Dichloroacetate prevents TGFβ-induced epithelial-mesenchymal transition of retinal pigment epithelial cells

Shukal, Dhaval; Bhadresha, Kinjal; Shastri, Bhoomi; Mehta, Deval; Vasavada, Abhay R.; Johar, Kaid

doi:10.1016/j.exer.2020.108072

Cited by 29 publications

(22 citation statements)

References 68 publications

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“…The PI3K/Akt pathway mediates a broad range of cellular functions, such as cell transformation, migration, proliferation, apoptosis, and gene expression ( Aguilar-Solis et al, 2017 ; Liu et al, 2019 ). During PVR, binding of TGF-β to its receptor activates PI3K, resulting in the phosphorylation of Akt; activated Akt inhibits glycogen synthase kinase 3β (GSK-3β), promoting EMT in RPE cells ( Shukal et al, 2020 ; Zhang et al, 2018a ). Researchers have found that inhibition or knockdown of GSK-3β promotes cell migration and collagen contraction in ARPE-19 cells, while GSK-3β overexpression and PI3K/Akt inhibitor reverse these cellular responses ( Huang et al, 2017 ).…”

Section: Survey Methodologymentioning

confidence: 99%

“… Hatanaka et al (2012) reported that PPAR-γ agonist pioglitazone could prevent TGF-β-induced morphological changes and the up-regulation of EMT-related markers in primary monkey RPE cells, through inhibition of the SMAD pathway. Some drugs, including dichloroacetate (DCA) ( Shukal et al, 2020 ), salinomycin (SNC) ( Heffer et al, 2019 ), resveratrol ( Ishikawa et al, 2015 ), protein kinase A inhibitor H89 ( Lyu et al, 2020 ) and heavy chain-hyaluronan/pentraxin3 ( He et al, 2017 ), reportedly inhibit EMT in an in vitro EMT cell model and prevent PVR development by blocking the activation of theTGF-β pathway. Thus, inhibition of EMT by pharmacological agents may be an effective strategy to prevent PVR development.…”

Section: Survey Methodologymentioning

confidence: 99%

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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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Section: Survey Methodologymentioning

confidence: 99%

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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“…Moreover, defects in the major energy sensor, AMP-activated protein kinase (AMPK), have been implicated in EMT of RPE [104]. Enhancing mitochondrial respiration using dichloroacetate, a structural analogue of pyruvate, blocked TGFβ2-induced EMT in RPE [105]. High glucose induces both EMT [106] and EndMT [107] in RPE and retinal endothelial cells, respectively, implicating the role of hyperglycaemia-induced metabolic dysfunction.…”

Section: Metabolic Dysfunction and Autophagy In Amdmentioning

confidence: 99%

EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

Shu

Butcher

Saint‐Geniez

2020

IJMS

174

138

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Epithelial–mesenchymal transition (EMT) and endothelial–mesenchymal transition (EndMT) are physiological processes required for normal embryogenesis. However, these processes can be hijacked in pathological conditions to facilitate tissue fibrosis and cancer metastasis. In the eye, EMT and EndMT play key roles in the pathogenesis of subretinal fibrosis, the end-stage of age-related macular degeneration (AMD) that leads to profound and permanent vision loss. Predominant in subretinal fibrotic lesions are matrix-producing mesenchymal cells believed to originate from the retinal pigment epithelium (RPE) and/or choroidal endothelial cells (CECs) through EMT and EndMT, respectively. Recent evidence suggests that EMT of RPE may also be implicated during the early stages of AMD. Transforming growth factor-beta (TGFβ) is a key cytokine orchestrating both EMT and EndMT. Investigations in the molecular mechanisms underpinning EMT and EndMT in AMD have implicated a myriad of contributing factors including signaling pathways, extracellular matrix remodelling, oxidative stress, inflammation, autophagy, metabolism and mitochondrial dysfunction. Questions arise as to differences in the mesenchymal cells derived from these two processes and their distinct mechanistic contributions to the pathogenesis of AMD. Detailed discussion on the AMD microenvironment highlights the synergistic interactions between RPE and CECs that may augment the EMT and EndMT processes in vivo. Understanding the differential regulatory networks of EMT and EndMT and their contributions to both the dry and wet forms of AMD can aid the development of therapeutic strategies targeting both RPE and CECs to potentially reverse the aberrant cellular transdifferentiation processes, regenerate the retina and thus restore vision.

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“…The PI3K/Akt pathway mediates a broad range of cellular functions, such as cell transformation, migration, proliferation, apoptosis, and gene expression (Aguilar-Solis et al 2017;Liu et al 2019). During PVR, binding of TGF-β to its receptor activates PI3K, resulting in the phosphorylation of Akt; activated Akt inhibits glycogen synthase kinase 3β (GSK-3β), promoting EMT in RPE cells (Shukal et al 2020;Zhang et al 2018a). Researchers have found that inhibition or knockdown of GSK-3β promotes cell migration and collagen contraction in ARPE-19 cells, while GSK-3β overexpression and PI3K/Akt inhibitor reverse these cellular responses (Huang et al 2017).…”

Section: Signaling Pathways Of Emtmentioning

confidence: 99%

“…Hatanaka et al (2012) reported that PPAR-γ agonist pioglitazone could prevent TGF-β-induced morphological changes and the upregulation of EMT-related markers in primary monkey RPE cells, through inhibition of the SMAD pathway. Some drugs, including dichloroacetate (DCA) (Shukal et al 2020), salinomycin (SNC) (Heffer et al 2019), resveratrol (Ishikawa et al 2015), protein kinase A inhibitor H89 (Lyu et al 2020) and heavy chain-hyaluronan/pentraxin3 (He et al 2017), reportedly inhibit EMT in an in vitro EMT cell model and prevent PVR development by blocking the activation of theTGF-β pathway. Thus, inhibition of EMT by pharmacological agents may be an effective strategy to prevent PVR development.…”

Section: Interventions Of Rpe Emtmentioning

confidence: 99%

Peer Review #1 of "Polarity and epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy (v0.1)"

2020

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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 SMADdependent pathway, Rho pathway, MAPK pathways, Jagged/Notch pathway, and Wnt/βcatenin 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.

show abstract

Dichloroacetate prevents TGFβ-induced epithelial-mesenchymal transition of retinal pigment epithelial cells

Cited by 29 publications

References 68 publications

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

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

EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

Peer Review #1 of "Polarity and epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy (v0.1)"

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