Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 606-8507 Kyoto, Japan.
Group for Neuronal Differentiation and Development, KAN Research Institute, Inc., 650-0047 Kobe, Japan.
Stem Cell Reports. 2014 Mar 6;2(3):337-50. doi: 10.1016/j.stemcr.2014.01.013. eCollection 2014 Mar 11.
Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (DA) neurons for cell replacement therapy for Parkinson's disease. However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. Here, we show that human iPSC-derived DA progenitor cells can be efficiently isolated by cell sorting using a floor plate marker, CORIN. We induced DA neurons using scalable culture conditions on human laminin fragment, and the sorted CORIN(+) cells expressed the midbrain DA progenitor markers, FOXA2 and LMX1A. When transplanted into 6-OHDA-lesioned rats, the CORIN(+) cells survived and differentiated into midbrain DA neurons in vivo, resulting in significant improvement of the motor behavior, without tumor formation. In particular, the CORIN(+) cells in a NURR1(+) cell-dominant stage exhibited the best survival and function as DA neurons. Our method is a favorable strategy in terms of scalability, safety, and efficiency and may be advantageous for clinical application.
人诱导多能干细胞（iPSCs）可为帕金森病的细胞替代治疗提供有前景的中脑多巴胺能（DA）神经元来源。然而，iPSC 衍生的供体细胞不可避免地包含致瘤或不合适的细胞。在这里，我们展示了使用细胞分选用人基板标记物 CORIN 可以有效地分离人 iPSC 衍生的 DA 祖细胞。我们使用人层粘连蛋白片段上可扩展的培养条件诱导 DA 神经元，分选的 CORIN(+)细胞表达中脑 DA 祖细胞标记物 FOXA2 和 LMX1A。当移植到 6-OHDA 损伤的大鼠中时，CORIN(+)细胞在体内存活并分化为中脑 DA 神经元，导致运动行为显著改善，没有肿瘤形成。特别是，NURR1(+)细胞优势阶段的 CORIN(+)细胞表现出最好的作为 DA 神经元的存活和功能。我们的方法在可扩展性、安全性和效率方面具有优势，可能有利于临床应用。
