Abstract:
PURPOSE:To investigate the role of N-cadherin and hepatocyte growth factor (HGF) in the invasion of collagen type I by human retinal pigment epithelial (RPE) cells. METHODS:RPE sheets from eight human eyes were used for characterization through Western blot analysis of the expression of cadherin in total lysates or after immunoprecipitation with anti beta-catenin antibody. First-passage primary cultures of RPE sheets were successfully established from 28 of 56 human eyes. First-passage primary RPE cell cultures on glass substrate, consisting of patches of cells, were used for immunocytochemistry. Fifteen first-passage primary RPE cell cultures in culture vessels were grown to confluence. Four of the 15 first-passage primary RPE cell cultures were investigated for cadherin expression by immunocytochemistry, and the other 11 were further subcultured for two to six passages. These 11 cultures were used for functional assays and investigated for expression of cadherin at regular time intervals. Cells from passage-3 to -4 primary RPE cell cultures were tested for invasion into collagen type I gels, with or without neutralizing antibodies for HGF and N-cadherin, respectively. Activation of the c-Met receptor for HGF and of focal adhesion kinase (FAK) was investigated by immunoprecipitation with anti-phosphotyrosine antibody, gel electrophoresis, and immunostaining on Western blot. Levels of HGF in conditioned medium (CM) of RPE cells were determined by ELISA. RESULTS:RPE cells in culture displayed two phenotypes: Both fibroblast-like and epithelioid cells were present in all 15 first-passage primary cultures and in further passaged cultures derived therefrom. When seeded on collagen, all RPE cells acquired a fibroblast-like phenotype and invaded the collagen type I gel. RPE cells also stimulated branching morphogenesis of MDCK/AZ epithelial canine kidney cell colonies inside collagen. HGF was found in RPE CM, suggesting an autocrine loop for invasion through its c-Met receptor. HGF-neutralizing antibody inhibited invasion of collagen. The major cadherin expressed by RPE cells in culture was N(euronal)-cadherin. Invasion of collagen by RPE cells was also inhibited by an N-cadherin-neutralizing antibody. N-cadherin and c-Met coimmunoprecipitated in RPE cells. FAK and c-Met were both phosphorylated in RPE cells in culture, and phosphorylation was inhibited by antibodies neutralizing either N-cadherin or HGF. CONCLUSIONS:The present investigation provides evidence for an autocrine HGF/c-Met loop that stimulates RPE cell invasion into collagen through FAK. The invasion-stimulatory molecule N-cadherin also activates FAK in invasive RPE cells.
journal_name
Invest Ophthalmol Vis Scijournal_title
Investigative ophthalmology & visual scienceauthors
Van Aken EH,De Wever O,Van Hoorde L,Bruyneel E,De Laey JJ,Mareel MMdoi
10.1167/iovs.01-1096keywords:
subject
Has Abstractpub_date
2003-02-01 00:00:00pages
463-72issue
2eissn
0146-0404issn
1552-5783journal_volume
44pub_type
杂志文章abstract:PURPOSE:To examine the signal transduction pathways involved in the activation of orbital fibroblast effector functions relevant to the pathogenesis of Graves' ophthalmopathy (GO). To determine, using antisense technology, whether the c-myc protooncogene is involved in cell proliferation and glycosaminoglycan (GAG) syn...
journal_title:Investigative ophthalmology & visual science
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abstract:PURPOSE:To reconstruct the role played by vascular endothelium in the elevation of circulating von Willebrand factor (vWf) in diabetic patients with microangiopathy and, specifically, to determine whether storage and synthesis of vWf is altered in diabetic retinal vessels. METHODS:Trypsin digests were prepared from re...
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abstract::The therapeutic effect of citrate on alkali-burned eyes is thought to be the result of inhibition of PMN activities while ascorbate apparently stimulates the production of new collagen by scorbutic fibroblasts. Attachment of PMNs to the vascular endothelium is the initial PMN response to mediators and must occur befor...
journal_title:Investigative ophthalmology & visual science
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更新日期:1988-06-01 00:00:00
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journal_title:Investigative ophthalmology & visual science
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更新日期:1993-05-01 00:00:00
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journal_title:Investigative ophthalmology & visual science
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doi:
更新日期:1997-02-01 00:00:00
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更新日期:1981-01-01 00:00:00
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doi:
更新日期:2002-08-01 00:00:00
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journal_title:Investigative ophthalmology & visual science
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更新日期:1985-08-01 00:00:00
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更新日期:1984-11-01 00:00:00
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journal_title:Investigative ophthalmology & visual science
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