Tauroursodeoxycholic acid increases neural stem cell pool and neuronal conversion by regulating mitochondria-cell cycle retrograde signaling
Tauroursodeoxycholic acid increases neural stem cell pool and neuronal conversion by regulating mitochondria-cell cycle retrograde signaling
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DOI：
10.4161/15384101.2014.962951
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发表时间：
2014-10
期刊：
影响因子：
4.3
通讯作者：
Joana M. Xavier;Ana L. Morgado;C. Rodrigues;S. Solá
中科院分区：
文献类型：
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作者：
Joana M. Xavier;Ana L. Morgado;C. Rodrigues;S. Solá
干细胞移植或神经损伤后的低存活率和分化率一直是干细胞治疗的主要问题。因此，进一步了解干细胞的长期存活和分化可能会发现新的靶点，从而发现和开发新的治疗方法。我们之前已经描述了线粒体凋亡相关事件在调节神经干细胞（NSC）命运中的影响。此外，内源性胆汁酸牛磺酸去氧胆酸（TUDCA）在线粒体水平上作为抗凋亡和抗氧化分子，在几种神经退行性疾病动物模型中显示出神经保护作用。在此，我们假设TUDCA也可能在NSC命运决定中发挥作用。我们发现，TUDCA可以阻止早期小鼠NSC分化中典型的线粒体凋亡事件，保持线粒体的完整性和功能，同时增强NSCs的自我更新潜能，加速细胞周期退出。有趣的是，TUDCA预防线粒体改变通过促进神经元而非星形胶质细胞转化来干扰NSC分化潜能。最后，对线粒体活性氧（mtROS）清除剂和三磷酸腺苷（ATP）合成酶的抑制表明，TUDCA的作用依赖于mtROS和ATP的调节水平。总之，这些数据强调了线粒体应激控制对NSC命运决定的重要性，并支持了TUDCA在这一过程中的新作用。
The low survival and differentiation rates of stem cells after either transplantation or neural injury have been a major concern of stem cell-based therapy. Thus, further understanding long-term survival and differentiation of stem cells may uncover new targets for discovery and development of novel therapeutic approaches. We have previously described the impact of mitochondrial apoptosis-related events in modulating neural stem cell (NSC) fate. In addition, the endogenous bile acid, tauroursodeoxycholic acid (TUDCA) was shown to be neuroprotective in several animal models of neurodegenerative disorders by acting as an anti-apoptotic and anti-oxidant molecule at the mitochondrial level. Here, we hypothesize that TUDCA might also play a role on NSC fate decision. We found that TUDCA prevents mitochondrial apoptotic events typical of early-stage mouse NSC differentiation, preserves mitochondrial integrity and function, while enhancing self-renewal potential and accelerating cell cycle exit of NSCs. Interestingly, TUDCA prevention of mitochondrial alterations interfered with NSC differentiation potential by favoring neuronal rather than astroglial conversion. Finally, inhibition of mitochondrial reactive oxygen species (mtROS) scavenger and adenosine triphosphate (ATP) synthase revealed that the effect of TUDCA is dependent on mtROS and ATP regulation levels. Collectively, these data underline the importance of mitochondrial stress control of NSC fate decision and support a new role for TUDCA in this process.