PMID- 23726881 OWN - NLM STAT- MEDLINE DCOM- 20131107 LR - 20220408 IS - 1096-0007 (Electronic) IS - 0014-4835 (Linking) VI - 113 DP - 2013 Aug TI - Transplantation of induced pluripotent stem cells without C-Myc attenuates retinal ischemia and reperfusion injury in rats. PG - 49-59 LID - S0014-4835(13)00126-7 [pii] LID - 10.1016/j.exer.2013.05.007 [doi] AB - Induced pluripotent stem cells (iPSC) are novel stem cell populations, but the role of iPSC in retinal ischemia and reperfusion (I/R) injury remains unknown. Since oncogene c-Myc is substantially contributed to tumor formation, in this study, we investigated the effects, mechanisms and safety of subretinal transplantation of iPSC without c-Myc (non-c-Myc iPSC) in a rat model of retinal I/R injury. Retinal I/R injury was induced by raising the intraocular pressure of Sprague-Dawley rats to 110 mmHg for 60 min. A subretinal injection of non-c-Myc iPSC or murine epidermal fibroblast was given 2 h after I/R injury. Electroretinograms (ERG) were performed to determine the functionality of the retinas. The surviving retinal ganglion cells (RGCs) and retinal apoptosis following I/R injury were determined by counting NeuN-positive cells in whole-mounted retinas and TUNEL staining, respectively. The generation of reactive oxygen species (ROS) and the activities of superoxide dismutase (SOD) and catalase (CAT) in the retinal tissues were determined by lucigenin- and luminol-enhanced chemiluminescence and enzyme-linked immunosorbent assay (ELISA). The degree of retinal oxidative damage was assessed by nitrotyrosine, acrolein, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) staining. The expression of brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and basic fibroblast growth factor (bFGF) in retinas was measured by immunohistochemistry and ELISA. We found that subretinal transplantation of non-c-Myc iPSC significantly suppressed the I/R-induced reduction in the ERG a- and b-wave ratio, attenuated I/R-induced loss of RGCs and remarkably ameliorated retinal morphological changes. Non-c-Myc iPSC potentially increased the activities of SOD and CAT, decreased the levels of ROS, which may account for preventing retinal cells from apoptotic cell death. In addition, the levels of BDNF and CNTF in retina were significantly elevated in non-c-Myc iPSC-treated eyes. Track the non-c-Myc iPSC after transplantation, most transplanted cells are remained in the subretinal space, with spare cells express neurofilament M markers at day 28. Six months after transplantation in I/R injured rats, no tumor formation was seen in non-c-Myc iPSC graft. In conclusion, non-c-Myc iPSC effectively rescued I/R-induced retinal damages and diminished tumorigenicity. Non-c-Myc iPSC transplantation attenuated retinal I/R injury, possibly via a mechanism involving the regulation of oxidative parameters and paracrinal secretion of trophic factors. CI - Copyright (c) 2013. Published by Elsevier Ltd. FAU - Fang, I-Mo AU - Fang IM AD - The Department of Ophthalmology, Taipei City Hospital Zhongxiao Branch, Taipei, Taiwan. FAU - Yang, Chung-May AU - Yang CM FAU - Yang, Chang-Hao AU - Yang CH FAU - Chiou, Shih-Hwa AU - Chiou SH FAU - Chen, Muh-Shy AU - Chen MS LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130528 PL - England TA - Exp Eye Res JT - Experimental eye research JID - 0370707 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Ciliary Neurotrophic Factor) RN - 0 (Myc protein, mouse) RN - 0 (Nerve Growth Factors) RN - 0 (Proto-Oncogene Proteins c-myc) RN - 0 (Reactive Oxygen Species) RN - 103107-01-3 (Fibroblast Growth Factor 2) RN - 88847-89-6 (8-Hydroxy-2'-Deoxyguanosine) RN - EC 1.11.1.6 (Catalase) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - G9481N71RO (Deoxyguanosine) SB - IM MH - 8-Hydroxy-2'-Deoxyguanosine MH - Animals MH - Apoptosis/drug effects MH - Brain-Derived Neurotrophic Factor/metabolism MH - Catalase/metabolism MH - Cell Count MH - Ciliary Neurotrophic Factor/metabolism MH - Deoxyguanosine/analogs & derivatives/pharmacology MH - Disease Models, Animal MH - Electroretinography MH - Enzyme-Linked Immunosorbent Assay MH - Fibroblast Growth Factor 2/metabolism MH - In Situ Nick-End Labeling MH - Induced Pluripotent Stem Cells/metabolism/*transplantation MH - Mice MH - Nerve Growth Factors/genetics/metabolism MH - Proto-Oncogene Proteins c-myc/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Reactive Oxygen Species/metabolism MH - Reperfusion Injury/metabolism/physiopathology/*prevention & control MH - Retinal Diseases/metabolism/physiopathology/*prevention & control MH - Retinal Vessels/physiopathology MH - *Stem Cell Transplantation MH - Superoxide Dismutase/metabolism OTO - NOTNLM OT - 8-OHdG OT - 8-hydroxy-2'-deoxyguanosine OT - BDNF OT - CAT OT - CL OT - CNTF OT - ERG OT - ROS OT - SOD OT - TUNEL OT - TdT-dUTP terminal nick-end labeling OT - bFGF OT - basic fibroblast growth factor OT - brain-derived neurotrophic factor OT - c-Myc OT - catalase OT - chemiluminescence OT - ciliary neurotrophic factor OT - electroretinogram OT - iPSC OT - induced pluripotent stem cells OT - induced pluropotent stem cells OT - ischemia-reperfusion injury OT - oxidative stress OT - paracrine OT - reactive oxygen species OT - superoxide dismutase EDAT- 2013/06/04 06:00 MHDA- 2013/11/08 06:00 CRDT- 2013/06/04 06:00 PHST- 2013/01/07 00:00 [received] PHST- 2013/04/25 00:00 [revised] PHST- 2013/05/13 00:00 [accepted] PHST- 2013/06/04 06:00 [entrez] PHST- 2013/06/04 06:00 [pubmed] PHST- 2013/11/08 06:00 [medline] AID - S0014-4835(13)00126-7 [pii] AID - 10.1016/j.exer.2013.05.007 [doi] PST - ppublish SO - Exp Eye Res. 2013 Aug;113:49-59. doi: 10.1016/j.exer.2013.05.007. Epub 2013 May 28.