Role of lysophosphatidic acid in the retinal pigment epithelium and photoreceptors |
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Authors: | Grace E. Lidgerwood Andrew J. Morris Alison Conquest Maciej Daniszewski Louise A. Rooney Shiang Y. Lim Damián Hernández Helena H. Liang Penelope Allen Paul P. Connell Robyn H. Guymer Alex W. Hewitt Alice Pébay |
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Affiliation: | 1. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia;2. Ophthalmology, Department of Surgery, The University of Melbourne, Melbourne, Australia;3. Division of Cardiovascular Medicine, University of Kentucky, College of Medicine and Veterans Affairs Medical Center, Lexington, KY, USA;4. O''Brien Institute Department, St Vincent Institute of Medical Research, Fitzroy, Australia.;5. Mater Misericordiae University Hospital, Dublin, Ireland;6. School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia |
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Abstract: | The human retina is a complex structure of organised layers of specialised cells that support the transmission of light signals to the visual cortex. The outermost layer of the retina, the retinal pigment epithelium (RPE), forms part of the blood retina barrier and is implicated in many retinal diseases. Lysophosphatidic acid (LPA) is a bioactive lipid exerting pleiotropic effects in various cell types, during development, normal physiology and disease. Its producing enzyme, AUTOTAXIN (ATX), is highly expressed by the pigmented epithelia of the human eye, including the RPE. Using human pluripotent stem cell (hPSC)-derived retinal cells, we interrogated the role of LPA in the human RPE and photoreceptors. hPSC-derived RPE cells express and synthesize functional ATX, which is predominantly secreted apically of the RPE, suggesting it acts in a paracrine manner to regulate photoreceptor function. In RPE cells, LPA regulates tight junctions, in a receptor-dependent mechanism, with an increase in OCCLUDIN and ZONULA OCCLUDENS (ZO)-1 expression at the cell membrane, accompanied by an increase in the transepithelial resistance of the epithelium. High concentration of LPA decreases phagocytosis of photoreceptor outer segments by the RPE. In hPSC-derived photoreceptors, LPA induces morphological rearrangements by modulating the actin myosin cytoskeleton, as evidenced by Myosin Light Chain l membrane relocation. Collectively, our data suggests an important role of LPA in the integrity and functionality of the healthy retina and blood retina barrier. |
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Keywords: | ATX/ENNP2 Autotaxin EMT Epithelial mesenchymal transition hESC Human embryonic stem cell hPSC Human pluripotent stem cell iPSC Induced pluripotent stem cell LC-MS Liquid Chromatography-Mass Spectroscopy LPA Lysophosphatidic acid RPE Retinal pigment epithelium TEER Transepithelial electrical resistance Lysophosphatidic acid Autotaxin Human pluripotent stem cell Optic cup Retinal pigment epithelium Tight junction |
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