Tissue Tectonics During Gastrulation In Bilaminar Disc Embryos

双层盘胚胎原肠胚形成过程中的组织构造

• 批准号: BB/X014908/1
• 负责人: Ramiro Alberio
• 金额: $ 86.93万
• 依托单位: University of Nottingham
• 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%2FX014908%2F1
• 关键词: Tissue; Tectonics; During; Gastrulation; Bilaminar

The mammalian body plan is established during gastrulation, where the basic cell layers from which all adult tissues derive are laid down for the first time. In humans, this process starts immediately after implantation, during the third week of development, and coincides with the period when most embryonic losses (~40%) occur during pregnancy. In this very early phase of development, the embryo establishes a spatial pattern of cellular organization controlled by genes and is, in part, influenced by the surrounding tissues contributing to the placenta. At this stage, the symmetry of the embryo breaks: the embryo is no longer a round disc, but instead cells on one end express different genes to those in the other end (in other words, the anterior-posterior axis emerges). How this break in symmetry is determined in non-rodent mammals (i.e. humans) is not yet clear. Our knowledge of gastrulation in humans is very limited because human embryos cannot be directly studied during this period. However, human and pig embryos (and most other mammals) start gastrulation from a flat disc epiblast. The flat disc is made of a bilaminar cell layer of epiblast and hypoblast cells and is surrounded by trophectoderm cells. Biochemical signals (known as morphogens) that orchestrate the onset of gastrulation in bilaminar disc embryos are not well known. Furthermore, the changes in the biophysical characteristics of epiblast cells in terms of size, shape, and movement during gastrulation in flat disc epiblasts are also unknown. In this proposal, we will study these processes using pig embryos as model system, due to their resemblance to human embryos at this stage. Furthermore, we will use human and pig stem cells model of gastrulation (gastruloids) to study the shared mechanisms of symmetry breaking and axial patterning across species. We will use a combination of in vivo, in vitro, and computational models to integrate biochemical, cell geometry and shape information across different developmental stages to establish fundamental principles of mammalian embryogenesis. The multi-scale (from individual cells to complex tissues), multispecies and multidisciplinary approaches selected for this project will provide a holistic new understanding of one of the key developmental processes of animals. The new knowledge of the mechanisms of gastrulation in bilaminar disc embryos gained in this project will provide a blueprint of the key principles governing the formation of a mammalian embryo. This work will impact our understanding of the development diversity and evolution of mammalian species; will have an impact in medicine by improving our understanding of the causes of early embryonic loss; and will enable the development of new methodologies for the generation of human organs in animals for xenotransplantation.

哺乳动物的身体结构是在原肠胚形成期间形成的，在原肠胚形成期间，所有成体组织的基本细胞层第一次形成。在人类中，这个过程在胚胎植入后立即开始，在发育的第三周，并且与大多数胚胎损失（约40%）发生在怀孕期间的时期相吻合。在这个非常早期的发育阶段，胚胎建立了由基因控制的细胞组织的空间模式，并且部分地受到周围组织的影响，这些组织有助于胎盘。在这个阶段，胚胎的对称性被打破：胚胎不再是一个圆盘，而是一端的细胞表达与另一端不同的基因（换句话说，前后轴出现）。这种对称性的破坏是如何在非啮齿类哺乳动物（即人类）中确定的尚不清楚。我们对人类原肠胚形成的了解非常有限，因为在此期间无法直接研究人类胚胎。然而，人类和猪的胚胎（以及大多数其他哺乳动物）从扁平的圆盘状外胚层开始原肠胚形成。扁平圆盘由上胚层和下胚层细胞的双层细胞层组成，并被滋养外胚层细胞包围。在双层盘胚胎中，协调原肠胚形成开始的生化信号（称为形态发生素）并不为人所知。此外，上胚层细胞的生物物理特性的变化，在大小，形状和运动在原肠胚形成过程中在平盘上胚层也是未知的。在这个提议中，我们将使用猪胚胎作为模型系统来研究这些过程，因为它们在这个阶段与人类胚胎相似。此外，我们将使用人类和猪的原肠胚形成（gastruloids）的干细胞模型来研究跨物种的对称性破缺和轴向模式的共同机制。我们将使用体内，体外和计算模型的组合，以整合不同发育阶段的生物化学，细胞几何形状和形状信息，以建立哺乳动物胚胎发生的基本原则。为该项目选择的多尺度（从单个细胞到复杂组织），多物种和多学科方法将为动物的关键发育过程之一提供全面的新理解。在这个项目中获得的双层盘胚胎原肠胚形成机制的新知识将提供一个蓝图的关键原则，管理哺乳动物胚胎的形成。这项工作将影响我们对哺乳动物物种的发育多样性和进化的理解;将通过提高我们对早期胚胎丢失原因的理解而对医学产生影响;并将能够开发在异种移植动物中产生人类器官的新方法。