Transplantation of reprogrammed embryonic stem cells improves visual function in a mouse model for retinitis pigmentosa.
Transplantation of reprogrammed embryonic stem cells improves visual function in a mouse model for retinitis pigmentosa.
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移植重新编程的胚胎干细胞可改善视网膜色素变性小鼠模型的视觉功能。
DOI：
10.1097/tp.0b013e3181d45a61
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发表时间：
2010
期刊：
影响因子：
6.2
通讯作者：
Tsang,StephenH
中科院分区：
文献类型：
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作者：
Wang,Nan-Kai;Tosi,Joaquin;Kasanuki,JenniferMie;Chou,ChaiLin;Kong,Jian;Parmalee,Nancy;Wert,KatherineJ;Allikmets,Rando;Lai,Chi-Chun;Chien,Chung-Liang;Nagasaki,Takayuki;Lin,Chyuan-Sheng;Tsang,StephenH
背景。为了研究C57BL/6J-Tyr c−2j/J （C2J）小鼠胚胎干（ES）细胞能否在体外分化为视网膜色素上皮（RPE）细胞，并在视网膜色素性视网膜炎模型Rpe65 rd12/Rpe65 rd12 C57BL6小鼠中恢复视网膜功能。方法：在PA6饲料上诱导黄色荧光蛋白（YFP）标记的C2J ES细胞分化为RPE样结构。rpe特异性标记物是在体外分化细胞中表达的。分化后，将ES细胞衍生的rpe样细胞移植到出生第5天Rpe65 rd12/Rpe65 rd12小鼠的视网膜下间隙。yfp标记的c2jes细胞的实时成像显示移植物存活。采用视网膜电图（ERGs）评价移植小鼠的功能结局。胚胎干细胞衍生的rpe样细胞依次表达多个rpe特异性标记物。移植后，yfp标记的细胞可以用实时成像跟踪长达7个月。虽然超过一半的小鼠伴有视网膜脱离或肿瘤发展，但四分之一的小鼠在移植的眼睛中显示出增加的视网膜电图反应。Rpe65 rd12/Rpe65 rd12小鼠移植rpe样细胞后，在7个月的时间内视力恢复明显，而注射生理盐水、PA6喂食剂或未分化的胚胎干细胞则没有恢复。结论：胚胎干细胞在形态学和功能上可以分化为rpe样细胞。基于这些发现，分化的胚胎干细胞有潜力开发新的rpe特异性疾病的治疗方法，如某些形式的视网膜色素变性和黄斑变性。然而，在开始治疗试验之前，严格控制视网膜脱离和畸胎瘤的发展是必要的。
Background.To study whether C57BL/6J-Tyr c− 2j/J (C2J) mouse embryonic stem (ES) cells can differentiate into retinal pigment epithelial (RPE) cells in vitro and then restore retinal function in a model for retinitis pigmentosa: Rpe65 rd12/Rpe65 rd12 C57BL6 mice.Methods.Yellow fluorescent protein (YFP)-labeled C2J ES cells were induced to differentiate into RPE-like structures on PA6 feeders. RPE-specific markers are expressed from differentiated cells in vitro. After differentiation, ES cell-derived RPE-like cells were transplanted into the subretinal space of postnatal day 5 Rpe65 rd12/Rpe65 rd12 mice. Live imaging of YFP-labeled C2J ES cells demonstrated survival of the graft. Electroretinograms (ERGs) were performed on transplanted mice to evaluate the functional outcome of transplantation.Results.RPE-like cells derived from ES cells sequentially express multiple RPE-specific markers. After transplantation, YFP-labeled cells can be tracked with live imaging for as long as 7 months. Although more than half of the mice were complicated with retinal detachments or tumor development, one fourth of the mice showed increased electroretinogram responses in the transplanted eyes. Rpe65 rd12/Rpe65 rd12 mice transplanted with RPE-like cells showed significant visual recovery during a 7-month period, whereas those injected with saline, PA6 feeders, or undifferentiated ES cells showed no rescue.Conclusions.ES cells can differentiate, morphologically, and functionally, into RPE-like cells. Based on these findings, differentiated ES cells have the potential for the development of new therapeutic approaches for RPE-specific diseases such as certain forms of retinitis pigmentosa and macular degeneration. Nevertheless, stringent control of retinal detachment and teratoma development will be necessary before initiation of treatment trials.