Regulation of cell fate decisions during gastrulation in mammals

在发育的前三周内早期胚胎丢失影响了约30%的妊娠。大多数这些损失是遗传异常的结果，在早期原肠胚形成期间表现出来，这是第一个胚胎谱系被指定的时期。人类的原肠胚形成过程尚不清楚，但利用干细胞建立的称为“类原肠胚”的体外模型可以概括形态发生过程，帮助我们了解关键基因在发育过程中的作用。我们的实验室率先在多种哺乳动物物种（人类、猪、牛）中使用这些系统，目的是更好地了解哺乳动物之间的进化差异。我们之前的研究表明，人类和猪在胚胎植入前的发育原理是相同的，比如形成一个扁平的胚胎盘，这与小鼠的卵筒有很大的不同。在本项目中，我们将检验扁盘胚原肠形成机制遵循不同基因调控和形态遗传学的假设。分析的重点将特别集中在中胚层和内胚层谱系的出现。结合体外（干细胞/类胃原体培养和细胞成像），体内胚胎操作（基因编辑），单细胞转录组学（生物信息学）和数学建模将用于研究关键发育基因和负责这些胚层分离的信号通路的作用。这里使用大型哺乳动物胚胎研究的范例将与小鼠胚胎的结果进行对比。新的认识将告知人类胚胎如何将细胞分配给基本胚层，并将扩大我们对可能导致妊娠失败的特定遗传异常的理解。这些发现也将对加强干细胞向特定谱系的分化方法具有关键意义，并对再生医学产生影响。

Early embryonic loss during the first three weeks of development affects ~30% pregnancies. Most of these losses are a result of genetic abnormalities, which become manifested during early gastrulation, the period when the first embryonic lineages are specified. The process of gastrulation is not well understood in humans, but emerging in vitro models called "gastruloids", using stem cells, can recapitulate morphogenetic processes that help us understand the role of critical genes during development. Our laboratory has pioneered the use of these systems in multiple mammalian species (human, pig, cow) with the aim of developing better understanding of the evolutionary differences between mammals. We previously showed that humans and pigs share principles of pre-implantation development, such as the formation of a flat embryonic disc, which differs considerably from the egg cylinder of mice. In this project we will test the hypothesis that the mechanisms of gastrulation in flat disc embryos follow distinct gene regulation and morphogenetics. The focus of the analysis will be particularly centred around the emergence of mesoderm and endoderm lineages. A combination in vitro (stem cell/gastruloids culture and cell imaging), in vivo embryo manipulation (gene editing), single cell transcriptomics (bioinformatics) and mathematical modelling will be used to study the roles critical developmental genes and signalling pathways responsible for the segregation of these germ layers. The paradigms studied here using large mammalian embryos will be contrasted with results in mouse embryos. The new understanding will inform how human embryos allocate cells towards basic germ layers and will expand our understanding of specific genetic abnormalities that may cause pregnancy failure. The findings will also be of key importance for enhancing the differentiation methods of stem cells towards specific lineages with an impact in regenerative medicine.