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Shigeo Tamiya, LanHsin Liu, Henry J. Kaplan; Tyrosine Kinase Inhibitors Prevent Retinal Pigment Epithelial Cell EMT and Growth. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6593.
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© ARVO (1962-2015); The Authors (2016-present)
Proliferative vitreoretinopathy (PVR) is the major complication of retinal reattachment surgery as well as ocular trauma. Past studies have indicated that epithelial-mesenchymal transition (EMT) and aberrant cell growth of retinal pigment epithelial (RPE) cells play a key role in the development of PVR. EMT and cell growth is regulated by a variety of tyrosine kinases in other cell types. In this study, the effect of tyrosine kinase inhibitors (TKIs) on RPE cell EMT and proliferation was examined using an in vitro RPE sheet culture model.
Porcine RPE sheets, isolated using dispase, were cultured on porcine lens capsules. The following TKIs were used: PP2, a Src family kinase (SFK) selective inhibitor which also inhibits c-kit, Abl, and PDGF-R; PP3, an inactive analogue of PP2; SU6656, a SFK specific inhibitor; dasatinib, a dual inhibitor of SFK and Abl; and imatinib, an inhibitor of c-kit, Abl, and PDGF-R. Migration distance of the edge of the sheet over a 6 day period was measured in the presence and absence of TKIs. In addition, an endpoint assay of proliferation was performed using the BrdU uptake method.
In the absence of TKIs, RPE cells at the edge of the sheet undergo EMT and start to migrate and proliferate. All TKIs tested significantly inhibited migration and proliferation. At 10microM, both PP2 and dasatinib inhibited migration by ~90% and the cells remained heavily pigmented suggesting that they failed to undergo EMT. Inactive compound PP3 had no effect on cell migration and proliferation similar to the vehicle control. In the presence of 10microM SU6656, some cells underwent EMT but migration was inhibited by 40%. At 10microM, imatinib also inhibited migration by ~50% but also induced some cell death.
Data obtained using a range of TKIs show that inhibition of tyrosine kinases affects RPE cell EMT, migration and proliferation. In particular, SFK inhibitors demonstrated that SFKs play a role, at least partially, in EMT and growth of RPE cells while other kinases could also be involved in these processes. As RPE cell EMT and growth has been indicated to play an important role in PVR formation, TKIs could potentially be used to prevent PVR.
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