A role of gp130–stimulating cytokines in retinal glial cell differentiation.

Abstract

Abstract: : Purpose: Various mediators are suggested to regulate the glial differentiation during eye development. This study is conducted in an attempt to clarify roles of cytokines such as leukemia inhibitory factor (LIF), a glycoprotein 130 (gp130)–stimulating cytokine, and bone morphogenetic protein (BMP) 2 in the differentiation of two types of retinal glial cells, astrocytes and Müller glia. Methods: Cell types were determined in eyeball sections and retinal explants from P0 gp130 knock out mice by immunohistochemical analyses. Effects of LIF and BMP 2 on differentiation of neural retinal explants from perinatal mice were determined by immunohistochemistry. Promoter activity of the glial fibrillary acidic protein (GFAP) gene was assessed using its fusion construct having the luciferase gene. Results: In the optic nerve head from P0 gp130^–/– mice the number of GFAP positive astrocytes were significantly decreased as compared with wild type littermates. In retial explants from P0 gp130^–/– mice the number of GFAP positive astrocytes were significantly decreased. No significant difference was found in the number of Müller glial cells. In addition, LIF and BMP2 synergistically induced GFAP promoter activation and astrocytogenesis of precursor cells isolated from P0 mouse retina. Furthermore, these two cytokines synergistically promoted differentiation of retinal astrocytes and Müller glial cells. Conclusions: In this study, we demonstrated that the gp130–signaling pathway plays an important role in retinal glial differentiation, in particular astrogenesis. We also showed that BMP2 and LIF synergistically promote differentiation of retinal precursor cells into GFAP–positive glial cells. Because these cytokines have been shown to be up–regulated in injured retinas, our results are not only biologically interesting but may also be important considering clinical relevance for retinal regenerative therapy.

Keywords: retinal development • retinal glia • transgenics/knock–outs