Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
J Neurosci Res. 2020 Aug;98(8):1575-1587. doi: 10.1002/jnr.24668. Epub 2020 Jun 7.
The transplantation of dopaminergic (DA) progenitors derived from pluripotent stem cells improves the behavior of Parkinson's disease model animals. However, the survival of DA progenitors is low, and the final yield of DA neurons is only approximately 0.3%-2% the number of transplanted cells. Zonisamide (ZNS) increases the number of survived DA neurons upon the transplantation of mouse-induced pluripotent stem (iPS) cell-derived DA progenitors in the rat striatum. In this study, we induced DA progenitors from human iPS cells and transplanted them into the striatum of female rats with daily administration of ZNS. The number of survived DA neurons was evaluated 1 and 4 months after transplantation by immunohistochemistry, which revealed that the number of survived DA neurons was significantly increased with the administration of ZNS. To assess the mechanism of action of ZNS, we performed a gene expression analysis to compare the gene expression profiles in striatum treated with or without ZNS. The analysis revealed that the expression of SLIT-and NTRK-like protein 6 (SLITRK6) was upregulated in rat striatum treated with ZNS. In conclusion, ZNS promotes the survival of DA neurons after the transplantation of human-iPS cell-derived DA progenitors in the rat striatum. SLITRK6 is suggested to be involved in this supportive effect of ZNS by modulating the environment of the host brain.
源自多能干细胞的多巴胺能（DA）祖细胞的移植改善了帕金森病模型动物的行为。然而，DA 祖细胞的存活率低，最终产生的 DA 神经元数量仅约为移植细胞数量的 0.3%-2%。唑尼沙胺（ZNS）在将源自小鼠诱导多能干细胞（iPS）细胞的 DA 祖细胞移植到大鼠纹状体后，增加了 DA 神经元的存活数量。在这项研究中，我们从人 iPS 细胞中诱导出 DA 祖细胞，并在雌性大鼠的纹状体中移植它们，同时每天给予 ZNS 治疗。通过免疫组织化学评估移植后 1 个月和 4 个月时存活的 DA 神经元数量，结果显示，给予 ZNS 治疗可显著增加存活的 DA 神经元数量。为了评估 ZNS 的作用机制，我们进行了基因表达分析，比较了用或不用 ZNS 处理的纹状体中的基因表达谱。分析结果显示，ZNS 处理的大鼠纹状体中 SLIT 和 NTRK 样蛋白 6（SLITRK6）的表达上调。综上所述，ZNS 促进了源自人 iPS 细胞的 DA 祖细胞在大鼠纹状体中的移植后 DA 神经元的存活。SLITRK6 可能通过调节宿主大脑的环境参与了 ZNS 的这种支持作用。
