Wang Lei, Ye Xiaoying, Zhao Qiang, Zhou Zhongcheng, Dan Jiameng, Zhu Yushan, Chen Quan, Liu Lin
State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University , Tianjin, China .
Stem Cells Dev. 2014 Oct 15;23(20):2422-34. doi: 10.1089/scd.2014.0059. Epub 2014 Aug 4.
Mature mitochondria with high oxidative phosphorylation undergo fission and fusion and morphogenesis to become immature mitochondria during induced pluripotent stem (iPS) induction from somatic cells. Dynamin-related protein 1 (Drp1) is involved in mitochondria fission and biogenesis in somatic cells. We tested the role of Drp1 in the induction and maintenance of pluripotency. We show that Drp1 band shift occurs in embryonic stem cells (ESCs) and iPS cells (iPSCs) induced from fibroblasts, in association with mitochondrial morphogenesis. However, knockdown of Drp1 by shRNA does not abrogate mitochondria morphogenesis and induction of iPSCs from fibroblasts. Also, knockdown of Drp1 affects neither mitochondria fission and function as shown by normal mitochondrial membrane potential, nor proliferation and pluripotency of ESCs. Nonetheless, Drp1 knockdown negatively influences terminal differentiation of ESCs, particularly in the lineage of neurogenesis in vitro and in vivo, coincident with delayed reduction of Oct4 and Nanog during mid-differentiation. Our data suggest that Drp1 is not critical for mitochondria biogenesis in stem cell proliferation but it is required for neurogenesis likely by downregulation of pluripotency-associated genes Nanog and Oct4. ESC differentiation model could be used to model role of Drp1 in neuron development and diseases.
在从体细胞诱导生成诱导多能干细胞（iPS）的过程中，具有高氧化磷酸化能力的成熟线粒体经历裂变、融合和形态发生，转变为不成熟的线粒体。动力相关蛋白1（Drp1）参与体细胞中的线粒体裂变和生物发生。我们测试了Drp1在多能性诱导和维持中的作用。我们发现，在胚胎干细胞（ESC）和成纤维细胞诱导产生的iPS细胞（iPSC）中，Drp1条带迁移与线粒体形态发生有关。然而，通过短发夹RNA（shRNA）敲低Drp1并不会消除线粒体形态发生，也不会阻止从成纤维细胞诱导生成iPSC。此外，敲低Drp1既不影响线粒体裂变和功能（线粒体膜电位正常表明其功能正常），也不影响ESC的增殖和多能性。尽管如此，Drp1敲低会对ESC的终末分化产生负面影响，特别是在体外和体内神经发生谱系中，这与分化中期Oct4和Nanog的延迟减少相一致。我们的数据表明，Drp1对干细胞增殖中的线粒体生物发生并不关键，但可能通过下调多能性相关基因Nanog和Oct4来促进神经发生。ESC分化模型可用于模拟Drp1在神经元发育和疾病中的作用。
