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通过黑质内移植实现黑质纹状体通路的解剖学和功能重建。

Anatomical and functional reconstruction of the nigrostriatal pathway by intranigral transplants.

作者信息

Gaillard Afsaneh, Decressac Mickael, Frappé Isabelle, Fernagut Pierre Olivier, Prestoz Laetitia, Besnard Stephan, Jaber Mohamed

机构信息

Institut de Physiologie et de Biologie Cellulaires, University of Poitiers, CNRS, 40 avenue recteur Pineau, 86022 Poitiers Cedex, France.

出版信息

Neurobiol Dis. 2009 Sep;35(3):477-88. doi: 10.1016/j.nbd.2009.07.003. Epub 2009 Jul 17.

Abstract

The main transplantation strategy in Parkinson's disease has been to place dopaminergic grafts not in their ontogenic site, the substantia nigra, but in their target area, the striatum with contrasting results. Here we have used green fluorescent protein transgenic mouse embryos as donors of ventral mesencephalic cells for transplantation into the pre-lesioned substantia nigra of an adult wild-type host. This allows distinguishing the transplanted cells and their projections from those of the host. Grafted cells integrated within the host mesencephalon and expressed the dopaminergic markers tyrosine hydroxylase, vesicular monoamine transporter 2 and dopamine transporter. Most of the dopaminergic cells within the transplant expressed the substantia nigra marker Girk2 while a lesser proportion expressed the ventral tegmental area marker calbindin. Mesencephalic transplants developed projections through the medial forebrain bundle to the striatum, increased striatal dopamine levels and restored normal behavior. Interestingly, only mesencephalic transplants were able to restore the nigrostriatal projections as dopamine neurons originating from embryonic olfactory bulb transplants send projections only in the close vicinity of the transplantation site that did not reach the striatum. Our results show for the first time the ability of intranigral foetal dopaminergic neurons grafts to restore the damaged nigrostriatal pathway in adult mice. Together with our previous findings of efficient embryonic transplantation within the pre-lesioned adult motor cortex, these results demonstrate that the adult brain is permissive to specific and long distance axonal growth. They further open new avenues in cell transplantation therapies applied for the treatment of neurodegenerative disorders such as Parkinson's disease.

摘要

帕金森病的主要移植策略一直是将多巴胺能移植物放置在其发生部位黑质之外,而是放置在其靶区域纹状体,结果却截然不同。在此,我们使用绿色荧光蛋白转基因小鼠胚胎作为腹侧中脑细胞的供体,将其移植到成年野生型宿主预先损伤的黑质中。这使得能够区分移植细胞及其投射与宿主细胞的投射。移植的细胞整合到宿主中脑内,并表达多巴胺能标记物酪氨酸羟化酶、囊泡单胺转运体2和多巴胺转运体。移植物中的大多数多巴胺能细胞表达黑质标记物Girk2,而较小比例的细胞表达腹侧被盖区标记物钙结合蛋白。中脑移植物通过内侧前脑束向纹状体发出投射,提高了纹状体多巴胺水平并恢复了正常行为。有趣的是,只有中脑移植物能够恢复黑质纹状体投射,因为源自胚胎嗅球移植物的多巴胺神经元仅在移植部位附近发出投射,无法到达纹状体。我们的结果首次表明,胎儿黑质内多巴胺能神经元移植物有能力恢复成年小鼠受损的黑质纹状体通路。连同我们之前关于在预先损伤的成年运动皮层内进行有效胚胎移植的发现,这些结果表明成年大脑允许特定的长距离轴突生长。它们进一步为应用于治疗帕金森病等神经退行性疾病的细胞移植疗法开辟了新途径。

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