Role of lysophosphatidic acid in the retinal pigment epithelium and photoreceptors

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

doi:10.1016/j.bbalip.2018.04.007

Role of lysophosphatidic acid in the retinal pigment epithelium and photoreceptors

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

Internal Medicine

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

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.

Original language	English
Pages (from-to)	750-761
Number of pages	12
Journal	Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume	1863
Issue number	7
DOIs	https://doi.org/10.1016/j.bbalip.2018.04.007
State	Published - Jul 2018

Bibliographical note

Publisher Copyright:
© 2018

Funding

The authors declare no conflict of interest. We thank J. Thomson (University of Wisconsin) for providing the iPSC line iPS (Foreskin) 4 clone 2; I. Trounce (Centre for Eye Research Australia) and M. Al-Ubaidi (University of Oklahoma, USA) for providing the immortalized mouse 661W line; Penny A. Mckelvie (St Vincent Hospital, Melbourne, Australia) for sectioning of the human eyes, Annie K. Mcauley (CERA) and Tejal Kulkarni (CERA) for technical assistance, the Lions Eye Donation Service (Melbourne) for providing human donor eyes, Alastair G. Stewart (University of Melbourne) for providing access to the EVOM2 voltohemeter, and the Melbourne Brain Centre's flow Cytometry core facility. This work was supported by grants from the National Health and Medical Research Council (NHMRC, 1059369), The Ophthalmic Research Institute of Australia, Retina Australia, the Joan and Peter Clemenger Foundation, the Philip Neal bequest, the Centre for Stem Cell Systems, the JEM Research Foundation, the Centre for Eye Research Australia Foundation, a NHMRC Dora Lush Biomedical Postgraduate Research Scholarship 1133237 (AC), a NHMRC Research Fellowship 1103013 (RHG), a NHMRC Practitioner Fellowship 1103329 (AWH), an Australian Research Council Future Fellowship FT140100047 (AP), Australian Postgraduate Award Scholarships (GEL, MD), an International Postgraduate Award Scholarships (MD), the University of Melbourne and Operational Infrastructure Support from the Victorian Government. GEL: concept and design, experimental work, interpretation of data, writing of manuscript, final approval of manuscript; AC, AM, MD, LAR, SYL, DH: experimental work, interpretation of data, final approval of manuscript; HHL, PA, PPC, RHG, AGS: provision of samples or equipment, final approval of manuscript; AWH: provision of samples, interpretation of data, final approval of manuscript; AP: concept and design, financial support, interpretation of data, writing of manuscript, final approval of manuscript.

Funders	Funder number
Centre for Eye Research Australia Foundation
Clemenger Foundation
Centre for Stem Cell Systems
Victorian State Government
The University of Melbourne
JEM Research Foundation
The Ophthalmic Research Institute of Australia
American Geriatrics Society
Future Fellowship FT140100047
Practitioner Fellowship 1103329
NHMRC Research	1103013, 1103329
Australian Research Council	FT140100047
Australian Research Council
NHMRC Dora Lush Biomedical Postgraduate Research Scholarship 1133237	1133237
Australian National Health and Medical Research Council	1059369
Australian National Health and Medical Research Council

Keywords

Autotaxin
Human pluripotent stem cell
Lysophosphatidic acid
Optic cup
Retinal pigment epithelium
Tight junction

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbalip.2018.04.007

Cite this

Lidgerwood, G. E., Morris, A. J., Conquest, A., Daniszewski, M., Rooney, L. A., Lim, S. Y., Hernández, D., Liang, H. H., Allen, P., Connell, P. P., Guymer, R. H., Hewitt, A. W., & Pébay, A. (2018). Role of lysophosphatidic acid in the retinal pigment epithelium and photoreceptors. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1863(7), 750-761. https://doi.org/10.1016/j.bbalip.2018.04.007

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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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doi = "10.1016/j.bbalip.2018.04.007",

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Lidgerwood, GE, Morris, AJ, Conquest, A, Daniszewski, M, Rooney, LA, Lim, SY, Hernández, D, Liang, HH, Allen, P, Connell, PP, Guymer, RH, Hewitt, AW & Pébay, A 2018, 'Role of lysophosphatidic acid in the retinal pigment epithelium and photoreceptors', Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, vol. 1863, no. 7, pp. 750-761. https://doi.org/10.1016/j.bbalip.2018.04.007

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AU - Lidgerwood, Grace E.

AU - Morris, Andrew J.

AU - Conquest, Alison

AU - Daniszewski, Maciej

AU - Rooney, Louise A.

AU - Lim, Shiang Y.

AU - Hernández, Damián

AU - Liang, Helena H.

AU - Allen, Penelope

AU - Connell, Paul P.

AU - Guymer, Robyn H.

AU - Hewitt, Alex W.

AU - Pébay, Alice

PY - 2018/7

Y1 - 2018/7

N2 - 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.

AB - 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.

KW - Autotaxin

KW - Human pluripotent stem cell

KW - Lysophosphatidic acid

KW - Optic cup

KW - Retinal pigment epithelium

KW - Tight junction

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JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids

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Role of lysophosphatidic acid in the retinal pigment epithelium and photoreceptors

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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