Multipotential neural precursors transplanted into the metachromatic leukodystrophy brain fail to generate oligodendrocytes but contribute to limit brain dysfunction
Multipotential neural precursors transplanted into the metachromatic leukodystrophy brain fail to generate oligodendrocytes but contribute to limit brain dysfunction
复制标题
DOI：
10.1159/000150127
复制
发表时间：
2008-01-01
影响因子：
2.9
通讯作者：
Bongarzone, E.
中科院分区：
文献类型：
--
作者：
Givogri, M. I.;Bottai, D.;Bongarzone, E.
神经干细胞似乎最适合用于神经系统疾病的再生治疗。然而，高水平的潜在毒性物质，如硫苷脂-在异染性脑白质营养不良（MLD）中积累-对这种再生能力的影响在很大程度上仍然不清楚。为了开始解决这个问题，体外和体内实验被用来检查暴露于异常高水平的硫苷脂的多能神经前体的行为。将分离的神经球移植到症状前MLD幼崽的脑中后，大多数供体来源的细胞分布在尾侧至喙侧方向，皮质中的数量较多。大多数（如果不是全部的话）供体细胞获得了星形胶质细胞表型。我们没有发现移植细胞在长期治疗的MLD小鼠（例如，长达1.5岁）中的少突胶质细胞或神经元定型的证据。这与我们的体外研究结果一致，即硫苷脂在诱导硫苷脂处理的表皮生长因子/成纤维细胞生长因子反应性神经球分化后阻断少突胶质细胞形成。移植的MLD小鼠表现出改善的芳基硫酸酯酶A（ARSA）活性和显著改善的硫苷脂代谢，神经退行性变和运动学习/记忆缺陷。此外，移植的细胞被证明是内源性脑细胞中积累的ARSA酶的来源，表明移植细胞和宿主细胞之间发生了酶交叉校正。这些结果提供了第一个洞察到的神经干细胞的干细胞特性和MLD环境的影响，在体内使用神经干细胞在细胞治疗的预期的硫苷脂的效果。版权所有（C）2008 S. Karger AG，巴塞尔。
Neural stem cells appear to be best suited for regenerative therapy in neurological diseases. However, the effects of high levels of potentially toxic substances such as sulfatides - which accumulate in metachromatic leukodystrophy (MLD) - on this regenerative ability are still largely unclear. To start addressing this question, in vitro and in vivo experiments were used to examine the behavior of multipotential neural precursors exposed to abnormally high levels of sulfatides. Following transplantation of dissociated neuro-spheres into the brain of presymptomatic MLD pups, the majority of donor-derived cells were distributed in a caudal to rostral direction, with higher numbers in the cortex. Most if not all of the donor cells acquired an astroglial phenotype. We found no evidence of oligodendrocyte or neuronal commitment of transplanted cells in long-term-treated MLD mice (e.g. up to 1.5 years of age). This was in line with our in vitro findings of sulfatides blocking oligodendrocyte formation after induction of differentiation in sulfatide-treated epidermal growth factor/fibroblast growth factor responsive neurospheres. Transplanted MLD mice showed an improved arylsulfatase A (ARSA) activity and a significant amelioration of sulfatide metabolism, neurodegeneration and motor-learning/memory deficits. Furthermore, transplanted cells were shown to act as a source of ARSA enzyme that accumulated in endogenous brain cells, indicating the occurrence of enzyme cross-correction between transplanted and host cells. These results provide a first insight into the effect of sulfatides on the stemness properties of neural stem cells and on the effects of the MLD environment on the in vivo expectations of using neural stem cells in cell therapy. Copyright (C) 2008 S. Karger AG, Basel.