Brain transplantation of genetically modified bone marrow stromal cells corrects CNS pathology and cognitive function in MPS VII mice
Brain transplantation of genetically modified bone marrow stromal cells corrects CNS pathology and cognitive function in MPS VII mice
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DOI：
10.1038/sj.gt.3302338
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发表时间：
2004-10-01
期刊：
影响因子：
5.1
通讯作者：
Eto, Y
中科院分区：
文献类型：
--
作者：
Sakurai, K;Iizuka, S;Eto, Y
目前用于溶酶体贮积病（LSD）的疗法、酶替代疗法和骨髓移植对于LSD的内脏器官病理学是有效的，但是它们对于LSD中的脑参与的有效性仍然是有争议的主题。作为一种替代方法，我们将基因修饰的骨髓基质（BMS）细胞移植到新生粘多糖沉积症VII（MPS VII）小鼠的侧脑室。MPS VII是LSD之一，由β-葡萄糖醛酸酶（GUSB）缺乏引起，导致糖胺聚糖（GAG）在脑中蓄积。移植后2周，嗅球、纹状体和大脑皮质内可见GUSB酶阳性细胞，各脑区酶活性均升高。移植后4周脑内GAG含量降至接近正常水平。虽然GUSB活性在8周后下降到纯合水平，但GAG的减少持续了16周。显微镜检查表明，在处理的动物脑中未发现溶酶体扩张。通过Morris水迷宫试验评价的MPS VII动物的认知功能显示，与未处理动物相比，MPS VII动物的认知功能显著改善。基因修饰的BMS细胞的脑移植似乎是治疗LSD的弥漫性CNS受累的有希望的方法。
Current therapies for lysosomal storage diseases (LSDs), enzyme replacement therapy and bone marrow transplantation are effective for visceral organ pathology of LSD, but their effectiveness for brain involvement in LSDs is still a subject of controversy. As an alternative approach, we transplanted genetically modified bone marrow stromal (BMS) cells to lateral ventricle of newborn mucopolysaccharidosis VII ( MPS VII) mice. MPS VII is one of LSDs and caused by deficiency of beta-glucuronidase (GUSB), resulting in accumulation of glycosaminoglycans (GAGs) in brain. At 2 weeks after transplantation, the GUSB enzyme-positive cells were identified in olfactory bulb, striatum and cerebral cortex, and the enzymatic activities in various brain areas increased. The GAGs contents in brain were reduced to near normal level at 4 weeks after transplantation. Although GUSB activity declined to homozygous level after 8 weeks, the reduction of GAGs persisted for 16 weeks. Microscopic examination indicated that the lysosomal distention was not found in treated animal brain. Cognitive function in MPS VII animals as evaluated by Morris Water Maze test in treated mice showed a marked improvement over nontreated animals. Brain transplantation of genetically modified BMS cells appears to be a promising approach to treat diffuse CNS involvement of LSDs.