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M. Kasaoka, F. M. Mo, K. Lashkari; Hepatocyte Growth Factor Modulates RPE Responses to Laser Injury and Induction of Proliferative Vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5779.
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RPE cell migration and transdifferentiation play an integral role in retinal response to laser injury and induction of proliferative vitreoretinopathy (PVR). We assessed whether hepatocyte growth factor (HGF) and its receptor (HGFR) participate in wound healing responses.
C57BL/6 mice underwent retinal diode laser photocoagulation and were sacrificed at intervals ranging between 1 hr and 14 days. Eye cups were prepared by dissecting out the retina. Both eyes cups and retinas were subjected for qRT-PCR, SDS-PAGE/Western blotting and immunohistochemistry (IHC) for HGF and HGFR. Phosphorylation of HGFR was determined by phosphospecific antibodies. Using a pigmented rabbit model of PVR, cells expressing a constitutively active form of HGFR were injected intravitrealy and eyes were assessed between days 1-28 by fundus photography and IHC.
Laser-treated eye cups showed a biphasic upregulation of HGF and HGFR by as much as 24 fold increase for HGFR within first hour and 6-7 fold increase in both HGF and HGFR by day 14. Laser injury induced transdifferentiation of RPE cells and their migration into the subretinal space at site of injury. This was correlated with phosphorylation of HGFR. Intravitreal injection of cells expressing constitutively active HGFR induced moderate to advanced stages of PVR in all rabbits by day 28.
HGF and HGFR are intimately involved in RPE wound healing responses and laser injury. HGFR activation after laser injury may induce RPE cells to migrate and transdifferentiate an early hallmark of PVR and aberrant wound healing. Abrogation of HGFR activity may be a future therapeutic target to minimize retinal damage by RPE migration within sites of injury.
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