Department of Neurological Sciences, University of Milan, Via Francesco Sforza 35, 20122 Milan, Italy.
Brain. 2010 Feb;133(Pt 2):465-81. doi: 10.1093/brain/awp318. Epub 2009 Dec 23.
Spinal muscular atrophy, characterized by selective loss of lower motor neurons, is an incurable genetic neurological disease leading to infant mortality. We previously showed that primary neural stem cells derived from spinal cord can ameliorate the spinal muscular atrophy phenotype in mice, but this primary source has limited translational value. Here, we illustrate that pluripotent stem cells from embryonic stem cells show the same potential therapeutic effects as those derived from spinal cord and offer great promise as an unlimited source of neural stem cells for transplantation. We found that embryonic stem cell-derived neural stem cells can differentiate into motor neurons in vitro and in vivo. In addition, following their intrathecal transplantation into spinal muscular atrophy mice, the neural stem cells, like those derived from spinal cord, survived and migrated to appropriate areas, ameliorated behavioural endpoints and lifespan, and exhibited neuroprotective capability. Neural stem cells obtained using a drug-selectable embryonic stem cell line yielded the greatest improvements. As with cells originating from primary tissue, the embryonic stem cell-derived neural stem cells integrated appropriately into the parenchyma, expressing neuron- and motor neuron-specific markers. Our results suggest translational potential for the use of pluripotent cells in neural stem cell-mediated therapies and highlight potential safety improvements and benefits of drug selection for neuroepithelial cells.
脊髓性肌萎缩症，其特征为下运动神经元选择性丧失，是一种不可治愈的遗传性神经疾病，导致婴儿死亡。我们之前表明，源自脊髓的原代神经干细胞可改善小鼠的脊髓性肌萎缩症表型，但这种原代来源的转化价值有限。在这里，我们表明胚胎干细胞的多能干细胞与源自脊髓的干细胞具有相同的潜在治疗效果，并为移植提供了作为无限来源的神经干细胞的巨大潜力。我们发现胚胎干细胞衍生的神经干细胞可以在体外和体内分化为运动神经元。此外，在将其鞘内移植到脊髓性肌萎缩症小鼠后，神经干细胞与源自脊髓的神经干细胞一样，存活并迁移到适当的区域，改善行为终点和寿命，并表现出神经保护能力。使用可选择药物的胚胎干细胞系获得的神经干细胞产生了最大的改善。与源自原代组织的细胞一样，胚胎干细胞衍生的神经干细胞适当地整合到实质中，表达神经元和运动神经元特异性标志物。我们的结果表明，多能细胞在神经干细胞介导的治疗中的应用具有转化潜力，并强调了神经上皮细胞药物选择的潜在安全性改善和益处。
