Folate antagonist, methotrexate induces neuronal differentiation of human embryonic stem cells transplanted into nude mouse retina
Folate antagonist, methotrexate induces neuronal differentiation of human embryonic stem cells transplanted into nude mouse retina
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DOI：
10.1016/j.neulet.2010.04.050
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发表时间：
2010-06-25
影响因子：
2.5
通讯作者：
Kunisada, Takahiro
中科院分区：
文献类型：
--
作者：
Hara, Akira;Taguchi, Ayako;Kunisada, Takahiro
移植的胚胎干细胞可以作为分化良好的神经视网膜细胞整合到成年小鼠的视网膜中。然而，移植的ES细胞也具有致瘤活性，因为它们具有向各种类型的组织多能分化的能力。在本研究中，通过玻璃体内注射N-甲基-D-天冬氨酸（NMDA）后20小时，将人ES细胞（hES）移植到成年裸鼠视网膜中。hES细胞移植后，给予叶酸拮抗剂甲氨蝶呤（MTX）以控制移植细胞的分化。移植后5周，免疫组化法检测hES细胞的神经元分化和致畸潜能。移植细胞的增殖活性通过有丝分裂指数和Ki-67增殖指数来确定。每天腹膜内MTX处理15天后，观察到显示未分化形态的Oct-4阳性hES细胞消失。MTX处理后存活的hES细胞中检测到有丝分裂和Ki-67增殖指数降低，神经元分化增加。这些结果表明，腹膜内MTX处理的hES细胞移植到裸鼠视网膜中的两个重要的影响：（1）MTX处理后的移植诱导神经元分化，和（2）MTX降低增殖活性和致瘤潜力。(C)2010爱思唯尔爱尔兰有限公司版权所有。
Transplanted embryonic stem (ES) cells can be integrated into the retinas of adult mice as well-differentiated neuroretinal cells. However, the transplanted ES cells also have a tumorigenic activity as they have the ability for multipotent differentiation to various types of tissues. In the present study, human ES (hES) cells were transplanted into adult nude mouse retinas by intravitreal injections 20h after intravitreal N-methyl-D-aspartate (NMDA) administration. After the transplantation of hES cells, the folate antagonist, methotrexate (MTX) was administrated in order to control the differentiation of the transplanted hES cells. Neuronal differentiation and teratogenic potential of hES cells were examined immunohistochemically 5 weeks after transplantation. The proliferative activity of transplanted cells was determined by both the mitotic index and the Ki-67 proliferative index. Disappearance of Oct-4-positive hES cells showing undifferentiated morphology was observed after intraperitoneal MTX treatment daily, for 15 days. Decreased mitotic and Ki-67 proliferative indices, and increased neuronal differentiation were detected in the surviving hES cells after the MTX treatment. These results suggest two important effects of intraperitoneal MTX treatment for hES cells transplanted into nude mouse retina: (1) MTX treatment following transplantation induces neuronal differentiation, and (2) MTX decreases proliferative activity and tumorigenic potential. (C) 2010 Elsevier Ireland Ltd. All rights reserved.