期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
卷 1863, 期 7, 页码 750-761出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2018.04.007
关键词
Lysophosphatidic acid; Autotaxin; Human pluripotent stem cell; Optic cup; Retinal pigment epithelium; Tight junction
资金
- National Health and Medical Research Council (NHMRC) [1059369]
- Ophthalmic Research Institute of Australia
- Retina Australia
- Joan and Peter Clemenger Foundation
- Philip Neal bequest
- Centre for Stem Cell Systems
- JEM Research Foundation
- Centre for Eye Research Australia Foundation
- NHMRC [1133237, 1103013, 1103329]
- Australian Research Council [FT140100047]
- Australian Postgraduate Award Scholarships
- International Postgraduate Award Scholarships
- University of Melbourne
- Victorian Government
- National Health and Medical Research Council of Australia [1103013, 1103329, 1059369, 1133237] Funding Source: NHMRC
- Australian Research Council [FT140100047] Funding Source: Australian Research Council
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 I 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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