Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health, Sacramento, California, USA.
Department of Neurology, University of California Davis Health, Sacramento, California, USA.
Stem Cells Transl Med. 2021 Jul;10(7):1033-1043. doi: 10.1002/sctm.20-0431. Epub 2021 Mar 12.
Huntington's disease (HD) is a fatal autosomal-dominant neurodegenerative disease caused by a trinucleotide CAG repeat expansion of the huntingtin gene (HTT) that affects 1 in every 10 000 individuals in the United States. Our lab developed a novel immune deficient HD mouse strain, the YACNSG, from a commonly used line, the YAC128 mouse, to enable transplantation studies using engineered human cells in addition to studying the impact of the immune system on disease progression. The primary goal of this project was to characterize this novel immune deQficient HD mouse model, using behavioral assays and histology to compare this new model to the immune competent YAC128 and immune deficient mice that had engraftment of a human immune system. Flow cytometry was used to confirm that the YACNSG strain lacked immune cells, and in vivo imaging was used to assess human mesenchymal stem/stromal cell (MSC) retention compared with a commonly used immune deficient line, the NSG mouse. We found that YACNSG were able to retain human MSCs longer than the immune competent YAC128 mice. We performed behavioral assessments starting at 4 months of age and continued testing monthly until 12 months on the accelerod and in the open field. At 12 months, brains were isolated and evaluated using immunohistochemistry for striatal volume. Results from these studies suggest that the novel immune deficient YACNSG strain of mice could provide a good model for human stem-cell based therapies and that the immune system appears to play an important role in the pathology of HD.
亨廷顿病（HD）是一种致命的常染色体显性神经退行性疾病，由亨廷顿基因（HTT）中的三核苷酸 CAG 重复扩展引起，在美国每 10000 人中就有 1 人受到影响。我们的实验室从常用的 YAC128 小鼠中开发了一种新型免疫缺陷 HD 小鼠品系，即 YACNSG，以能够进行工程化人类细胞的移植研究，除了研究免疫系统对疾病进展的影响。该项目的主要目标是使用行为测定和组织学来比较这种新型免疫缺陷 HD 小鼠模型，以确定该新型免疫缺陷 HD 小鼠模型的特征，该模型与免疫功能正常的 YAC128 和具有人类免疫系统植入的免疫缺陷小鼠进行比较。流式细胞术用于确认 YACNSG 品系缺乏免疫细胞，体内成像用于评估与人骨髓间充质干细胞/基质细胞（MSC）保留的比较，与常用的免疫缺陷 NSG 小鼠进行比较。我们发现 YACNSG 能够比免疫功能正常的 YAC128 小鼠更长时间地保留人类 MSC。我们从 4 个月大开始进行行为评估，并继续每月进行测试，直到在加速器和开阔场中进行 12 个月的测试。在 12 个月时，分离大脑并使用免疫组织化学评估纹状体体积。这些研究的结果表明，新型免疫缺陷 YACNSG 小鼠品系可能为基于人类干细胞的治疗提供良好的模型，并且免疫系统似乎在 HD 的病理学中发挥重要作用。
