Oxygen regulates proliferation of neural stem cells through Wnt/β-catenin signalling
Oxygen regulates proliferation of neural stem cells through Wnt/β-catenin signalling
复制标题
DOI：
10.1016/j.mcn.2015.06.006
复制
发表时间：
2015-07-01
影响因子：
3.5
通讯作者：
Storch, Alexander
中科院分区：
文献类型：
--
作者：
Braunschweig, Lena;Meyer, Anne K.;Storch, Alexander
降低的氧水平（1- 5%O-2，在本文中称为“生理氧”）对干细胞培养物是有益的，导致增强的增殖、更好的存活和更高的分化潜力，但潜在的分子机制仍然难以捉摸。最近发现了生理氧和经典Wnt通路之间的潜在联系，但这种信号通路对各种干细胞特性（如增殖、干细胞维持和分化能力）的差异参与仍然是个谜。我们在这里证明了在原代组织特异性胎鼠神经干细胞中，在生理毒性细胞培养后，Wnt靶基因转录增加，活性β-连环蛋白稳定。敲除主要的氧传感分子，缺氧诱导因子-1 α（HIF-1 α），对Wnt激活没有影响，假设物理氧诱导Wnt途径独立于HIF-1 α。为了确定物理氧诱导的Wnt/β-连环蛋白信号传导的生理相关性，我们检查了Wnt激活和抑制后的增殖、细胞周期动力学、存活和干细胞维持。而生存和干细胞的维护似乎是独立的Wnt途径，我们的研究提供了第一个证据，Wnt/β-连环蛋白信号积极刺激增殖的生理毒性细胞通过影响细胞周期调控。总之，我们的研究结果提供了对氧介导的神经干细胞自我更新活性调节的机制性见解。(C)2015 Elsevier Inc. All rights reserved.
Reduced oxygen levels (1-5% O-2, named herein 'physioxia') are beneficial for stem cell cultures leading to enhanced proliferation, better survival and higher differentiation potential, but the underlying molecular mechanisms remain elusive. A potential link between physioxia and the canonical Wnt pathway was found recently, but the differential involvement of this signalling pathway for the various stem cell properties such as proliferation, stem cell maintenance, and differentiation capacity remains enigmatic. We here demonstrate increased Wnt target gene transcription and stabilised active beta-catenin upon physioxic cell culture in primary tissue-specific foetal mouse neural stem cells. Knock-out of the main oxygen sensing molecule, hypoxia-inducible factor-1 alpha (Hif-1 alpha), had no impact on Wnt activation assuming that physioxia induces the Wnt pathway independently of Hif-1 alpha. To determine the physiological relevance of physioxia-induced Wnt/beta-catenin signalling, we examined proliferation, cell cycle kinetics, survival and stem cell maintenance upon Wnt activation and inhibition. Whereas survival and stem cell maintenance seem to be independent of the Wnt pathway, our studies provide first evidence that Wnt/beta-catenin signalling positively stimulates proliferation of physioxic cells by affecting cell cycle regulation. Together, our results provide mechanistic insight into oxygen-mediated regulation of the self-renewal activity of neural stem cells. (C) 2015 Elsevier Inc. All rights reserved.