Potential use of embryonic stem cells for the treatment of mouse parkinsonian models: Improved behavior by transplantation of in vitro differentiated dopaminergic neurons from embryonic stem cells
Potential use of embryonic stem cells for the treatment of mouse parkinsonian models: Improved behavior by transplantation of in vitro differentiated dopaminergic neurons from embryonic stem cells
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DOI：
10.1634/stemcells.21-2-171
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发表时间：
2003-01-01
期刊：
影响因子：
5.2
通讯作者：
Sakaki, T
中科院分区：
文献类型：
--
作者：
Nishimura, F;Yoshikawa, M;Sakaki, T
背景和目标。本研究的目的是检查小鼠胚胎干细胞（ES）来源的酪氨酸羟化酶阳性（TH+）细胞移植到帕金森病小鼠的疗效，使用行为测试和免疫组化评价。使用五步体外分化方法将携带增强型绿色荧光蛋白（EGFP）基因的未分化ES细胞分化为含有TH+神经元的细胞群。这些ES细胞衍生的细胞被用作同种异体移植物;在帕金森病小鼠中，通过注射6-羟基多巴胺（6-OHDA）制成。将15只偏侧帕金森病小鼠分为3组。注射6-OHDA 4周后，第1、2和3组小鼠分别接受磷酸盐缓冲液、1 × 10（4）个移植细胞和1 × 10（5）个移植细胞植入其去多巴胺神经支配的纹状体。移植后2周，在移植物移植组（组2和组3）中观察到旋转行为改善。第2组小鼠表现出持续的旋转行为减少，而第3组小鼠在移植后4、6和8周表现出向损伤侧的同侧旋转。在第3组的一只小鼠中观察到肿瘤形成。第2组和第3组小鼠移植后8周，移植部位可见TH+细胞，部分细胞呈GFP免疫阳性，表明存在ES细胞来源的多巴胺能神经元。移植体外分化的ES细胞改变帕金森病小鼠的旋转行为。我们的研究结果表明，帕金森病的ES细胞的潜在可用性。
Background and Aims. The purpose of the present study was to examine the efficacy of transplantation of mouse embryonic-stem- (ES)-cell-derived tyrosine hydroxylase-positive (TH+) cells into Parkinsonian mice using behavioral tests and immunohistochemical evaluation.Methods. Undifferentiated ES cells carrying the enhanced green fluorescent protein (EGFP) gene were differentiated into a cell population containing TH+ neurons using a five-step in vitro differentiation method. These ES-cell-derived cells were used as allografts; in Parkinsonian mice, made by administering injections of 6-hydroxydopamine (6-OHDA). Fifteen hemiparkinsonian mice were divided into three groups. Four weeks after 6-OHDA injection, mice in groups 1, 2, and 3 received phosphate-buffered saline, 1 x 10(4) graft cells, and 1 x 10(5) graft cells, respectively, into their dopamine-denervated striata.Results. Improved rotational behavior was observed in the graft-transplanted groups (groups 2 and 3) 2 weeks after transplantation. Mice in group 2 displayed a continuous maintenance of reduced rotational behavior, while those in group 3 showed ipsilateral rotation toward the lesioned side at 4, 6, and 8 weeks after transplantation. Tumor formation was observed in one mouse in group 3. TH+ cells were found at the grafted sites 8 weeks after transplantation in mice in groups 2 and 3, some of which were immunopositive to GFP, demonstrating the presence of dopaminergic neurons derived from the ES cells.Conclusion. Transplantation of in vitro differentiated ES cells changed rotational behavior in Parkinsonian mice. Our results suggest the potential availability of ES cells for Parkinson's disease.