Magavi Sanjay S P, Lois Carlos
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Dev Neurobiol. 2008 Dec;68(14):1527-37. doi: 10.1002/dneu.20677.
Transplantation of embryonic or stem cell derived neurons has been proposed as a potential therapy for several neurological diseases. Previous studies reported that transplanted embryonic neurons extended long-distance projections through the adult brain exclusively to appropriate targets. We transplanted E14 lateral ganglionic eminence (LGE) and E15 cortical precursors from embryonic mice into the intact adult brain and analyzed the projections formed by transplanted neurons. In contrast to previous studies, we found that transplanted embryonic neurons formed distinct long-distance projections to both appropriate and ectopic targets. LGE neurons transplanted into the adult striatum formed projections not only to the substantia nigra, a normal target, but also to the claustrum and through all layers of fronto-orbital cortex, regions that do not normally receive striatal input. In some cases, inappropriate projections outnumbered appropriate projections. To examine the relationship between the donor cells and host brain in establishing the pattern of projections, we transplanted cortical precursors into the adult striatum. Despite their heterotopic location, cortical precursors not only predominantly formed projections appropriate for cortical neurons, but they also formed projections to inappropriate targets. Transplantation of GFP-expressing cells into beta-galactosidase-expressing mice confirmed that the axonal projections were not created by the fusion of donor and host cells. These results suggest that repairing the brain using transplantation may be more complicated than previously expected, because exuberant ectopic projections could result in brain dysfunction. Understanding the signals regulating axonal extension in the adult brain will be necessary to harness stem cells or embryonic neurons for effective neuronal-replacement therapies.
胚胎或干细胞衍生神经元的移植已被提议作为几种神经疾病的潜在治疗方法。先前的研究报道，移植的胚胎神经元在成体大脑中仅向合适的靶标延伸出长距离投射。我们将来自胚胎小鼠的E14侧神经节隆起（LGE）和E15皮质前体细胞移植到完整的成体大脑中，并分析移植神经元形成的投射。与先前的研究相反，我们发现移植的胚胎神经元向合适和异位靶标都形成了明显的长距离投射。移植到成体纹状体的LGE神经元不仅向正常靶标黑质形成投射，还向屏状核以及穿过额眶皮质的所有层形成投射，而这些区域通常不接受纹状体输入。在某些情况下，不适当的投射数量超过了适当的投射。为了研究供体细胞与宿主大脑在建立投射模式中的关系，我们将皮质前体细胞移植到成体纹状体中。尽管它们处于异位位置，但皮质前体细胞不仅主要形成了适合皮质神经元的投射，还形成了向不适当靶标的投射。将表达绿色荧光蛋白（GFP）的细胞移植到表达β-半乳糖苷酶的小鼠中证实，轴突投射不是由供体细胞与宿主细胞融合产生的。这些结果表明，利用移植修复大脑可能比先前预期的更为复杂，因为过多的异位投射可能导致脑功能障碍。为了将干细胞或胚胎神经元用于有效的神经元替代疗法，了解调节成体大脑中轴突延伸的信号将是必要的。
