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Integrin activation or alpha 9 expression allows retinal pigmented epithelial cell adhesion on Bruch's membrane in wet age-related macular degeneration

Integrin activation or alpha 9 expression allows retinal pigmented epithelial cell adhesion on Bruch's membrane in wet age-related macular degeneration
Integrin activation or alpha 9 expression allows retinal pigmented epithelial cell adhesion on Bruch's membrane in wet age-related macular degeneration

Retinal pigment epithelial cell malfunction is a causative feature of age-related macular degeneration, and transplantation of new retinal pigment epithelial cells is an attractive strategy to prevent further progression and visual loss. However, transplants have shown limited efficacy, mainly because transplanted cells fail to adhere and migrate onto pathological Bruch's membrane. Adhesion to Bruch's membrane is integrin-mediated. Ageing of Bruch's membrane leads to a decline in integrin ligands and, added to this, wet age-related macular degeneration leads to upregulation of anti-adhesive molecules such as tenascin-C. We have therefore investigated whether manipulation of integrin function in retinal pigment epithelial cells can restore their adhesion and migration on wet age-related macular degeneration-damaged Bruch's membrane. Using spontaneously immortalized human retinal pigment epithelial cells (adult retinal pigment epithelium-19), we show that adhesion and migration on the Bruch's membrane components is integrin-dependent and enhanced by integrin-activating agents manganese and TS2/16. These allowed cells to adhere and migrate on low concentrations of ligand, as would be found in aged Bruch's membrane. We next developed a method for stripping cells from Bruch's membrane so that adhesion and migration assays can be performed on its surface. Integrin activation had a moderate effect on enhancing retinal pigmented epithelial cell adhesion and migration on normal human and rat Bruch's membrane. However, on Bruch's membrane prepared from human wet age-related macular degeneration-affected eyes, adhesion was lower and integrin activation had a much greater effect. A candidate molecule for preventing retinal pigmented epithelial interaction with age-related macular degeneration-affected Bruch's membrane is tenascin-C which we confirm is present at high levels in wet age-related macular degeneration membrane. We show that tenascin-C is anti-adhesive for retinal pigmented epithelial cells, but after integrin activation, they can adhere and migrate on it using alphaVbeta3 integrin. Alternatively, we find that transduction of retinal pigmented epithelial cells with alpha9 integrin, a tenascin-C-binding integrin, led to a large increase in alpha9beta1-mediated adhesion and migration on tenascin-C. Both expression of alpha9 integrin and integrin activation greatly enhanced the ability of retinal pigment epithelial cells to adhere to tenascin-rich wet age-related macular degeneration-affected Bruch's membranes. Our results suggest that manipulation of retinal pigment epithelial cell integrins through integrin activating strategies, or expression of new integrins such as alpha9, could be effective in improving the efficacy of retinal pigment epithelial cell transplantation in wet age-related macular degeneration-affected eyes.

Integrins, retinal pigment epithelium, Bruch's membrane, tenascin-c, age-related macular degeneration
0006-8950
448-464
Afshari, Fardad T.
de0c61c1-1d49-4f60-8b14-f828a1446c14
Kwok, Jessica C.
29521ef5-70b3-4827-9b7d-93bbf88cbe06
Andrews, Melissa R.
ae987a2f-878e-4ae3-a7a3-a7170712096c
Blits, Bas
424cb0bc-63d2-4112-a2d5-c5ddd014790c
Martin, Keith R.
33ec4b82-8d76-4ab1-9a34-3abfa7d0f56d
Faissner, Andreas
c19f1d2b-1cbb-43ba-a45d-7d9c9c2cb10e
Ffrench-Constant, Charles
e9a015d3-a5b8-4789-bd19-d21d7dcabf77
Fawcett, James W.
4549730e-9f62-45b8-820b-8a9c98d1058b
Afshari, Fardad T.
de0c61c1-1d49-4f60-8b14-f828a1446c14
Kwok, Jessica C.
29521ef5-70b3-4827-9b7d-93bbf88cbe06
Andrews, Melissa R.
ae987a2f-878e-4ae3-a7a3-a7170712096c
Blits, Bas
424cb0bc-63d2-4112-a2d5-c5ddd014790c
Martin, Keith R.
33ec4b82-8d76-4ab1-9a34-3abfa7d0f56d
Faissner, Andreas
c19f1d2b-1cbb-43ba-a45d-7d9c9c2cb10e
Ffrench-Constant, Charles
e9a015d3-a5b8-4789-bd19-d21d7dcabf77
Fawcett, James W.
4549730e-9f62-45b8-820b-8a9c98d1058b

