Induced Pluripotent Stem Cells Without c-Myc Ameliorate Retinal Oxidative Damage via Paracrine Effects and Reduced Oxidative Stress in Rats

Abstract

Purpose: To investigate the efficacy and mechanisms of non-c-Myc induced pluripotent stem cell (iPSC) transplantation in a rat model of retinal oxidative damage. Methods: 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 brainderived neurotrophic factor, ciliary neurotrophic factor, basic fibroblast growth factor (bFGF), stromal cellderived factor (SDF)-1a, 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-1a.Results: 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-1a, followed by bFGF, accompanied by a significant improvement in the ERG. In vitro studies confirmed that treatment with SDF-1a 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. Conclusions: We demonstrated the potential benefits of non-c-Myc iPSC transplantation for treating oxidativedamage-induced retinal diseases. SDF-1a and bFGF play important roles in facilitating the amelioration of retinal oxidative damage after non-c-Myc iPSC transplantation.

Effect of human umbilical cord blood mesenchymal stem cells administered by intravenous or intravitreal routes on cryo‐induced retinal injury

“…Furthermore, a significant increase in hmox‐1 and txn‐2 mRNA expression was seen in both hUCBMSCs treated groups with significantly higher levels in the intravitreal group compared to the intravenous group. In line with our results, Fang et al recorded a significant decrease in nitrotyrosine in stem cell treated group and mentioned that the therapeutic mechanisms of stem cell transplantation were partially due to reduced retinal oxidative stress . In addition, Cai at al.…”

“…Fang et al recorded similar results. They attributed the functional improvements observed after stem cell transplantation to bFGF as its secretion occurred from days 7 to 21, concurrent with periods of functional improvement . Moreover, Zhang and Wang found that the expression of bFGF by MSCs continued for several months .…”

Therapeutic Benefits of Induced Pluripotent Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension

“…Furthermore, iPSC-based therapy was shown to decrease high tidal volume ventilation-induced inflammation, oxidative stress, and MIP-2 production via the inhibition of the NF-κB/NKRF pathways. Notably, the iPSC-conditioned medium revealed beneficial effects equal to those of iPSCs [ 32 , 33 ]. In our study, the phosphorylated level of the NF-κB p65 subunit was lower in rats receiving iPSC-based therapy than rats treated with MCT alone ( Fig 7 ).…”

“…Murine iPSCs were kindly provided by Dr. Shih-Hwa Chiou [ 32 – 34 ]. M ouse e mbryonic f ibroblasts (MEFs), used as feeder cells, were cultured to confluence and subsequently treated with 10 μg/mL mitomycin C for 3 h to inhibit proliferation.…”

“…I nduced p luripotent s tem c ells (iPSCs) are reprogrammed from adult somatic cells via the transduction of defined transcription factors; evidence suggests that iPSCs are virtually indistinguishable from ESCs [ 29 , 30 ]. Studies have demonstrated the ameliorative effects of iPSCs via a paracrine mechanism with respect to both cardiac function after myocardial infarction [ 31 ] and retinal oxidative damage [ 32 ]. Interestingly, studies performed by Chiou et al suggested that iPSCs attenuate the severity of endotoxin-induced acute lung injury or ventilator-induced lung injury via the suppression of NF-κB ( n uclear f actor k appa-light-chain-enhancer of activated B cells) signaling and neutrophil accumulation [ 33 , 34 ].…”