Intrinsic resistance of neural stem cells to toxic metabolites may make them well suited for cell non‐autonomous disorders: evidence from a mouse model of Krabbe leukodystrophy-猫眼课题宝

神经干细胞对有毒代谢物的内在抵抗力可能使它们非常适合细胞非自主性疾病：克拉伯脑白质营养不良小鼠模型的证据

DOI：

发表时间：

2006

期刊：

Journal of Neurochemistry

影响因子：

4.7

通讯作者：

中科院分区：

医学2区

文献类型：

作者：

Roseanne M. Taylor;Jean;J. Palacino;Kate A. Bower;Jianxue Li;M. Vanier;D. Wenger;R. Sidman;E. Snyder

虽然移植的神经干细胞（NSC）已经显示出在许多神经障碍的模型中具有细胞替代的前景，但是这些实例通常是在宿主细胞由于细胞自主病因学（即相对支持性环境中的“病”细胞）而变得功能障碍的条件下。长期以来，人们一直认为在有毒环境中进行细胞替代是不可能的;供体细胞会以与内源性细胞大致相同的方式死亡。许多代谢性疾病的特点是这种情况，这表明它们将是细胞替代疗法的不良靶点。另一方面，这些疾病的模型可以证明是测试在这种具有挑战性的条件下细胞替代能力的理想模型。在抽搐（twi）小鼠中-与Krabbe或球样细胞脑白质营养不良（GLD）患者一样，其作为真实模型-半乳糖苷酶（GalC）活性的丧失导致毒糖脂psychosine的积累。 Twi小鼠，像患有GLD的儿童一样，表现出不可阻挡的神经功能恶化，可能是由于功能障碍和最终退化的少突胶质细胞以及髓鞘丢失。据信，GLD病理生理学与充满精神碱的环境有关，该环境不仅杀死宿主少突胶质细胞，而且理论上杀死置于该环境中的任何新细胞。通过将神经干细胞植入新生和幼年/年轻成年twi小鼠的脑中，我们已经确定广泛的少突胶质细胞替代和髓鞘再生是可行的。神经干细胞似乎是内在的耐精神病-更是在其未分化状态比体外定向成为少突胶质细胞。这种抗性可以通过将NSC工程化以过表达GalC来增强。一些移植了这种工程神经干细胞的twi小鼠有更厚的白色神经束，寿命比预期长2-3倍。虽然他们的大脑中有可检测到的GalC水平，但更重要的是，他们的精神病水平低于在年轻时死亡的twi小鼠。这种基于分化状态的抗性概念扩展到人类神经干细胞，它们同样可以在双脑中生存。总而言之，这些结果表明了关于针对退行性疾病的细胞疗法的一些要点，其中具有突出的细胞非自主成分：如果使用对毒性环境具有抗性的细胞，则细胞替代是可能的。此外，成功治疗的一个重要方面可能不仅是细胞替代，而且是宿主细胞的交叉校正，以提供酶活性并因此产生抗性。虽然单独的少突胶质细胞替代并不足以治疗GLD（即使是广泛的），但是细胞和分子两者的替代-例如用可以成为少突胶质细胞和GalC的“泵”的NSC-作为多学科策略的有希望的基础出现。大多数神经系统疾病都是复杂的，可能需要多方面的方法，也许神经干细胞作为“胶水”。

While transplanted neural stem cells (NSCs) have been shown to hold promise for cell replacement in models of a number of neurological disorders, these examples have typically been under conditions where the host cells become dysfunctional due to a cell autonomous etiology, i.e. a ‘sick’ cell within a relatively supportive environment. It has long been held that cell replacement in a toxic milieu would not likely be possible; donor cells would succumb in much the same way as endogenous cells had. Many metabolic diseases are characterized by this situation, suggesting that they would be poor targets for cell replacement therapies. On the other hand, models of such diseases could prove ideal for testing the capacity for cell replacement under such challenging conditions. In the twitcher (twi ) mouse – as in patients with Krabbe or globoid cell leukodystrophy (GLD), for which it serves as an authentic model – loss of galactocerebrosidase (GalC) activity results in the accumulation of psychosine, a toxic glycolipid. Twi mice, like children with GLD, exhibit inexorable neurological deterioration presumably as a result of dysfunctional and ultimately degenerated oligodendrocytes with loss of myelin. It is believed that GLD pathophysiology is related to a psychosine‐filled environment that kills not only host oligodendrocytes but theoretically any new cells placed into that milieu. Through the implantation of NSCs into the brains of both neonatal and juvenile/young adult twi mice, we have determined that widespread oligodendrocyte replacement and remyelination is feasible. NSCs appear to be intrinsically resistant to psychosine – more so in their undifferentiated state than when directed ex vivo to become oligodendrocytes. This resistance can be enhanced by engineering the NSCs to over‐express GalC. Some twi mice grafted with such engineered NSCs had thicker white tracts and lived 2–3 times longer than expected. While their brains had detectable levels of GalC, it was probably more significant that their psychosine levels were lower than in twi mice that died at a younger age. This concept of resistance based on differentiation state extended to human NSCs which could similarly survive within the twi brain. Taken together, these results suggest a number of points regarding cellular therapies against degenerative diseases with a prominent cell non‐autonomous component: Cell replacement is possible if cells resistant to the toxic environment are employed. Furthermore, an important aspect of successful treatment will likely be not only cell replacement but also cross‐correction of host cells to provide them with enzyme activity and hence resistance. While oligodendrocyte replacement alone was not a sufficient treatment for GLD (even when extensive), the replacement of both cells and molecules – e.g. with NSCs that could both become oligodendrocytes and ‘pumps’ for GalC – emerges as a promising basis for a multidisciplinary strategy. Most neurological disease are complex in this way and will likely require multifaceted approaches, perhaps with NSCs serving as the ‘glue’.