Afshari, Fardad T., Kwok, Jessica C., Andrews, Melissa R., Blits, Bas, Martin, Keith R., Faissner, Andreas, Ffrench-Constant, Charles and Fawcett, James W. (2010) Integrin activation or alpha 9 expression allows retinal pigmented epithelial cell adhesion on Bruch's membrane in wet age-related macular degeneration. Brain, 133 (2), 448-464. (doi:10.1093/brain/awp319).

Record type: Article

Abstract

Retinal pigment epithelial cell malfunction is a causative feature of age-related macular degeneration, and transplantation of new retinal pigment epithelial cells is an attractive strategy to prevent further progression and visual loss. However, transplants have shown limited efficacy, mainly because transplanted cells fail to adhere and migrate onto pathological Bruch's membrane. Adhesion to Bruch's membrane is integrin-mediated. Ageing of Bruch's membrane leads to a decline in integrin ligands and, added to this, wet age-related macular degeneration leads to upregulation of anti-adhesive molecules such as tenascin-C. We have therefore investigated whether manipulation of integrin function in retinal pigment epithelial cells can restore their adhesion and migration on wet age-related macular degeneration-damaged Bruch's membrane. Using spontaneously immortalized human retinal pigment epithelial cells (adult retinal pigment epithelium-19), we show that adhesion and migration on the Bruch's membrane components is integrin-dependent and enhanced by integrin-activating agents manganese and TS2/16. These allowed cells to adhere and migrate on low concentrations of ligand, as would be found in aged Bruch's membrane. We next developed a method for stripping cells from Bruch's membrane so that adhesion and migration assays can be performed on its surface. Integrin activation had a moderate effect on enhancing retinal pigmented epithelial cell adhesion and migration on normal human and rat Bruch's membrane. However, on Bruch's membrane prepared from human wet age-related macular degeneration-affected eyes, adhesion was lower and integrin activation had a much greater effect. A candidate molecule for preventing retinal pigmented epithelial interaction with age-related macular degeneration-affected Bruch's membrane is tenascin-C which we confirm is present at high levels in wet age-related macular degeneration membrane. We show that tenascin-C is anti-adhesive for retinal pigmented epithelial cells, but after integrin activation, they can adhere and migrate on it using alphaVbeta3 integrin. Alternatively, we find that transduction of retinal pigmented epithelial cells with alpha9 integrin, a tenascin-C-binding integrin, led to a large increase in alpha9beta1-mediated adhesion and migration on tenascin-C. Both expression of alpha9 integrin and integrin activation greatly enhanced the ability of retinal pigment epithelial cells to adhere to tenascin-rich wet age-related macular degeneration-affected Bruch's membranes. Our results suggest that manipulation of retinal pigment epithelial cell integrins through integrin activating strategies, or expression of new integrins such as alpha9, could be effective in improving the efficacy of retinal pigment epithelial cell transplantation in wet age-related macular degeneration-affected eyes.

Full text not available from this repository.

More information

Accepted/In Press date: 28 October 2009
e-pub ahead of print date: 10 February 2010
Published date: February 2010
Keywords: Integrins, retinal pigment epithelium, Bruch's membrane, tenascin-c, age-related macular degeneration
Organisations: Biomedicine

Identifiers

Local EPrints ID: 411368
URI: http://eprints.soton.ac.uk/id/eprint/411368
ISSN: 0006-8950
PURE UUID: c6f76eb8-d0e2-430b-a119-bb8b4b1567a9
ORCID for Melissa R. Andrews: ORCID iD orcid.org/0000-0001-5960-5619

Catalogue record

Date deposited: 19 Jun 2017 16:31
Last modified: 20 Jul 2019 00:28

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