Glial cell expression of hepatocyte growth factor in vitreoretinal proliferative disease

Abstract

The hepatocyte growth factor (HGF) has been crucially implicated in the development of proliferative retinal diseases; however, it is unclear whether retinal glial cells express or respond to HGF. Therefore, we examined the expression of HGF and of the receptor for HGF, c-Met, by immunohistochemical costaining with glial fibrillary acidic protein (GFAP) in epiretinal membranes of patients with proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR), respectively. Furthermore, it was determined whether cells of the human retinal glial cell line, MIO-M1, secrete HGF protein, and whether HGF stimulates proliferation and chemotaxis, and secretion of the vascular endothelial growth factor (VEGF). Neuroretinas of patients with PVR express elevated mRNA level for HGF in comparison to control retinas. In epiretinal membranes of patients with PVR or PDR, immunoreactivity for HGF and for c-Met, respectively, partially colocalized with immunoreactivity for GFAP. Fetal bovine serum and basic fibroblast growth factor, but not heparin-binding epidermal or plateletderived growth factors, evoked HGF secretion by cultured retinal glial cells. HGF displayed only a marginal effect on cell proliferation while it stimulated chemotaxis. HGF promoted the secretion of VEGF, via activation of the phosphatidylinositol-3 kinase. It is concluded that glial cells in epiretinal membranes express both HGF protein and c-Met receptors. The results suggest an autocrine/paracrine role of HGF in glial cell responses during proliferative vitreoretinal disorders as well as in retinal neovascularization, by stimulating of VEGF release.

Stage specificity of novel growth factor expression during development of proliferative vitreoretinopathy

“…29 It was recently reported that glial cells in epiretinal membranes express both HGF and its receptor, c-Met. 24 The results from this study reveal that the coexpression of HGF and glial is far more frequent than with RPE cells at all stages of PVR. Furthermore, the overall HGF expression peaks during mid stage PVR when glia numbers appear relatively low (Figure 2).…”

“…22 HGF is a pleiotropic growth factor that has mitogenic, morphogenic, and motogenic activities when cultured with epithelial cells and glial cells. 5,6,14,15,[23][24][25] It has been reported that HGF, a glycoprotein that mediates epithelial-mesenchymal interactions in many tissues, [26][27][28] has autocrine-paracrine activity in RPE 15 and is a major regulator of RPE barrier function. 29 It was recently reported that glial cells in epiretinal membranes express both HGF and its receptor, c-Met.…”

Involvement of Müller glial cells in epiretinal membrane formation

“…In epiretinal membranes of patients with PVR or PDR, immunoreactivities for HGF and for the receptor of HGF, c-Met, are expressed by various cell types, including glial and pigment epithelial cells [120,122,123]. HGF stimulates the chemotaxis (but not proliferation) of cultured Müller cells, and promotes the secretion of VEGF [120]. Blood serum and bFGF increase the secretion of HGF from Müller cells [120].…”

“…HGF is expressed in the inner retina within 24 hours of ischemia-reperfusion, probably by Müller cells [119], suggesting a role of this factor in the early response of the cells to ischemic/hypoxic insults. Neuroretinas of patients with PVR (but apparently not control retinas) express HGF [45,120]. HGF is elevated in the vitreous of patients with PDR [121].…”

Proteomic characterization of harvested pseudopodia with differential gel electrophoresis and specific antibodies

“…2,4,[11][12][13][14] Expression of HGF and Met are associated with tumor progression. 3,4,15,16 In other types of malignant cells, downstream events induced by HGF signaling have been shown to include increased glycolysis 17 and phoshorylation of AnxI.…”