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

我们都很自然地对如何从父母的精子和卵子发育成早期胚胎感兴趣。但由于明显的伦理原因，我们不能在人类身上进行适当研究早期胚胎发育所需的实验。这就是为什么实验动物模型系统，特别是早期小鼠胚胎，被用来告诉我们早期动物发育的过程。人们普遍认为，控制小鼠早期胚胎发育的机制或多或少将直接适用于早期人类胚胎。(到目前为止，这些假设部分是正确的，但早期人类胚胎发育的显著例外正在开始被发现，见下文)。随着人类受精技术的进步，多余的人类胚胎使人们能够在实验室中鉴定和培养非常早期(幼稚)的胚胎干细胞系，用于重要的生物医学研究。这些基于干细胞的模型现在可以在实验室中用于研究早期人类胚胎发育的各个方面。总的来说，从老鼠身上学到的许多东西在这些人类早期胚胎干细胞中确实看起来很相似。但在老鼠和人类之间似乎有意想不到的差异，特别是在一种名为WNT信号的分子机制上。WNT细胞信号允许胚胎细胞相互通信。在小鼠和人类中，WNT信号似乎以不同的方式调控早期胚胎发育；特别是一方面控制胚胎干细胞是否将保持胚胎干细胞，另一方面改变它们的身份并开始构建胚胎器官。因此，现在是研究WNT信号在这些非常早期人类发育的新干细胞模型中功能的最佳时机。1.我们将研究WNT信号机制是如何在早期人类胚胎细胞中运作的，以控制它们在一段时间内保留干细胞(干性)与采用几个胚胎外或胚胎细胞命运中的一个的决定。(胚胎外组织对于人类和哺乳动物动物的发育是必不可少的，因为胚胎外组织将形成胎盘和卵黄囊，这两者都形成并喂养发育中的胎儿(未出生的婴儿))。我们将研究WNT信号如何控制特定的基因(直接靶点)，进而调节干细胞和随后的细胞命运。3.我们将研究WNT信号如何与其他控制机制相互作用，以协调这些后续胚胎/胚胎外途径的干性和采用。我们这个雄心勃勃的研究项目的重点是开发一种新的范式，研究这个古老的WNT细胞信号级联如何引导早期人类发育。我们的发现随后将需要与小鼠胚胎进行直接比较，并尽可能与人类胚胎进行比较。这种比较将使我们能够了解老鼠和人类早期发育之间的异同，这将进一步阐明从老鼠(和其他研究动物模型)获得的知识的哪些方面可以直接应用于人类发育，哪些不应该直接应用于人类发育。所获得的洞察力最终将对人类生育、流产、先天出生缺陷和更广泛的健康研究产生重大影响。

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.