Comparative transcriptional control of establishment, maintenance and collapse of naive pluripotency in rodents and primates in vivo

啮齿动物和灵长类动物体内幼稚多能性建立、维持和崩溃的比较转录控制

• 批准号: BB/M004023/1
• 负责人: Jennifer Nichols
• 金额: $ 125.05万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM004023%2F1
• 关键词: Comparative; transcriptional; control; establishment; maintenance

The value of stem cell lines that can multiply in culture and retain the capacity to become any tissue type in the body is immense, both from the point of view of generating animal models for research, and to produce patient-specific human tissue for drug screening or cell replacement therapy. Stem cells derived from the founder tissue of the foetus in the early mouse embryo, known as pluripotent embryonic stem (ES) cells, have been proven to generate any type of adult tissue, including the germ cells, by observing their contribution to animals produced after integrating ES cells into a host embryo. Human ES cells, however, have characteristics distinct from mouse ES cells; this is evident in their molecular attributes, morphology and culture requirements. In fact, human ES cells resemble much more closely the cells found in more mature mouse embryos that have already implanted in the uterus and are considered to be 'primed' for differentiation. These cells are harder to grow and are more restricted in their differentiation repertoire compared with mouse ES cells. In the interests of therapeutic relevance, it would be highly desirable to understand how to capture cells from human embryos that are more akin to mouse ES cells. Although attempts have been made to produce such cells, either by manipulating the culture conditions in which they are grown, or by means of 'reprogramming' strategies that can revert adult cell types to a more embryonic condition, it has not been possible to capture human cells that can thrive in such a state. We believe that the only way to overcome this obstacle is to understand how these founder embryonic cells are formed in mouse embryos, from which true ES cell lines can be readily obtained. The ultimate goal is to use this knowledge as a blueprint to probe the development of early human embryos (or non-human primate embryos as a model for humans) and exploit alternative pathways to capture similar pluripotent cells from primates. In addition to discovering how to derive the ideal type of stem cells from human embryos, this knowledge will be used to generate useful cells from adult tissues and patient samples. In this project we plan to expand on our previous work to produce a detailed molecular portrait of mouse embryos before, during and after the stage in animal development when pluripotent cells are naturally produced. We will make use of genetic modification strategies to explore the importance of master control genes in this process. In addition, we can add highly specific chemicals to the culture medium that activate or suppress different cellular behaviours to reveal how these control genes are turned on or off. We have already begun to identify molecular differences between rodent (mouse) and primate (marmoset) embryos. We will extend this concept and then test how marmoset embryos respond to external signals that we predict may be beneficial to development. We will use this information to target specific pathways that could be enhanced or inhibited to allow pluripotent cells to be captured, thereby providing the essential starting point to create useful tissues for drug screening and, ultimately, cell replacement therapy.

无论是从产生用于研究的动物模型的角度，还是从产生用于药物筛选或细胞替代疗法的患者特异性人体组织的角度来看，可以在培养中繁殖并保持成为体内任何组织类型的能力的干细胞系的价值都是巨大的。来自早期小鼠胚胎中胎儿的创始组织的干细胞，称为多能胚胎干细胞（ES），已被证明可以产生任何类型的成体组织，包括生殖细胞，通过观察它们对将ES细胞整合到宿主胚胎后产生的动物的贡献。然而，人ES细胞具有不同于小鼠ES细胞的特征;这在其分子属性、形态和培养要求中是明显的。事实上，人类胚胎干细胞与已经植入子宫的更成熟的小鼠胚胎中发现的细胞更相似，并且被认为是分化的“启动”。与小鼠ES细胞相比，这些细胞更难生长，并且在其分化谱中更受限制。为了治疗相关性的利益，非常希望了解如何从人类胚胎中捕获更类似于小鼠ES细胞的细胞。尽管已经尝试通过操纵它们生长的培养条件或通过可以将成体细胞类型恢复到更胚胎状态的“重编程”策略来产生这样的细胞，但还不可能捕获可以在这种状态下茁壮成长的人类细胞。我们认为，克服这一障碍的唯一方法是了解这些创始人胚胎细胞是如何在小鼠胚胎中形成的，从中可以很容易地获得真正的ES细胞系。最终目标是利用这些知识作为蓝图，探索早期人类胚胎（或非人类灵长类动物胚胎作为人类模型）的发育，并利用替代途径从灵长类动物中捕获类似的多能细胞。除了发现如何从人类胚胎中获得理想类型的干细胞外，这些知识还将用于从成人组织和患者样本中产生有用的细胞。在这个项目中，我们计划扩展我们以前的工作，在动物发育阶段自然产生多能细胞之前，期间和之后产生小鼠胚胎的详细分子画像。我们将利用基因改造策略来探讨主控基因在这一过程中的重要性。此外，我们可以在培养基中添加高度特异性的化学物质，激活或抑制不同的细胞行为，以揭示这些控制基因是如何打开或关闭的。我们已经开始识别啮齿动物（小鼠）和灵长类动物（绒猴）胚胎之间的分子差异。我们将扩展这一概念，然后测试绒猴胚胎如何响应我们预测可能有利于发育的外部信号。我们将利用这些信息来靶向可以增强或抑制的特定途径，以捕获多能细胞，从而为药物筛选和最终细胞替代疗法创造有用的组织提供必要的起点。

项目成果

Single cell transcriptome analysis of human, marmoset and mouse embryos reveals common and divergent features of preimplantation development.

• DOI: 10.1242/dev.167833
• 发表时间: 2018-11-09
• 期刊: Development (Cambridge, England)
• 作者: Boroviak T;Stirparo GG;Dietmann S;Hernando-Herraez I;Mohammed H;Reik W;Smith A;Sasaki E;Nichols J;Bertone P
• 通讯作者: Bertone P

Distinct phospho-variants of STAT3 regulate naïve pluripotency and developmental pace in vivo

STAT3 的独特磷酸化变体调节体内幼稚多能性和发育速度

• DOI: 10.1101/2022.03.08.483469
• 发表时间: 2022
• 作者: Azami T

Lineage-Specific Profiling Delineates the Emergence and Progression of Naive Pluripotency in Mammalian Embryogenesis.

• DOI: 10.1016/j.devcel.2015.10.011
• 发表时间: 2015-11-09
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Boroviak T;Loos R;Lombard P;Okahara J;Behr R;Sasaki E;Nichols J;Smith A;Bertone P
• 通讯作者: Bertone P

The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression.

• DOI: 10.1016/j.molcel.2018.06.003
• 发表时间: 2018-07-05
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Bornelöv S;Reynolds N;Xenophontos M;Gharbi S;Johnstone E;Floyd R;Ralser M;Signolet J;Loos R;Dietmann S;Bertone P;Hendrich B
• 通讯作者: Hendrich B

The blueprint of primate preimplantation development

灵长类动物植入前发育蓝图

• DOI: 10.1016/j.mod.2017.04.107
• 发表时间: 2017
• 期刊: Mechanisms of Development
• 影响因子: 2.6
• 作者: Boroviak T