Use of a Human Artificial Chromosome for Delivering Trophic Factors in a Rodent Model of Amyotrophic Lateral Sclerosis.
Use of a Human Artificial Chromosome for Delivering Trophic Factors in a Rodent Model of Amyotrophic Lateral Sclerosis.
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DOI：
10.1038/mtna.2015.28
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发表时间：
2015-10-06
期刊：
影响因子：
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通讯作者：
Nakashima K
中科院分区：
文献类型：
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作者：
Watanabe Y;Kazuki Y;Kazuki K;Ebiki M;Nakanishi M;Nakamura K;Yoshida Yamakawa M;Hosokawa H;Ohbayashi T;Oshimura M;Nakashima K
人类人工染色体（HAC）作为附加体维持在细胞内并避免随机整合到宿主基因组中。它可以转移多个和/或大的转基因沿着其调控元件，从而类似于天然染色体。使用此HAC系统，我们建立了间充质干细胞（MSC），同时表达肝细胞生长因子，胶质细胞源性神经营养因子，和胰岛素样生长因子1，称为HAC-MSC。该细胞系为稳定移植和全面分析提供了机会。然后，我们将这些细胞用于治疗神经退行性疾病，肌萎缩侧索硬化症。将HAC-MSCs经第四脑室（CV）或静脉内（i. v.）在不同年龄的受体小鼠中进行输注。同窝出生和性别匹配的小鼠进行假手术。与对照组相比，通过CV移植延长寿命和移植后60天静脉输注延迟起效的趋势令人鼓舞。此外，我们证实了通过CV移植在100天时的寿命在统计学上显著增加。在移植缺乏HAC的MSC的小鼠中没有观察到这种效果。我们成功地提高了使用HAC的MSC的营养潜力。这种策略可能是治疗神经退行性疾病的一个有前途的方向。
A human artificial chromosome (HAC) is maintained as an episome within a cell and avoids random integration into the host genome. It can transfer multiple and/or large transgenes along with their regulatory elements thereby resembling native chromosomes. Using this HAC system, we established mesenchymal stem cells (MSCs) that simultaneously expressed hepatocyte growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor 1, termed HAC-MSCs. This cell line provides an opportunity for stable transplantation and thorough analyses. We then introduced the cells for the treatment of a neurodegenerative disorder, amyotrophic lateral sclerosis. The HAC-MSCs were transplanted via the fourth cerebral ventricle (CV) or intravenous (i.v.) infusion at various ages of recipient mice. Littermate- and sex-matched mice underwent a sham procedure. Compared to the controls, there was an encouraging trend of increased life span via CV transplantation and delayed onset in i.v. infusion 60 days after transplantation. Further, we confirmed a statistically significant increase in life span via CV transplantation at 100 days. This effect was not seen in mice transplanted with MSCs lacking the HAC. We successfully enhanced the trophic potential of the MSCs using the HAC. This strategy could be a promising direction for the treatment of neurodegenerative disorders.