Inhibition of Mitochondrial Complex III Blocks Neuronal Differentiation and Maintains Embryonic Stem Cell Pluripotency
Inhibition of Mitochondrial Complex III Blocks Neuronal Differentiation and Maintains Embryonic Stem Cell Pluripotency
复制标题
DOI：
10.1371/journal.pone.0082095
复制
发表时间：
2013-12-02
期刊：
影响因子：
3.7
通讯作者：
Ramalho-Santos, Joao
中科院分区：
文献类型：
--
作者：
Pereira, Sandro L.;Graos, Mario;Ramalho-Santos, Joao
干细胞生物学中的一个关键细胞器，作为干细胞多能性和分化的调节剂。在这项研究中，我们试图了解在小鼠胚胎干细胞神经元分化过程中线粒体复合物III抑制的效果。当暴露于抗霉素A（一种特定的复合物III抑制剂）时，胚胎干细胞未能分化为多巴胺能神经元，即使在接受特定的分化方案时，也能保持高的Oct 4水平。线粒体抑制作用影响培养物中存在的不同细胞群体，诱导分化细胞中的细胞损失，但不诱导小鼠胚胎干细胞的凋亡。观察到总体增殖率降低，对应于S期的轻微停滞。此外，抗霉素A治疗诱导HIF-1 α蛋白水平的一致增加。目前的工作表明，线粒体代谢是神经元分化的关键，并强调通过药理学方法调节线粒体功能可以在控制干细胞维持/分化的背景下是有用的。
The mitochondrion is emerging as a key organelle in stem cell biology, acting as a regulator of stem cell pluripotency and differentiation. In this study we sought to understand the effect of mitochondrial complex III inhibition during neuronal differentiation of mouse embryonic stem cells. When exposed to antimycin A, a specific complex III inhibitor, embryonic stem cells failed to differentiate into dopaminergic neurons, maintaining high Oct4 levels even when subjected to a specific differentiation protocol. Mitochondrial inhibition affected distinct populations of cells present in culture, inducing cell loss in differentiated cells, but not inducing apoptosis in mouse embryonic stem cells. A reduction in overall proliferation rate was observed, corresponding to a slight arrest in S phase. Moreover, antimycin A treatment induced a consistent increase in HIF-1 alpha protein levels. The present work demonstrates that mitochondrial metabolism is critical for neuronal differentiation and emphasizes that modulation of mitochondrial functions through pharmacological approaches can be useful in the context of controlling stem cell maintenance/ differentiation.