Induced pluripotent stem cells without c-Myc ameliorate retinal oxidative damage via paracrine effects and reduced oxidative stress in rats.

Abstract

To investigate the efficacy and mechanisms of non-c-Myc induced pluripotent stem cell (iPSC) transplantation in a rat model of retinal oxidative damage. Paraquat was intravitreously injected into Sprague-Dawley rats. After non-c-Myc iPSC transplantation, retinal function was evaluated by electroretinograms (ERGs). The generation of reactive oxygen species (ROS) was determined by lucigenin- and luminol-enhanced chemiluminescence. The expression of brain-derived neurotrophic factor, ciliary neurotrophic factor, basic fibroblast growth factor (bFGF), stromal cell-derived factor (SDF)-1α, and CXCR4 was measured by immunohistochemistry and ELISA. An in vitro study using SH-SY5Y cells was performed to verify the protective effects of SDF-1α. Transplantation of non-c-Myc iPSCs effectively promoted the recovery of the b-wave ratio in ERGs and significantly ameliorated retinal damage. Non-c-Myc iPSC transplantation decreased ROS production and increased the activities of superoxide dismutase and catalase, thereby reducing retinal oxidative damage and apoptotic cells. Moreover, non-c-Myc iPSC transplantation resulted in significant upregulation of SDF-1α, followed by bFGF, accompanied by a significant improvement in the ERG. In vitro studies confirmed that treatment with SDF-1α significantly reduced apoptosis in a dose-dependent manner in SH-SY5Y cells. Most transplanted cells remained in the subretinal space, with spare cells expressing neurofilament M markers at day 28. Six months after transplantation, no tumor formation was seen in animals with non-c-Myc iPSC grafts. We demonstrated the potential benefits of non-c-Myc iPSC transplantation for treating oxidative-damage-induced retinal diseases. SDF-1α and bFGF play important roles in facilitating the amelioration of retinal oxidative damage after non-c-Myc iPSC transplantation.