Mitochondrial Dynamics in the Control of the Pluripotent States
多能状态控制中的线粒体动力学
基本信息
- 批准号:MR/N009371/1
- 负责人:
- 金额:$ 92.25万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2016
- 资助国家:英国
- 起止时间:2016 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
At the beginning of development of an embryo, cells start off with the potential to give rise to all the cell types and tissues that will form the newborn organism. This potential is called pluripotency, and those cells that are pluripotent hold great promise for regenerative medicine. This promise is not only due to their future clinical applications in cellular therapies, but also because now patient specific pluripotent cells can be generated for "disease-in-a-dish" approaches to understand human diseases. Stem cell therapies are being developed for diseases ranging from diabetes to neurodegenerative disorders and a stem cell based mechanism is thought to underlie different forms of cancer. Over the last few years considerable efforts have been invested into identifying the signalling and gene regulatory networks that regulate the pluripotent state and control the first steps of differentiation, when cells start to acquire a lineage specific identity. These studies have identified the key molecular features that provide pluripotent cell identity. In contrast to this, we know relatively little about the cell biology changes that accompany exit from the pluripotent state, for example how the different organelles of the cell adapt to the different environments they encounter during the first stages of differentiation. Of particular interest are mitochondria, that are not only the powerhouse of the cell, but also regulate a diverse range of cellular processes, including the ability of the cell to respond to cell death signals, their potential to differentiate, as well as how they respond to the different signalling pathways that regulate cell identity and function.We have identified that during the first stages of differentiation, cells undergo a dramatic change in the morphology of their mitochondria, suggesting that mitochondrial dynamics change during exit of pluripotency. Additionally we have found that the first stages of differentiation, cells alter their metabolism and their response to cell death stimuli, becoming hypersensitive to death signals. In this proposal we will investigate how mitochondrial dynamics impact of these changes. We will do this by using a combination of experiments performed in pluripotent mouse stem lines and mouse embryos, that allow us to readily determine the in vivo relevance of our data, as well as human embryonic stem cell models, that provide us with insight of the conservation in human of our findings. Specifically we will do three things.In the first place we will study in detail, at the ultrastructural level, the precise changes that occur in mitochondrial morphology as cells exit the pluripotent state. We will do this by analysing the distribution of mitochondrial proteins in pluripotent and differentiating cells, as well as by imaging mitochondrial dynamics upon exit of pluripotency. We will then manipulate mitochondrial dynamics and study how this affects cell identity. For this we will study three cellular processes that are likely to be affected by mitochondrial changes, the cells metabolism, it's ability to respond to cell death stimuli, and its potential to differentiate into the different lineages that will form the embryo. Finally, we will exploit the significant knowledge of the signalling pathways that maintain pluripotency and that drive differentiation, to identify novel signalling inputs that regulate mitochondrial dynamics and function in stem cells. Together, these experiments will provide a unique insight into an essential, but understudied aspect of early embryonic development, the dynamics of the mitochondria, as well as addressing how they impact on the process of differentiation.
在胚胎发育的初期,细胞具有产生所有细胞类型和组织的潜力,这些细胞和组织将形成新生的有机体。这种潜能被称为多能性,这些多能性的细胞为再生医学带来了巨大的希望。这一前景不仅是因为它们未来在细胞治疗中的临床应用,也是因为现在可以产生患者特有的多能细胞,用于“盘中疾病”的方法来理解人类疾病。干细胞疗法正在被开发用于治疗从糖尿病到神经退行性疾病的各种疾病,一种基于干细胞的机制被认为是不同形式癌症的基础。在过去的几年里,人们在识别信号和基因调控网络方面投入了大量的努力,这些网络调节多能性状态并控制分化的第一步,当细胞开始获得谱系特有的身份时。这些研究已经确定了提供多潜能细胞身份的关键分子特征。相比之下,我们对退出多能性状态所伴随的细胞生物学变化知之甚少,例如细胞的不同细胞器如何适应它们在分化的第一阶段遇到的不同环境。特别令人感兴趣的是线粒体,它不仅是细胞的动力源,而且调节着一系列不同的细胞过程,包括细胞对细胞死亡信号的反应能力,它们分化的潜力,以及它们如何对调节细胞身份和功能的不同信号通路做出反应。我们已经发现,在分化的第一阶段,细胞线粒体的形态发生了戏剧性的变化,这表明在退出多能性的过程中,线粒体的动力学发生了变化。此外,我们还发现,在分化的第一阶段,细胞改变了它们的新陈代谢和对细胞死亡刺激的反应,对死亡信号变得高度敏感。在这项提案中,我们将研究线粒体动力学如何影响这些变化。我们将使用在多能小鼠干细胞系和小鼠胚胎中进行的一系列实验来实现这一点,这些实验使我们能够容易地确定我们的数据以及人类胚胎干细胞模型的体内相关性,这些模型为我们提供了对我们的发现在人类中的保守性的洞察力。具体地说,我们将做三件事。首先,我们将在超微结构水平上详细研究细胞退出多能性状态时线粒体形态发生的精确变化。我们将通过分析线粒体蛋白在多能性和分化细胞中的分布,以及在多能性退出时对线粒体动力学进行成像来实现这一点。然后,我们将操纵线粒体动力学,并研究这如何影响细胞特性。为此,我们将研究三个可能受到线粒体变化影响的细胞过程,细胞新陈代谢,它对细胞死亡刺激的反应能力,以及它分化成形成胚胎的不同谱系的可能性。最后,我们将利用维持多能性和驱动分化的信号通路的重要知识,确定调节干细胞中线粒体动力学和功能的新信号输入。总之,这些实验将为早期胚胎发育的一个重要但未被充分研究的方面提供独特的见解,即线粒体的动力学,以及它们如何影响分化过程。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Detecting Genetic Mosaicism in Cultures of Human Pluripotent Stem Cells.
