A Flavonoid Compound Promotes Neuronal Differentiation of Embryonic Stem Cells via PPAR-β Modulating Mitochondrial Energy Metabolism.
A Flavonoid Compound Promotes Neuronal Differentiation of Embryonic Stem Cells via PPAR-β Modulating Mitochondrial Energy Metabolism.
复制标题
类黄酮化合物通过 PPAR-β 调节线粒体能量代谢促进胚胎干细胞的神经元分化
DOI：
10.1371/journal.pone.0157747
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Lou YJ
中科院分区：
文献类型：
--
作者：
Mei YQ;Pan ZF;Chen WT;Xu MH;Zhu DY;Yu YP;Lou YJ
关于线粒体代谢在胚胎干细胞神经分化中的作用，人们知之甚少。通过使用小分子，本研究研究了小鼠胚胎干细胞来源的神经前体细胞中细胞能量代谢的模式。黄酮类化合物4a能有效地促进ES细胞在形态和功能上向神经元分化。检测神经前体细胞中过氧化物酶体增殖物激活受体(PPAR)的表达和定位。与溶剂对照相比，PPAR-β的表达显著上调。PPAR-β激动剂L165041单独或与化合物4a合用可显著促进神经元分化，而拮抗剂GSK0660则阻断化合物4a的促神经发生作用。一贯地，在ES细胞中敲除PPAR-β可以取消化合物4a诱导的神经元分化。有趣的是，我们发现线粒体融合蛋白Mfn2也被sh-PPAR-β取消，导致线粒体钙瞬变([Ca2+]M)异常以及线粒体生物能量学受损。综上所述，我们证明了PPAR-β通过Mfn2和线粒体钙离子调节线粒体能量代谢，在黄酮类化合物4a诱导的神经元分化中起重要作用。
Relatively little is known regarding mitochondrial metabolism in neuronal differentiation of embryonic stem (ES) cells. By using a small molecule, present research has investigated the pattern of cellular energy metabolism in neural progenitor cells derived from mouse ES cells. Flavonoid compound 4a faithfully facilitated ES cells to differentiate into neurons morphologically and functionally. The expression and localization of peroxisome proliferator-activated receptors (PPARs) were examined in neural progenitor cells. PPAR-β expression showed robust upregulation compared to solvent control. Treatment with PPAR-β agonist L165041 alone or together with compound 4a significantly promoted neuronal differentiation, while antagonist GSK0660 blocked the neurogenesis-promoting effect of compound 4a. Consistently, knockdown of PPAR-β in ES cells abolished compound 4a-induced neuronal differentiation. Interestingly, we found that mitochondrial fusion protein Mfn2 was also abolished by sh-PPAR-β, resulting in abnormal mitochondrial Ca2+ ([Ca2+]M) transients as well as impaired mitochondrial bioenergetics. In conclusion, we demonstrated that by modulating mitochondrial energy metabolism through Mfn2 and mitochondrial Ca2+, PPAR-β took an important role in neuronal differentiation induced by flavonoid compound 4a.