SOD1/Rag2 Mice with Low Copy Number of SOD1 Gene as a New Long-Living Immunodeficient Model of ALS
SOD1/Rag2 Mice with Low Copy Number of SOD1 Gene as a New Long-Living Immunodeficient Model of ALS
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DOI：
10.1038/s41598-018-37235-w
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发表时间：
2019-01-28
影响因子：
4.6
通讯作者：
Stanaszek, L.
中科院分区：
文献类型：
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作者：
Majchrzak, M.;Drela, K.;Stanaszek, L.
关于肌萎缩侧索硬化症（ALS）的最新研究强调了胶质细胞在疾病发展中的作用。因此，可以怀疑治疗ALS的有效治疗策略将是替换有缺陷的神经胶质。人类神经胶质祖细胞（hGRP）替代策略的基本问题之一是细胞在体内变得完全功能所需的时间。大多数流行的高拷贝数SOD 1突变小鼠的寿命可能太短，无法承认移植细胞的好处。我们致力于开发具有较低转基因拷贝数和较长寿命的ALS免疫缺陷rag 2（-）/（-）模型。对获得的hSOD 1/rag 2双突变小鼠进行了表征。QPCR分析显示hSOD 1转基因的拷贝数在我们的菌落中变化（4-8个拷贝）。转基因拷贝数的差异可以转化为对寿命的显著影响。长寿命和短寿命hSOD 1/rag 2小鼠的死亡早在死亡前一个月就出现肌肉无力。重要的是，基于磁共振成像，我们发现突变小鼠表现出异常的延髓运动核。总之，我们开发了长寿命的双突变hSOD 1/rag 2小鼠，这可能是一个有前途的模型，用于测试人类干细胞的治疗效用。
The most recent research concerning amyotrophic lateral sclerosis (ALS) emphasizes the role of glia in disease development. Thus, one can suspect that the effective therapeutic strategy in treatment of ALS would be replacement of defective glia. One of the basic problems with human glial progenitors (hGRPs) replacement strategies is the time needed for the cells to become fully functional in vivo. The lifespan of most popular high copy number SOD1 mutant mice might be too short to acknowledge benefits of transplanted cells. We focused on developing immunodeficient rag2(-)/(-) model of ALS with lower number of transgene copies and longer lifespan. The obtained hSOD1/rag2 double mutant mice have been characterized. QPCR analysis revealed that copy number of hSOD1 transgene varied in our colony (4-8 copies). The difference in transgene copy number may be translated to significant impact on the lifespan. The death of long-and short-living hSOD1/rag2 mice is preceded by muscular weakness as early as one month before death. Importantly, based on magnetic resonance imaging we identified that mutant mice demonstrated abnormalities within the medullar motor nuclei. To conclude, we developed long-living double mutant hSOD1/rag2 mice, which could be a promising model for testing therapeutic utility of human stem cells.