- DOI:10.1016/j.stemcr.2016.10.003
- 发表时间:2016-11-08
- 期刊:
- 影响因子:5.9
- 作者:Baker, Duncan;Hirst, Adam J.;Gokhale, Paul J.;Juarez, Miguel A.;Williams, Steve;Wheeler, Mark;Bean, Kerry;Allison, Thomas F.;Moore, Harry D.;Andrews, Peter W.;Barbaric, Ivana
- 通讯作者:Barbaric, Ivana
Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signaling.
- DOI:10.1101/gad.336917.120
- 发表时间:2020-12-01
- 期刊:
- 影响因子:10.5
- 作者:Lawlor K;Marques-Torrejon MA;Dharmalingham G;El-Azhar Y;Schneider MD;Pollard SM;Rodríguez TA
- 通讯作者:Rodríguez TA
Author Correction: P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development.
- DOI:10.1038/s41467-018-05718-z
- 发表时间:2018-08-02
- 期刊:
- 影响因子:16.6
- 作者:Bowling S;Di Gregorio A;Sancho M;Pozzi S;Aarts M;Signore M;Schneider MD;Martinez-Barbera JP;Gil J;Rodríguez TA
- 通讯作者:Rodríguez TA
P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development.
- DOI:10.1038/s41467-018-04167-y
- 发表时间:2018-05-02
- 期刊:
- 影响因子:16.6
- 作者:Bowling S;Di Gregorio A;Sancho M;Pozzi S;Aarts M;Signore M;D Schneider M;Martinez-Barbera JP;Gil J;Rodríguez TA
- 通讯作者:Rodríguez TA
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Tristan Rodriguez其他文献
GR-05 Essential roles for microRNAs in stem cell maintenance in the early mouse embryo
- DOI:
10.1016/j.mod.2009.06.945 - 发表时间:
2009-08-01 - 期刊:
- 影响因子:
- 作者:
Thomas Spruce;Bárbara Pernaute;Aida di Gregorio;Bradley Cobb;Matthias Merkenschlager;Miguel Manzanares;Tristan Rodriguez - 通讯作者:
Tristan Rodriguez
13-P058 The mitogen activated protein kinase p38 amplifies Nodal signalling in anterior/posterior axis development in the mouse embryo
- DOI:
10.1016/j.mod.2009.06.531 - 发表时间:
2009-08-01 - 期刊:
- 影响因子:
- 作者:
Melanie Clements;Tristan Rodriguez - 通讯作者:
Tristan Rodriguez
Tristan Rodriguez的其他文献
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{{ truncateString('Tristan Rodriguez', 18)}}的其他基金
Unravelling the pathways that mediate cell competition during embryonic differentiation
揭示胚胎分化过程中介导细胞竞争的途径
- 批准号:
BB/W016079/1 - 财政年份:2023
- 资助金额:
$ 92.25万 - 项目类别:
Research Grant
Mechanisms of selection against cells with mitochondrial dysfunction during mammalian development
哺乳动物发育过程中线粒体功能障碍细胞的选择机制
- 批准号:
MR/W02425X/1 - 财政年份:2022
- 资助金额:
$ 92.25万 - 项目类别:
Research Grant
Mechanisms regulating the timing of developmental events in the early mouse embryo
调节早期小鼠胚胎发育事件时间的机制
- 批准号:
MR/T028637/1 - 财政年份:2020
- 资助金额:
$ 92.25万 - 项目类别:
Research Grant
Understanding the mechanisms of aneuploid cell elimination during early mammalian development
了解早期哺乳动物发育过程中非整倍体细胞消除的机制
- 批准号:
BB/S008284/1 - 财政年份:2019
- 资助金额:
$ 92.25万 - 项目类别:
Research Grant
Pathways governing the competitive behaviour of pluripotent cells
控制多能细胞竞争行为的途径
- 批准号:
MR/P018467/1 - 财政年份:2017
- 资助金额:
$ 92.25万 - 项目类别:
Research Grant
Mechanisms of miRNA regulation of early embryonic development
miRNA调控早期胚胎发育的机制
- 批准号:
MR/K00090X/1 - 财政年份:2013
- 资助金额:
$ 92.25万 - 项目类别:
Research Grant
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