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首页> 美国卫生研究院文献>Springer Open Choice >Bezafibrate Upregulates Mitochondrial Biogenesis and Influence Neural Differentiation of Human-Induced Pluripotent Stem Cells
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Bezafibrate Upregulates Mitochondrial Biogenesis and Influence Neural Differentiation of Human-Induced Pluripotent Stem Cells

机译：苯扎贝特上调线粒体生物发生并影响人类诱导的多能干细胞的神经分化。

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Bezafibrate (BZ) regulates mitochondrial biogenesis by activation of PPAR’s receptors and enhancing the level of PGC-1α coactivator. In this report, we investigated the effect of BZ on the expression of genes (1) that are linked to different pathways involved in mitochondrial biogenesis, e.g., regulated by PPAR’s receptors or PGC-1α coactivator, and (2) involved in neuronal or astroglial fate, during neural differentiation of hiPSC. The tested cell populations included hiPSC-derived neural stem cells (NSC), early neural progenitors (eNP), and neural progenitors (NP). RNA-seq analysis showed the expression of PPARA, PPARD receptors and excluded PPARG in all tested populations. The expression of PPARGC1A encoding PGC-1α was dependent on the stage of differentiation: NSC, eNP, and NP differed significantly as compared to hiPSC. In addition, BZ-evoked upregulation of PPARGC1A, GFAP, S100B, and DCX genes coexist with downregulation of MAP2 gene only at the eNP stage of differentiation. In the second task, we investigated the cell sensitivity and mitochondrial biogenesis upon BZ treatment. BZ influenced the cell viability, ROS level, mitochondrial membrane potential, and total cell number in concentration- and stage of differentiation-dependent manner. Induction of mitochondrial biogenesis evoked by BZ determined by the changes in the level of SDHA and COX-1 protein, and mtDNA copy number, as well as the expression of NRF1, PPARGC1A, and TFAM genes, was detected only at NP stage for all tested markers. Thus, developmental stage-specific sensitivity to BZ of neurally differentiating hiPSC can be linked to mitochondrial biogenesis, while fate commitment decisions to PGC-1α (encoded by PPARGC1A) pathway.Electronic supplementary materialThe online version of this article (10.1007/s12035-018-1368-2) contains supplementary material, which is available to authorized users.
机译：苯扎贝特（BZ）通过激活PPAR受体并增强PGC-1α共激活剂的水平来调节线粒体的生物发生。在本报告中，我们研究了BZ对基因表达的影响（1），其与参与线粒体生物发生的不同途径相关，例如受PPAR受体或PGC-1α共激活因子调控，以及（2）与神经元或星形胶质细胞有关命运，在hiPSC的神经分化过程中。测试的细胞群包括hiPSC衍生的神经干细胞（NSC），早期神经祖细胞（eNP）和神经祖细胞（NP）。 RNA-seq分析显示在所有测试人群中PPARA，PPARD受体和排除的PPARG的表达。编码PGC-1α的PPARGC1A的表达取决于分化阶段：与hiPSC相比，NSC，eNP和NP差异显着。此外，仅在分化的eNP阶段，BZ引起的PPARGC1A，GFAP，S100B和DCX基因上调与MAP2基因下调共存。在第二个任务中，我们研究了BZ治疗后的细胞敏感性和线粒体生物发生。 BZ以浓度依赖性和分化依赖性的方式影响细胞活力，ROS水平，线粒体膜电位和总细胞数。由BZ引起的线粒体生物发生的诱导取决于SDHA和COX-1蛋白水平的变化，mtDNA拷贝数以及NRF1，PPARGC1A和TFAM基因的表达。标记。因此，神经分化的hiPSC对BZ的发育阶段特异性敏感性可以与线粒体的生物发生有关，而对PGC-1α（由PPARGC1A编码）的命运决定则是电子的。电子补充材料本文的在线版本（10.1007 / s12035-018- 1368-2）包含补充材料，授权用户可以使用。

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