Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson's disease
Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson's disease
复制标题
DOI：
10.1523/jneurosci.3719-06.2006
复制
发表时间：
2006-11-29
影响因子：
5.3
通讯作者：
Borlongan, Cesario V.
中科院分区：
文献类型：
--
作者：
Yasuhara, Takao;Matsukawa, Noriyuki;Borlongan, Cesario V.
神经干细胞具有高度的自我更新和向神经元分化的潜能。我们在这里探讨是否移植人神经干细胞克隆的v-myc基因转移，HB1.F3细胞，是一个可行的治疗帕金森氏病的选择。在体内，与对照组（载体、单次推注或持续微泵输注营养因子或杀死的细胞移植物）相比，当立体定向移植（同一天损伤-移植范例）到6-羟基多巴胺损伤的大鼠纹状体中时，绿色荧光蛋白标记的HB 1.F3细胞（3 μ l PBS中有200，000个活细胞）显著改善帕金森病行为症状。这种移植物衍生的功能效应伴随着沿着黑质纹状体途径的酪氨酸羟化酶（TH）免疫反应性的保存。移植的HB1.F3细胞在损伤的脑中存活，其中一些细胞被神经元标记物丝裂原活化蛋白2标记，并被突触素阳性终末装饰。此外，移植大鼠脑室下区内源性神经发生被激活。为了进一步探索HB1.F3细胞移植的神经保护机制，我们进行了细胞培养研究，发现少量HB1.F3细胞TH和多巴胺和cAMP调节的磷蛋白32阳性，尽管大多数细胞巢蛋白阳性，表明成熟和未成熟细胞的混合群体。将HB1.F3上清液给予人源性多巴胺能SH-SY 5 Y细胞和胎鼠腹侧中脑多巴胺能神经元，通过Bcl-2上调抑制细胞凋亡而保护其免受6-羟基多巴胺神经毒性，Bcl-2上调被单独的抗干细胞因子抗体阻断，单独的磷脂酰肌醇3-激酶/Akt抑制剂LY 294002 [2-（4-吗啉基）-8-苯基-1（4 H）-苯并吡喃-4-酮]，或两者的组合。这些结果表明，HB 1.F3细胞移植发挥神经保护作用，对多巴胺能耗竭在体外和体内，因为营养因子分泌和神经元分化。
Neural stem cells (NSCs) possess high potencies of self-renewal and neuronal differentiation. We explored here whether transplantation of human NSCs cloned by v-myc gene transfer, HB1.F3 cells, is a feasible therapeutic option for Parkinson's disease. In vivo, green fluorescent protein-labeled HB1.F3 cells (200,000 viable cells in 3 mu l of PBS) when stereotaxically transplanted (same-day lesiontransplant paradigm) into the 6-hydroxydopamine-lesioned striatum of rats significantly ameliorated parkinsonian behavioral symptoms compared with controls (vehicle, single bolus, or continuous minipump infusion of trophic factor, or killed cell grafts). Such graft-derived functional effects were accompanied by preservation of tyrosine hydroxylase (TH) immunoreactivity along the nigrostriatal pathway. Grafted HB1.F3 cells survived in the lesioned brain with some labeled with neuronal marker mitogen-activated protein 2 and decorated with synaptophysin-positive terminals. Furthermore, endogenous neurogenesis was activated in the subventricular zone of transplanted rats. To further explore the neuroprotective mechanisms underlying HB1.F3 cell transplantation, we performed cell culture studies and found that a modest number of HB1.F3 cells were TH and dopamine and cAMP-regulated phosphoprotein 32 positive, although most cells were nestin positive, suggesting a mixed population of mature and immature cells. Administration of the HB1.F3 supernatant to human derived dopaminergic SH-SY5Y cells and fetal rat ventral mesencephalic dopaminergic neurons protected against 6-hydroxydopamine neurotoxicity by suppressing apoptosis through Bcl-2 upregulation, which was blocked by anti-stem cell factor antibody alone, the phosphatidylinositol 3-kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one] alone, or a combination of both. These results suggest that HB1.F3 cell transplantation exerts neuroprotective effects against dopaminergic depletion in vitro and in vivo because of trophic factor secretion and neuronal differentiation.