Graduate Program in Biomedical Sciences, University of California at San Diego, La Jolla, California, USA; Program in Stem Cell and Regenerative Biology, Sanford-Burnham Medical Research Institute, La Jolla, California, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA; Departments of Psychiatry, Neurosurgery, and Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Neurology, University of Colorado School of Medicine, Denver, Colorado, USA; Department of Neurosurgery and Physical Medicine and Rehabilitation, Harvard Medical School, Boston, Massachusetts, USA; Gene Therapy Center and Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Graduate Program in Biomedical Sciences, University of California at San Diego, La Jolla, California, USA; Program in Stem Cell and Regenerative Biology, Sanford-Burnham Medical Research Institute, La Jolla, California, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA; Departments of Psychiatry, Neurosurgery, and Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Neurology, University of Colorado School of Medicine, Denver, Colorado, USA; Department of Neurosurgery and Physical Medicine and Rehabilitation, Harvard Medical School, Boston, Massachusetts, USA; Gene Therapy Center and Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Stem Cells Transl Med. 2014 Jun;3(6):692-701. doi: 10.5966/sctm.2013-0208. Epub 2014 Apr 17.
Transplanted multipotent human fetal neural stem cells (hfNSCs) significantly improved the function of parkinsonian monkeys in a prior study primarily by neuroprotection, with only 3%-5% of cells expressing a dopamine (DA) phenotype. In this paper, we sought to determine whether further manipulation of the neural microenvironment by overexpression of a developmentally critical molecule, glial cell-derived neurotrophic factor (GDNF), in the host striatum could enhance DA differentiation of hfNSCs injected into the substantia nigra and elicit growth of their axons to the GDNF-expressing target. hfNSCs were transplanted into the midbrain of 10 green monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine. GDNF was delivered concomitantly to the striatum via an adeno-associated virus serotype 5 vector, and the fate of grafted cells was assessed after 11 months. Donor cells remained predominantly within the midbrain at the injection site and sprouted numerous neurofilament-immunoreactive fibers that appeared to course rostrally toward the striatum in parallel with tyrosine hydroxylase-immunoreactive fibers from the host substantia nigra but did not mature into DA neurons. This work suggests that hfNSCs can generate neurons that project long fibers in the adult primate brain. However, in the absence of region-specific signals and despite GDNF overexpression, hfNSCs did not differentiate into mature DA neurons in large numbers. It is encouraging, however, that the adult primate brain appeared to retain axonal guidance cues. We believe that transplantation of stem cells, specifically instructed ex vivo to yield DA neurons, could lead to reconstruction of some portion of the nigrostriatal pathway and prove beneficial for the parkinsonian condition.
在先前的一项研究中，移植的多能人胎脑神经干细胞（hfNSCs）主要通过神经保护作用显著改善了帕金森病猴的功能，其中只有 3%-5%的细胞表达多巴胺（DA）表型。在本文中，我们试图确定通过在宿主纹状体中超表达发育关键分子胶质细胞源性神经营养因子（GDNF）来进一步操纵神经微环境，是否可以增强注射到黑质中的 hfNSCs 的 DA 分化，并促使其轴突生长到表达 GDNF 的靶标。hfNSCs 被移植到 10 只暴露于 1-甲基-4-苯基-1,2,3,6-四氢吡啶的绿猴的中脑。GDNF 通过腺相关病毒血清型 5 载体同时递送到纹状体，并且在 11 个月后评估移植细胞的命运。供体细胞主要位于注射部位的中脑内，并长出许多神经丝免疫反应性纤维，这些纤维似乎与宿主黑质中的酪氨酸羟化酶免疫反应性纤维平行向纹状体方向伸展，但没有成熟为 DA 神经元。这项工作表明，hfNSCs 可以产生在成年灵长类动物大脑中投射长纤维的神经元。然而，在缺乏区域特异性信号的情况下，尽管 GDNF 过表达，hfNSCs 也没有大量分化为成熟的 DA 神经元。然而，令人鼓舞的是，成年灵长类动物大脑似乎保留了轴突导向线索。我们相信，移植经过专门体外指令产生 DA 神经元的干细胞，可以导致黑质纹状体通路的一部分重建，并对帕金森病状况有益。
