WNT signalling in the transition from naïve pluripotency to early cell lineages in human development

WNT 信号传导在人类发育中从幼稚多能性向早期细胞谱系的转变

• 批准号: BB/Y001974/1
• 负责人: Stefan Hoppler
• 金额: $ 80.47万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY001974%2F1
• 关键词: WNT; signalling; transition; na; ve

We are all naturally interested in how we develop as an early embryo from the sperm and egg of our parents. But for obvious ethical reasons, we cannot perform on humans the experiments needed to properly investigate early embryogenesis. That is why experimental animal model systems, particularly early mouse embryos, have been used to inform us about processes of early animal development. It has been generally assumed that the mechanisms governing early mouse embryo development will be more or less directly applicable to early human embryos. (To date, these assumptions have been partially correct, but notable exceptions to early human embryonic development are beginning to be uncovered, see below). With advances in human fertilisation technology, surplus human embryos have allowed the identification and culturing in the laboratory of very early (naïve) embryonic stem cell lines for important biomedical research. These stem cell-based models can now be used in the laboratory to study aspects of early human embryo development. Generally, much of what has been learned from mice indeed appears similar in these human early embryonic stem cells. But there appear to be unexpected differences between mouse and human, particularly in a molecular mechanism called WNT signalling. WNT cell signalling allows embryonic cells to communicate to each other. WNT signalling appears to regulate early embryo development differently in mouse and human; particularly while controlling whether embryonic stem cells will remain embryonic stem cells on the one hand versus on the other hand, changing their identity and proceeding to start building the organs of the embryo.Now is therefore the perfect time to investigate WNT signalling function in these new stem cell models of very early human development. 1. We will study how the WNT signalling mechanism operates in early human embryonic cells to control their decision between remaining stem cells (stemness) for a while versus adopting one of several extra-embryonic or embryonic cell fates that they will later follow. (Extra-embryonic tissues are essential for human and mammalian animal development, since extra-embryonic tissues will form the placenta and yolk sac, which both pattern and feed the developing foetus (unborn baby)).2. We will study how WNT signalling controls specific genes (direct targets), which in turn then regulate stemness and subsequent cell fate. 3. We will study how WNT signalling interacts with other control mechanisms to coordinate stemness and adoption of these subsequent embryonic/extra-embryonic paths. Our focus for this ambitious research project is to develop a new paradigm for how this ancient WNT cell signalling cascade guides early human development. Our findings will subsequently require a direct comparison to mouse embryos and as far as appropriate in human embryos. This comparison will allow us to understand the similarities and differences between mouse and human early development, and this will furthermore elucidate which aspects of knowledge gained from the mouse (and other research animal models) can and which should not directly be applied to human development. The insights gained will eventually have overarching implications for the study of human fertility, miscarriages, congenital birth defects, and health more generally.

我们都对我们如何从父母的精子和鸡蛋中成为早期胚胎的发展自然感兴趣。但是出于明显的道德原因，我们无法对人类进行适当研究早期胚胎发生所需的实验。这就是为什么使用实验性动物模型系统，尤其是早期小鼠胚胎的原因，已被用来告知我们早期动物发育过程的过程。人们普遍认为，管理早期胚胎发育的机制（迄今为止，这些假设是正确的，但对早期人类胚胎的部分例外是正确的，但随着人类施肥技术的进步，人类胚胎的进步允许盈余的人类胚胎的识别和文化，在早期的胚胎干细胞研究中，这些实验室的实验室可以实现这些重要的生物研究。在这些早期的胚胎中，从小鼠和人类中有意外的差异，胚胎的发育实际上是相似的。另一方面，改变其身份并开始建立胚胎的器官。 1。我们将研究Wnt信号传导机制如何在人类早期的胚胎细胞中运作，以控制其剩余的干细胞（STEMNNES）之间的决策一段时间，而不是采用稍后将遵循的几种胚胎外或胚胎细胞命运之一。 （由于外界动物的发育对于人类和哺乳动物的动物发育至关重要，因为外胚型组织会形成placeta和蛋黄囊，卵形和蛋黄囊是模式和喂养发育中的footus（未出生的婴儿）。2。我们将研究Wnt信号如何控制特定基因（直接靶标），然后调节茎和随后的序列细胞命运。 3。我们将研究Wnt信号如何与其他控制机制相互作用，以协调这些随后的胚胎/胚胎外侧路径。我们对这个雄心勃勃的研究项目的重点是为这种古老的Wnt细胞信号级联如何指导早期人类发展的新范式开发一个新的范式。随后，我们的发现将需要与小鼠胚胎进行直接比较，并在人类胚胎中进行适当的比较。这种比较将使我们能够理解小鼠和人类早期发展之间的相似性和差异，这将阐明从小鼠（和其他研究动物模型）所获得的知识方面可以并且不应直接应用于人类发展。获得的见解最终将对研究人类的生育能力，流产，先天性先天缺陷和健康的总体影响。