Prolonged Maturation Culture Favors a Reduction in the Tumorigenicity and the Dopaminergic Function of Human ESC-Derived Neural Cells in a Primate Model of Parkinson's Disease
Prolonged Maturation Culture Favors a Reduction in the Tumorigenicity and the Dopaminergic Function of Human ESC-Derived Neural Cells in a Primate Model of Parkinson's Disease
复制标题
DOI：
10.1002/stem.1060
复制
发表时间：
2012-05-01
期刊：
影响因子：
5.2
通讯作者：
Takahashi, Jun
中科院分区：
文献类型：
--
作者：
Doi, Daisuke;Morizane, Asuka;Takahashi, Jun
为了使胚胎干细胞（embryonic stem cells，ESC）在神经系统疾病中的安全应用，评价人ESC源神经细胞在灵长类动物体内的致瘤性和功能至关重要。我们在此首次比较了植入帕金森病灵长类动物模型脑中的具有不同神经分化阶段的hESC衍生细胞的生长和功能。我们在此表明，细胞制剂中存在的表达ESC标志物的残留未分化细胞可以诱导猴脑中的肿瘤形成。与此相反，通过脑源性神经营养因子/胶质细胞系源性神经营养因子（BDNF/GDNF）处理42天培养成熟的细胞制剂没有形成肿瘤，并且主要作为多巴胺能（DA）神经元存活。此外，接受这种移植的猴子表现出至少12个月的行为改善。这些结果支持了这样的观点，即如果适当成熟，hESC可以作为DA神经元的来源，而不会在灵长类动物大脑中形成任何肿瘤。干细胞2012;30：935945
For the safe clinical application of embryonic stem cells (ESCs) for neurological diseases, it is critical to evaluate the tumorigenicity and function of human ESC (hESC)-derived neural cells in primates. We have herein, for the first time, compared the growth and function of hESC-derived cells with different stages of neural differentiation implanted in the brains of primate models of Parkinson's disease. We herein show that residual undifferentiated cells expressing ESC markers present in the cell preparation can induce tumor formation in the monkey brain. In contrast, a cell preparation matured by 42-day culture with brain-derived neurotrophic factor/glial cell line-derived neurotrophic factor (BDNF/GDNF) treatment did not form tumors and survived as primarily dopaminergic (DA) neurons. In addition, the monkeys with such grafts showed behavioral improvement for at least 12 months. These results support the idea that hESCs, if appropriately matured, can serve as a source for DA neurons without forming any tumors in a primate brain. STEM CELLS 2012;30:935945