From the Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, Tampa (H.N., J.Y.L., P.R.S., C.V.B.).
Department of Molecular Biosciences, University of California Davis (E.N.).
Stroke. 2019 Aug;50(8):2197-2206. doi: 10.1161/STROKEAHA.119.025249. Epub 2019 Jun 27.
Background and Purpose- Retinal ischemia is a major cause of visual impairment in stroke patients, but our incomplete understanding of its pathology may contribute to a lack of effective treatment. Here, we investigated the role of mitochondrial dysfunction in retinal ischemia and probed the potential of mesenchymal stem cells (MSCs) in mitochondrial repair under such pathological condition. Methods- In vivo, rats were subjected to middle cerebral artery occlusion then randomly treated with intravenous MSCs or vehicle. Laser Doppler was used to evaluate the blood flow in the brain and the eye, while immunohistochemical staining assessed cellular degeneration at days 3 and 14 poststroke. In vitro, retinal pigmented epithelium cells were exposed to either oxygen-glucose deprivation or oxygen-glucose deprivation and coculture with MSCs, and subsequently, cell death and mitochondrial function were examined immunocytochemically and with Seahorse analyzer, respectively. Results- Middle cerebral artery occlusion significantly reduced blood flow in the brain and the eye accompanied by mitochondrial dysfunction and ganglion cell death at days 3 and 14 poststroke. Intravenous MSCs elicited mitochondrial repair and improved ganglion cell survival at day 14 poststroke. Oxygen-glucose deprivation similarly induced mitochondrial dysfunction and cell death in retinal pigmented epithelium cells; coculture with MSCs restored mitochondrial respiration, mitochondrial network morphology, and mitochondrial dynamics, which likely attenuated oxygen-glucose deprivation-mediated retinal pigmented epithelium cell death. Conclusions- Retinal ischemia is closely associated with mitochondrial dysfunction, which can be remedied by stem cell-mediated mitochondrial repair.
背景与目的-视网膜缺血是中风患者视力障碍的主要原因，但我们对其病理的理解不充分可能导致缺乏有效的治疗方法。在这里，我们研究了线粒体功能障碍在视网膜缺血中的作用，并探讨了间充质干细胞（MSCs）在这种病理条件下进行线粒体修复的潜力。
方法-在体内，大鼠接受大脑中动脉闭塞，然后随机接受静脉注射 MSCs 或载体治疗。激光多普勒用于评估大脑和眼睛的血流，而免疫组织化学染色评估中风后第 3 天和第 14 天的细胞变性。在体外，视网膜色素上皮细胞暴露于氧葡萄糖剥夺或氧葡萄糖剥夺和与 MSCs 共培养，随后通过免疫细胞化学和 Seahorse 分析仪分别检查细胞死亡和线粒体功能。
结果-大脑中动脉闭塞显著降低了大脑和眼睛的血流，伴随着线粒体功能障碍和中风后第 3 天和第 14 天的神经节细胞死亡。静脉注射 MSCs 可引发线粒体修复，并改善中风后第 14 天的神经节细胞存活。氧葡萄糖剥夺同样诱导视网膜色素上皮细胞的线粒体功能障碍和细胞死亡；与 MSCs 共培养可恢复线粒体呼吸、线粒体网络形态和线粒体动力学，这可能减轻氧葡萄糖剥夺介导的视网膜色素上皮细胞死亡。
结论-视网膜缺血与线粒体功能障碍密切相关，可通过干细胞介导的线粒体修复来补救。
