The Complex Interplay between ERK1/2, TGFβ/Smad, and Jagged/Notch Signaling Pathways in the Regulation of Epithelial-Mesenchymal Transition in Retinal Pigment Epithelium Cells

Chen, Xiaoyun; Xiao, Wei; Wang, Wencong; Luo, Lixia; Ye, Shaobi; Liu, Yizhi

doi:10.1371/journal.pone.0096365

Cited by 48 publications

(40 citation statements)

References 27 publications

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“…In the posterior eye, they are the likely causative factor behind the EMT of the RPE, a process that includes marked structural and functional alterations such as loss of the outer blood-retina barrier, reduced expression of RPE-characteristic genes, upregulation of αSMA and change from a cuboidal to a more spindle-shaped phenotype. Quite comparable changes as observed here in vivo have been reported for TGF-β-treated cultured RPE cells from various mammalian species (Gamulescu et al 2006;Kurosaka et al 1996;Lee et al 2001;Jun and Joo 2016;Tamiya and Kaplan 2016;Dvashi et al 2015;Yang et al 2016;Chen et al 2014). Overall, there is strong evidence that TGF-β signaling is among the most potent inducers of EMT in numerous epithelial cell types in and outside the eye (Miettinen et al 1994;Saika et al 2004;Roberts et al 2006;Thiery et al 2009;Thiery and Sleeman 2006;Kalluri and Neilson 2003;Guarino et al 2009;Hales et al 1994;Xu et al 2009).…”

Section: Discussionsupporting

confidence: 86%

“…Since in culture conditions transforming growth factor-β (TGF-β) signaling has been reported to be a potent mediator of EMT in RPE cells (Gamulescu et al 2006;Kurosaka et al 1996;Lee et al 2001;Chen et al 2014;Tamiya and Kaplan 2016;Dvashi et al 2015;Jun and Joo 2016;Yang et al 2016), we studied the retinal phenotype of βB1-TGF-β1 mice, a transgenic mouse strain with an ocular overexpression of active TGF-β1 (Flügel-Koch et al 2002). Here, we show that the RPE of βB1-TGF-β1 mice undergoes an EMT, a process that becomes manifest after birth.…”

Section: Introductionmentioning

confidence: 99%

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Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

Ohlmann

Scholz

Koch

et al. 2016

Histochem Cell Biol

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Epithelial-to-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is commonly observed at sites of choroidal neovascularization in patients suffering from age-related macular degeneration. To learn in an experimental model how RPE EMT affects the biology of the choroidal vasculature, we studied transgenic mice (βB1-TGF-β1) with ocular overexpression of transforming growth factor-β1 (TGF-β1). RPE EMT was detectable at postnatal day (P)1 and included marked structural and functional alterations such as loss of the outer blood-retina barrier and reduced mRNA expression of the RPE-characteristic molecules Rlbp1, Rpe65, Rbp1 and Vegfa. Moreover, vascular endothelial growth factor (VEGF) was not detectable by immunohistochemistry at the RPE/choroid interface, while RPE cells stained intensely for α-smooth muscle actin. The choriocapillaris, the characteristic choroidal capillary network adjacent to the RPE, developed normally and was not obviously changed in embryonic transgenic eyes but was absent at P1 indicating its atrophy. At around the same time, photoreceptors stopped to differentiate and photoreceptor apoptosis was abundant in the second week of life. Structural changes were also seen in the retinal vasculature of transgenic animals, which did not form intraretinal vessels, and the hyaloid vasculature, which did not regress. In addition, the amounts of retinal HIF-1α and its mRNA were markedly reduced. We conclude that high amounts of active TGF-β1 in the mouse eye cause transdifferentiation of the RPE to a mesenchymal phenotype. The loss of epithelial differentiation leads to the diminished synthesis of RPE-characteristic molecules including that of VEGF. Lack of RPE-derived VEGF causes atrophy of the choriocapillaris, a scenario that disrupts photoreceptor differentiation and finally results in photoreceptor apoptosis. Lack of retinal vessel formation and of hyaloid vessel regression might be caused by the decrease in the metabolic requirements of the neuroretina leading to low amounts of retinal HIF-1α. In summary, our data indicate that failure of RPE differentiation may well precede and cause atrophy of the choriocapillaris. In contrast, RPE EMT is not sufficient to cause choroidal neovascularization.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

