Schackel Stefanie, Pauly Marie-Christin, Piroth Tobias, Nikkhah Guido, Döbrössy Máté D
Lab of Stereotaxy and Interventional Neurosciences, Department of Stereotactic and Functional Neurosurgery, University Freiburg - Medical Centre, Freiburg, Germany.
Behav Brain Res. 2013 Nov 1;256:56-63. doi: 10.1016/j.bbr.2013.07.053. Epub 2013 Aug 3.
Neural cell replacement therapy using fetal striatal cells has provided evidence of disease modification in clinical trials in Huntington's disease (HD) patients, although the results have been inconsistent. One of the contributing factors to the variable outcome could be the different capacity of transplanted cells derived from the primordial striatum to proliferate and maturate into striatal projection neurons. Based on the rodent lesion model of HD, the current study investigated how intrastriatal-striatal grafts from variable aged donors develop in vivo and how they influence functional recovery. Young adult female Sprague-Dawley rats were lesioned unilaterally in the dorso-striatum with quinolinic acid (0.12 M) and transplanted 14 days later with single cell suspension grafts equivalent of one whole ganglionic eminence (WGE) from donors of embryonic developmental age E13, E14, or E15; animals with or without striatal lesion served as controls. All animals were tested on the Cylinder and the Corridor tests, as well as on apomorphine-induced rotation at baseline, post-lesion/pre-grafting, and at 6 and 10 weeks post-grafting. A week prior to perfusion, a sub-group in each grafted group received fluorogold injections into the ipsilateral globus pallidus to study graft efferent projections. In summary, the data demonstrates that the age of the embryonic donor tissue has an impact on both the graft mediated functional recovery, and on the in vivo cellular composition of the striatal transplant. E13 tissue grafts gave the best overall outcome indicating that WGE from different donor ages have different potential to promote functional recovery. Understanding the stages and process in rodent striatal development could improve tissue selection in clinical trials of cell therapy in HD.
使用胎儿纹状体细胞的神经细胞替代疗法在亨廷顿病（HD）患者的临床试验中已提供了疾病改善的证据，尽管结果并不一致。结果差异的一个促成因素可能是源自原始纹状体的移植细胞增殖并成熟为纹状体投射神经元的能力不同。基于HD的啮齿动物损伤模型，本研究调查了来自不同年龄供体的纹状体内纹状体移植物在体内的发育情况以及它们如何影响功能恢复。将年轻成年雌性Sprague-Dawley大鼠单侧背侧纹状体用喹啉酸（0.12 M）损伤，并在14天后移植来自胚胎发育年龄E13、E14或E15供体的相当于一个完整神经节隆起（WGE）的单细胞悬液移植物；有或无纹状体损伤的动物作为对照。所有动物在圆柱体和走廊试验中进行测试，以及在基线、损伤后/移植前、移植后6周和10周进行阿扑吗啡诱导的旋转测试。在灌注前一周，每个移植组的一个亚组接受向同侧苍白球注射荧光金以研究移植物传出投射。总之，数据表明胚胎供体组织的年龄对移植物介导的功能恢复以及纹状体移植物的体内细胞组成都有影响。E13组织移植物总体效果最佳，表明来自不同供体年龄的WGE促进功能恢复的潜力不同。了解啮齿动物纹状体发育的阶段和过程可以改善HD细胞治疗临床试验中的组织选择。
