hUC-MSCs抑制神经元核内包涵体形成治疗SCA3型的研究

Spinocerebellar ataxia type 3 (SCA3) is the most uinversal type of SCA which is a heterogeneous group of hereditary neurodegenerative disease in our country and there is no effective treatment.The documents and our earlier research have shown that human umbilical cord mesenchymal stem cell (hUC-MSCs) transplantation has emerged as a promising therapeutic approach for SCA. The objectives of this study were to assess the feasibility, efficiency of hUC-MSCs transplantation in SCA3 and find the relative molecular mechanism.We perform this study with the B6.SCA3-YAC-84Q transgene mice as SCA3 model and resolve the under questions from entity to molecular level: 1. whether hUC-MSCs promote functional recovery and protect the SCA3 model from neuron loss by inhibiting the procedure of forming the neuronal intranuclear inclusions? 2. The pivotal role of paracrining function of hUC-MSCs in cure SCA3 mouse model. 3.Finding the relative molecular mechanisms of that hUC-MSCs could play a neuroprotection function in SCA3 mouse model. From all of the study, we may find a new therapeutic strategy for SCA3 and other polyglutamine diseases.

脊髓小脑性共济失调3型(SCA3)是我国常见的遗传性神经系统变性疾病，目前尚无有效的预防和治疗手段。文献和我们前期研究提示人脐带间充质干细胞（hUC-MSCs）是一种理想的治疗SCA的种子细胞。为了进一步探讨hUC-MSCs在SCA3这类多聚谷氨酰胺疾病中具有的治疗作用及其可能机制，本课题将从整体到分子水平，以B6.SCA3-YAC-84Q转基因小鼠为SCA3动物模型，研究：1、hUC-MSCs是否能够抑制神经元核内包涵体形成，避免神经元损伤，从而改善共济失调症状？2、hUC-MSCs是否通过旁分泌作用对SCA3发挥神经保护功能?3、hUC-MSCs上述神经保护作用的相关分子机制。我们期望通过阐明hUC-MSCs对SCA3型治疗作用可能的分子机制，为干细胞临床应用治疗此类多聚谷氨酰胺疾病奠定坚实的基础。

脊髓小脑性共济失调3型（SCA3）是我国常见的遗传性神经系统变性疾病，目前尚无有效的预防和治疗手段。含PolyQs的ATX3蛋白发生错误折叠，形成蛋白聚集物导致神经元核内包涵体形成可能是整个发病机制的核心环节。增加分子伴侣HSP70水平，同时降低caspase表达，能够抑制突变ATX3蛋白的聚集和毒性作用，减少神经元核内包涵体形成和神经元凋亡，增加神经元的存活率。. hUC-MSCs具有MSCs普遍的替代、调节免疫抑制炎症、营养及旁分泌等作用，而且具有独特的优点，是目前干细胞治疗方面的最优选择。本研究以SCA3转基因小鼠为在体研究模型，确定hUC-MSCs是否通过旁分泌途径对SCA3发挥治疗和神经保护作用，并试图阐明其作用机制。主要结果如下：（1）hUC-MSCs能够改善SCA3的共济失调症状，在体内减少小脑浦肯野细胞的死亡，抑制突变ATX3蛋白的聚集和核内包涵体的生成。（2）hUC-MSCs通过旁分泌IGF-1增加胞内HSP70表达水平以减少突变ATX3蛋白的聚集。（3）hUC-MSCs通过旁分泌IGF-1抑制体内caspase3.9的表达，减少突变ATX3蛋白的毒性和神经元凋亡。. 综上所述，hUC-MSCs通过旁分泌IGF-1增加HSP70水平，同时降低caspase3,9的表达，抑制突变ATX3蛋白的聚集和毒性作用，减少核内包涵体形成和神经元凋亡，发挥脑保护作用。本研究为干细胞的转化医学研究提供了一定的理论基础。.. SCI论文正在整理中，近期准备投稿。