Survival and Functional Restoration of Human Fetal Ventral Mesencephalon Following Transplantation in a Rat Model of Parkinson's Disease
Survival and Functional Restoration of Human Fetal Ventral Mesencephalon Following Transplantation in a Rat Model of Parkinson's Disease
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DOI：
10.3727/096368912x654984
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发表时间：
2013-01-01
影响因子：
3.3
通讯作者：
Nikkhah, Guido
中科院分区：
文献类型：
--
作者：
Rath, Anika;Klein, Alexander;Nikkhah, Guido
在过去的几十年中，通过脑内移植胎儿多巴胺能神经元的细胞替代疗法已经成为患有帕金森病的患者的有希望的治疗选择。然而，人类胎儿组织的有限可用性以及伦理问题，缺乏替代的非胎儿供体细胞，以及缺乏标准化的移植方案，阻止了神经修复治疗成为患有神经退行性疾病的患者的常规程序。提高移植物存活率、手术技术和确定最佳靶区对于进一步优化这种新型治疗至关重要。在本研究中，将来自7- 9周龄人胎儿的人原代胎儿腹侧中脑来源的组织移植到6-羟基多巴胺损伤的成年Sprague道利大鼠中。移植物存活，纤维生长，和药物诱导的旋转行为长达14周移植后比较不同的纹状体内移植技术（完整的单细胞悬浮液与部分组织块悬浮液注射玻璃毛细管或金属套管）和黑质内玻璃毛细管注射的完整（单细胞）悬浮液。结果表明，与所有其他组相比，纹状体内移植部分（组织块）悬浮液的多巴胺神经元存活率更高，安非他明诱导的旋转（过度补偿）减少更多，纤维生长更广泛。包括黑质内组在内的所有组中阿扑吗啡诱导的旋转偏差均显着降低。这些数据证实，人腹侧中脑衍生的细胞作为一种活细胞来源，在异种移植范例中存活，并功能性地整合到宿主组织中。与大鼠供体细胞相反，通过仅制备含有组织块的部分悬浮液来保持原始（胎儿）神经元网络似乎对人类细胞有益，尽管注射需要对宿主造成更大组织创伤的金属套管。此外，同位黑质内移植物可能代表PD中“经典”异位纹状体内靶位点的互补移植方法。
Cell replacement therapy by intracerebral transplantation of fetal dopaminergic neurons has become a promising therapeutic option for patients suffering from Parkinson's disease during the last decades. However, limited availability of human fetal tissue as well as ethical issues, lack of alternative nonfetal donor cells, and the absence of standardized transplantation protocols have prevented neurorestorative therapies from becoming a routine procedure in patients suffering from neurodegenerative diseases. Improvement of graft survival, surgery techniques, and identification of the optimal target area are imperative for further optimization of this novel treatment. In the present study, human primary fetal ventral mesencephalon-derived tissue from 7- to 9-week-old human fetuses was transplanted into 6-hydroxydopamine-lesioned adult Sprague Dawley rats. Graft survival, fiber outgrowth, and drug-induced rotational behavior up to 14 weeks posttransplantation were compared between different intrastriatal transplantation techniques (full single cell suspension vs. partial tissue pieces suspension injected by glass capillary or metal cannula) and the intranigral glass capillary injection of a full (single cell) suspension. The results demonstrate a higher survival rate of dopamine neurons, a greater reduction in amphetamine-induced rotations (overcompensation), and more extensive fiber outgrowth for the intrastriatally transplanted partial (tissue pieces) suspension compared to all other groups. Apomorphine-induced rotational bias was significantly reduced in all groups including the intranigral group. The data confirm that human ventral rnesencephalon-derived cells serve as a viable cell source, survive in a xenografting paradigm, and functionally integrate into the host tissue. In contrast to rat donor cells, keeping the original (fetal) neuronal network by preparing only a partial suspension containing tissue pieces seems to be beneficial for human cells, although a metal cannula that causes greater tissue trauma to the host is required for injection. In addition, homotopic intranigral grafts may represent a complimentary grafting approach to the "classical" ectopic intrastriatal target site in PD.