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M. Kasaoka, K. Lashkari; Modulation of HGF-HGFR/cMet Receptor System Can Dominate RPE Wound Healing Responses After Retinal Laser Injury. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3424.
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We have previously shown that HGFR/cMet receptor plays an integral role in retinal responses to laser injury including RPE cell migration and transdifferentiation. We assessed whether modulation of receptor activity including constitutive activation or abrogation of HGFR/cMet could lead to altered wound healing response to retinal laser injury.
C57BL/6 mice and TPRmet/C57BL/6 mice (expressing constitutively active form of HGFR/cMet) and 129-C57BL/6-met fl/fl mice (expressing floxed HGFR/c-Met subject to deletion by Cre recombinase) were treated either with retinal diode laser photocoagulation or sham photocoagulation and sacrificed at intervals ranging between 3 hr and 14 days. In 129-C57BL/6-met fl/fl mice, HGFR/cMet was knocked out by subretinal injection of AAV-Cre:AAV-GFP (ratio, 9:1) two weeks prior to laser injury. AAV-GFP was used for control. At each time point eyes were prepared for qRT-PCR to detect mRNA expression and immunohistochemistry (IHC) to document RPE and retinal wound healing responses to laser injury.
mRNA expression of HGF and HGFR/cMet in laser-treated retina were significantly increased at all time points as compared to sham injury, peaking at 3 hours and 12 hours for HGF and HGFR/cMet, respectively. In response to laser injury, TPRmet/C57BL/6 mice exhibited autophosphorylation of the HGFR/cMet receptor in the RPE monolayer and more robust RPE migration into the retina at the site of injury. Migrating RPE cells expressed phosphorylated receptor. In 129-C57BL/6-met fl/fl mice, Cre induced significant reduction in HGFR/cMet expression by PCR and in the RPE monolayer, as well as reduction in RPE cell migration into the retina and restoration of RPE layer after laser injury.
HGF-HGFR/cMet receptor system is intimately involved in RPE wound healing responses after laser injury. Constitutive activation of HGFR/cMet enhanced RPE responses to laser injury including migration and transdifferentiation. Abrogation of HGFR/cMet receptor activity tapered wound healing responses in RPE cells. Control of HGFR/cMet activity may be a good future therapeutic target to minimize visual deficits due to aberrant wound healing responses after retinal laser injury.
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