE and ARPE-19 cell lines.

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

Cited by 37 publications

References 38 publications

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

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

Polarity and epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy

Role of Epithelial-Mesenchymal Transition in Retinal Pigment Epithelium Dysfunction

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