Inhibition of Notch signaling facilitates the differentiation of human-induced pluripotent stem cells into neural stem cells
Inhibition of Notch signaling facilitates the differentiation of human-induced pluripotent stem cells into neural stem cells
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抑制Notch信号促进人诱导多能干细胞分化为神经干细胞
DOI：
10.1007/s11010-014-2130-3
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发表时间：
2014-10-01
影响因子：
4.3
通讯作者：
Deng, Zhi-Feng
中科院分区：
文献类型：
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作者：
Chen, Chun-Yuan;Liao, Wei;Deng, Zhi-Feng
来源于诱导多能干细胞（iPSC）的神经干细胞（NSC）正在成为基于细胞的脑疾病治疗的吸引人的来源。因此，重要的是要了解调控iPSC向NSC分化的分子机制。众所周知，Notch信号传导控制干细胞特征的保留并驱动干细胞命运。然而，需要进一步的研究来调查Notch信号传导在iPSC的NSC分化中的作用。在这项研究中，我们成功地产生了神经干细胞从人类iPSCs使用无血清培养基补充维甲酸（RA）在体外。然后，我们评估了Notch信号相关分子和一些miRNA（9，34 a，200 b）表达的变化，这些miRNA通过靶向Notch信号发挥其调节作用。此外，我们使用γ-分泌酶抑制剂（DAPT）来干扰Notch信号传导。数据显示，在分化过程中，Notch信号相关分子的水平下降，而那些miRNA增加。Notch信号的抑制加速了神经花环结构的形成以及NSC和成熟神经细胞标志物基因的表达。这表明Notch信号负调控人iPSC的神经化，并且该过程可能受到一些miRNA的调控。
Neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) are becoming an appealing source of cell-based therapies of brain diseases. As such, it is important to understand the molecular mechanisms that regulate the differentiation of iPSCs toward NSCs. It is well known that Notch signaling governs the retention of stem cell features and drives stem cells fate. However, further studies are required to investigate the role of Notch signaling in the NSCs differentiation of iPSCs. In this study, we successfully generated NSCs from human iPSCs using serum-free medium supplemented with retinoic acid (RA) in vitro. We then assessed changes in the expression of Notch signaling-related molecules and some miRNAs (9, 34a, 200b), which exert their regulation by targeting Notch signaling. Moreover, we used a γ-secretase inhibitor (DAPT) to disturb Notch signaling. Data revealed that the levels of the Notch signaling-related molecules decreased, whereas those miRNAs increased, during this differentiation process. Inhibition of Notch signaling accelerated the formation of the neural rosette structures and the expression of NSC and mature neurocyte marker genes. This suggests that Notch signaling negatively regulated the neuralization of human iPSCs, and that this process may be regulated by some miRNAs.