Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA.
Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15921-6. doi: 10.1073/pnas.1010209107. Epub 2010 Aug 23.
Recent advances in deriving induced pluripotent stem (iPS) cells from patients offer new possibilities for biomedical research and clinical applications, as these cells could be used for autologous transplantation. We differentiated iPS cells from patients with Parkinson's disease (PD) into dopaminergic (DA) neurons and show that these DA neurons can be transplanted without signs of neurodegeneration into the adult rodent striatum. The PD patient iPS (PDiPS) cell-derived DA neurons survived at high numbers, showed arborization, and mediated functional effects in an animal model of PD as determined by reduction of amphetamine- and apomorphine-induced rotational asymmetry, but only a few DA neurons projected into the host striatum at 16 wk after transplantation. We next applied FACS for the neural cell adhesion molecule NCAM on differentiated PDiPS cells before transplantation, which resulted in surviving DA neurons with functional effects on amphetamine-induced rotational asymmetry in a 6-OHDA animal model of PD. Morphologically, we found that PDiPS cell-derived non-DA neurons send axons along white matter tracts into specific close and remote gray matter target areas in the adult brain. Such findings establish the transplantation of human PDiPS cell-derived neurons as a long-term in vivo method to analyze potential disease-related changes in a physiological context. Our data also demonstrate proof of principle of survival and functional effects of PDiPS cell-derived DA neurons in an animal model of PD and encourage further development of differentiation protocols to enhance growth and function of implanted PDiPS cell-derived DA neurons in regard to potential therapeutic applications.
最近在从患者中诱导多能干细胞（iPS）方面的进展为生物医学研究和临床应用提供了新的可能性，因为这些细胞可用于自体移植。我们将帕金森病（PD）患者的 iPS 细胞分化为多巴胺能（DA）神经元，并表明这些 DA 神经元可以在没有神经退行性变迹象的情况下移植到成年啮齿动物纹状体中。PD 患者 iPS（PDiPS）细胞衍生的 DA 神经元大量存活，表现出分支，并通过减少安非他命和阿扑吗啡诱导的旋转不对称性来介导 PD 动物模型中的功能效应，但只有少数 DA 神经元在移植后 16 周投射到宿主纹状体中。接下来，我们在移植前对分化的 PDiPS 细胞进行了神经细胞黏附分子 NCAM 的 FACS 分析，结果表明，在 6-OHDA 诱导的 PD 动物模型中，具有功能效应的存活 DA 神经元对安非他命诱导的旋转不对称性有影响。形态学上，我们发现 PDiPS 细胞衍生的非 DA 神经元沿着白质束发出轴突，进入成年大脑中特定的近和远程灰质靶区。这些发现确立了人类 PDiPS 细胞衍生神经元的移植作为一种长期的体内方法，用于在生理环境下分析潜在的与疾病相关的变化。我们的数据还证明了在 PD 动物模型中 PDiPS 细胞衍生的 DA 神经元的存活和功能效应的原理，并鼓励进一步开发分化方案，以增强植入的 PDiPS 细胞衍生的 DA 神经元的生长和功能，以实现潜在的治疗应用。
