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10.1186/s13073-015-0183-x http://scihub22266oqcxt.onion/10.1186/s13073-015-0183-x C4491894!4491894!26150894     free     free     free Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Genome+Med 2015 ; 7 (1): ä Nephropedia Template TP {{tp|p=26150894|t=2015. Restoration of mesenchymal retinal pigmented epithelial cells by TGF? pathway inhibitors: implications for age-related macular degeneration |pdf=|usr=}}{{26150894}} gab.com Text Restoration of mesenchymal retinal pigmented epithelial cells by TGF pathway inhibitors: implications for age-related macular degeneration JO: Genome Med http://www.kidney.de/pget.php?&tw=1&pmid=26150894 #FOAvip Background: Age-related macular degeneration (AMD) is a leading cause of blindness. Most vision loss occurs following the transition from a disease of deposit formation and inflammation to a disease of neovascular fibrosis and/or cell death. Here, we investigate how repeated wound stimulus leads to seminal changes in gene expression and the onset of a perpetual state of stimulus-independent wound response in retinal pigmented epithelial (RPE) cells, a cell-type central to the etiology of AMD. Methods: Transcriptome wide expression profiles of human fetal RPE cell cultures as a function of passage and time post-plating were determined using Agilent 44 K whole genome microarrays and RNA-Seq. Using a systems level analysis, differentially expressed genes and pathways of interest were identified and their role in the establishment of a persistent mesenchymal state was assessed using pharmacological-based experiments. Results: Using a human fetal RPE cell culture model that considers monolayer disruption and subconfluent culture as a proxy for wound stimulus, we show that prolonged wound stimulus leads to terminal acquisition of a mesenchymal phenotype post-confluence and altered expression of more than 40 % of the transcriptome. In contrast, at subconfluence fewer than 5 % of expressed transcripts have two-fold or greater expression differences after repeated passage. Protein-protein and pathway interaction analysis of the genes with passage-dependent expression levels in subconfluent cultures reveals a 158-node interactome comprised of two interconnected modules with functions pertaining to wound response and cell division. Among the wound response genes are the TGF? pathway activators: TGFB1, TGFB2, INHBA, INHBB, GDF6, CTGF, and THBS1. Significantly, inhibition of TGFBR1/ACVR1B mediated signaling using receptor kinase inhibitors both forestalls and largely reverses the passage-dependent loss of epithelial potential; thus extending the effective lifespan by at least four passages. Moreover, a disproportionate number of RPE wound response genes have altered expression in neovascular and geographic AMD, including key members of the TGF? pathway. Conclusions: In RPE cells the switch to a persistent mesenchymal state following prolonged wound stimulus is driven by lasting activation of the TGF? pathway. Targeted inhibition of TGF? signaling may be an effective approach towards retarding AMD progression and producing RPE cells in quantity for research and cell-based therapies. Electronic supplementary material: The online version of this article (doi:10.1186/s13073-015-0183-x) contains supplementary material, which is available to authorized users. Twit Text FOAVip Restoration of mesenchymal retinal pigmented epithelial cells by TGF pathway inhibitors: implications for age-related macular degeneration ????Genome Med http://www.kidney.de/pget.php?&tw=1&pmid=26150894 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=26150894 #FOAvip English Wikipedia <ref>{{Cite pmid|26150894}}</ref> Restoration of mesenchymal retinal pigmented epithelial cells by TGF? pathway inhibitors: implications for age-related macular degeneration #MMPMID26150894 Radeke MJ; Radeke CM; Shih YH; Hu J; Bok D; Johnson LV; Coffey PJ Genome Med 2015[]; 7 (1): ä PMID26150894show ga Background: Age-related macular degeneration (AMD) is a leading cause of blindness. Most vision loss occurs following the transition from a disease of deposit formation and inflammation to a disease of neovascular fibrosis and/or cell death. Here, we investigate how repeated wound stimulus leads to seminal changes in gene expression and the onset of a perpetual state of stimulus-independent wound response in retinal pigmented epithelial (RPE) cells, a cell-type central to the etiology of AMD. Methods: Transcriptome wide expression profiles of human fetal RPE cell cultures as a function of passage and time post-plating were determined using Agilent 44 K whole genome microarrays and RNA-Seq. Using a systems level analysis, differentially expressed genes and pathways of interest were identified and their role in the establishment of a persistent mesenchymal state was assessed using pharmacological-based experiments. Results: Using a human fetal RPE cell culture model that considers monolayer disruption and subconfluent culture as a proxy for wound stimulus, we show that prolonged wound stimulus leads to terminal acquisition of a mesenchymal phenotype post-confluence and altered expression of more than 40 % of the transcriptome. In contrast, at subconfluence fewer than 5 % of expressed transcripts have two-fold or greater expression differences after repeated passage. Protein-protein and pathway interaction analysis of the genes with passage-dependent expression levels in subconfluent cultures reveals a 158-node interactome comprised of two interconnected modules with functions pertaining to wound response and cell division. Among the wound response genes are the TGF? pathway activators: TGFB1, TGFB2, INHBA, INHBB, GDF6, CTGF, and THBS1. Significantly, inhibition of TGFBR1/ACVR1B mediated signaling using receptor kinase inhibitors both forestalls and largely reverses the passage-dependent loss of epithelial potential; thus extending the effective lifespan by at least four passages. Moreover, a disproportionate number of RPE wound response genes have altered expression in neovascular and geographic AMD, including key members of the TGF? pathway. Conclusions: In RPE cells the switch to a persistent mesenchymal state following prolonged wound stimulus is driven by lasting activation of the TGF? pathway. Targeted inhibition of TGF? signaling may be an effective approach towards retarding AMD progression and producing RPE cells in quantity for research and cell-based therapies. Electronic supplementary material: The online version of this article (doi:10.1186/s13073-015-0183-x) contains supplementary material, which is available to authorized users. äRestoration of mesenchymal retinal pigmented epithelial cells by TGF? 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