Ohlmann

Scholz

Koch

et al. 2016

Histochem Cell Biol

View full text Add to dashboard Cite

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“…Other eye-specific myofibroblast precursors are cells derived from the lamina cribrosa in glaucoma (Kirwan et al, 2005;Wallace et al, 2014) and Müller cells in proliferative diabetic retinopathy (Guidry et al, 2009). EMT is another local source to possibly generate ocular myofibroblasts from human lens epithelial cells (Dawes et al, 2009;Liu et al, 1994;Lovicu et al, 2015;Nishi et al, 1996), retinal pigment epithelial cells (Chen et al, 2014;Parapuram et al, 2009), and corneal epithelial progenitor cells (Kawakita et al, 2005;Kawakita et al, 2013). Special to the eye is the possible M A N U S C R I P T…”

Section: Myofibroblast Precursors Of the Eyementioning

confidence: 99%

Myofibroblasts

Hinz¹

2016

Experimental Eye Research

362

341

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Myofibroblasts are activated in response to tissue injury with the primary task to repair lost or damaged extracellular matrix. Enhanced collagen secretion and subsequent contraction - scarring - are part of the normal wound healing response and crucial to restore tissue integrity. Due to myofibroblasts ability to repair but not regenerate, accumulation of scar tissue is always associated with reduced organ performance. This is a fair price to pay by the body for not falling apart. Whereas myofibroblasts typically vanish after successful repair, dysregulation of the normal repair process can lead to persistent myofibroblast activation, for instance by chronic inflammation or mechanical stress in the tissue. Excessive repair leads to the accumulation of stiff collagenous ECM contractures - fibrosis - with dramatic consequences for organ function. The clinical need to terminate detrimental myofibroblast activities has stimulated researchers to answer a number of essential questions: where do myofibroblasts come from, what are the factors leading to their activation, how do we discriminate myofibroblasts from other cells, what is the molecular basis for their contractile activity, and how can we stop or at least control them? This article reviews the current state of the myofibroblast literature by emphasizing their role in ocular repair and fibrosis. It appears that although the eye is quite an extraordinary organ, ocular myofibroblasts behave or misbehave just like their siblings in other organs.

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“…TGFβ2 activates the p38 MAPK pathway and blockade of this pathway inhibited the expression and synthesis of collagen type I in human RPE cells (Kimoto et al, 2004). Chen et al showed that TGFβ2 induced the activation of ERK1/2 and Jagged/Notch signaling in human RPE cells (Chen et al, 2014b). Inhibition of ERK1/2 signaling using U0126 prevented the progression of EMT in RPE cells by abrogating both the Smad and Jagged/Notch signaling pathways (Chen et al, 2014b).…”

Section: Proliferative Retinal Diseasementioning

confidence: 99%

Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis

Shu

Lovicu

2017

Progress in Retinal and Eye Research

284

239

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Wound healing is one of the most complex biological processes to occur in life. Repair of tissue following injury involves dynamic interactions between multiple cell types, growth factors, inflammatory mediators and components of the extracellular matrix (ECM). Aberrant and uncontrolled wound healing leads to a non-functional mass of fibrotic tissue. In the eye, fibrotic disease disrupts the normally transparent ocular tissues resulting in irreversible loss of vision. A common feature in fibrotic eye disease is the transdifferentiation of cells into myofibroblasts that can occur through a process known as epithelial-mesenchymal transition (EMT). Myofibroblasts rapidly produce excessive amounts of ECM and exert tractional forces across the ECM, resulting in the distortion of tissue architecture. Transforming growth factor-beta (TGFβ) plays a major role in myofibroblast transdifferentiation and has been implicated in numerous fibrotic eye diseases including corneal opacification, pterygium, anterior subcapsular cataract, posterior capsular opacification, proliferative vitreoretinopathy, fibrovascular membrane formation associated with proliferative diabetic retinopathy, submacular fibrosis, glaucoma and orbital fibrosis. This review serves to introduce the pathological functions of the myofibroblast in fibrotic eye disease. We also highlight recent developments in elucidating the multiple signaling pathways involved in fibrogenesis that may be exploited in the development of novel anti-fibrotic therapies to reduce ocular morbidity due to scarring.

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The Complex Interplay between ERK1/2, TGFβ/Smad, and Jagged/Notch Signaling Pathways in the Regulation of Epithelial-Mesenchymal Transition in Retinal Pigment Epithelium Cells

Cited by 48 publications

References 27 publications

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

Epithelial–mesenchymal transition of the retinal pigment epithelium causes choriocapillaris atrophy

Myofibroblasts

Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis

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