Regulation of cell fate decisions during gastrulation in mammals

哺乳动物原肠胚形成过程中细胞命运决定的调节

• 批准号: 2746225
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2746225
• 关键词: Regulation; cell; fate; decisions; during

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.

在发育的前三周早期胚胎丢失影响约30%的妊娠。大多数这些损失是遗传异常的结果，这些异常在原肠胚形成早期（第一个胚胎谱系被指定的时期）表现出来。原肠胚形成的过程在人类中还没有得到很好的理解，但是使用干细胞的被称为“类原肠胚”的体外模型可以重现形态发生过程，帮助我们理解关键基因在发育过程中的作用。我们的实验室率先在多个哺乳动物物种（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。我们之前已经证明，人类和猪在胚胎植入前的发育过程中有着相同的原则，例如形成一个扁平的胚胎盘，这与小鼠的卵柱有很大的不同。在这个项目中，我们将测试的假设，即原肠胚形成的机制，在平盘胚胎遵循不同的基因调控和形态发生学。分析的重点将特别集中在中胚层和内胚层谱系的出现。体外（干细胞/类胃体细胞培养和细胞成像），体内胚胎操作（基因编辑），单细胞转录组学（生物信息学）和数学建模的组合将用于研究关键发育基因和信号通路的作用，负责这些胚层的分离。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。新的理解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。这些发现对于增强干细胞向特定谱系的分化方法具有关键重要性，并对再生医学产生影响。