Deciphering the mechanisms facilitating rapid uterine invasion of implanting human embryos

破译促进植入人类胚胎快速侵入子宫的机制

• 批准号: BB/Y005120/1
• 负责人: Jennifer Nichols
• 金额: $ 44.46万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY005120%2F1
• 关键词: Deciphering; mechanisms; facilitating; rapid; uterine

Most of what we understand about mammalian development has been garnered by studying mouse embryos. However, although the early stages, prior to implantation in the uterus, appear to be quite similar between species, the method of implantation can vary enormously. Following fertilisation, all mammalian embryos undergo several rounds of cell division to form a spherical structure. This comprises trophectoderm on the outside, an 'inner cell mass' (ICM) that will segregate into epiblast, the founder of the foetus, and hypoblast that will form the yolk sac on the inside. The ICM is displaced to one side by an expanding cavity (the 'blastocoel'), that defines this stage as the 'blastocyst'. The whole structure is surrounded by a protective 'zona pellucida' to allow it to travel along the oviduct to the uterus. Subtle differences in the details of how blastocysts of different mammals form have been reported, but the subsequent process of implantation can vary enormously. After hatching from the zona pellucida, mouse embryos become encased in decidual tissue secreted by the uterus which persists throughout the early stages of tissue specification and they do not make direct contact with maternal tissue until after the first trimester. In contrast, human blastocysts implant directly into the uterine wall via rapid invasion by the trophectoderm that overlies the ICM. This invasion is essential to secure the embryo within the womb and establish the connection to the mother for exchange of nutrients and waste for development of the foetus. During our studies with human blastocysts under our HFEA licence we have noticed that the trophectoderm overlying the ICM (known as the 'polar' trophectoderm) becomes several layers thick as the embryos mature in preparation for implantation. The mechanism by which polar trophectoderm expands has not been studied, so we have developed methods for sequential labelling of the outside cells to determine whether the rapid expansion of the human trophectoderm occurs by replication of trophectoderm cells or by recruitment and conversion of cells from the underlying ICM, to satisfy the demand for implanting trophectoderm tissue. We suspect that expansion of the human trophectoderm is prone to become out of control, leading to abnormal development, since we observe trophectoderm overgrowth at the expense of derivatives of the ICM in around 1/3 of embryos left over from IVF treatment from multiple clinics, donated to our project with informed consent. We hypothesise that this aberrant overgrowth of the human trophectoderm may be a consequence of the evolutionary need for rapid attachment and invasion into the uterus, which is not the case in the mouse. Furthermore, some of the known problems arising during early human pregnancies, such as ectopic implantation, early post-implantation failure, or formation of a hydatidiform mole composed entirely of trophectoderm tissue, may be an abnormal downstream consequence attributable to the rapid trophectoderm expansion required for human implantation. These malfunctions rarely, if ever, occur during implantation of mouse embryos. We will use various molecular analyses to investigate trophectoderm formation and growth. Not only will the output from this project further our understanding of how embryos from some non-rodent mammals prepare for implantation, it will also provide a discrete and tractable system with which to investigate how multiple layers can form from a single epithelium, which may share features with other systems in the body. The blastocyst stage of development can be modelled using stem cell lines that can be induced to assemble into tissues closely resembling trophectoderm, epiblast and hypoblast. We will use our knowledge of the instructive signals required to specify each lineage to build models of trophectoderm overgrowth and thereby scrutinise the mechanisms by which it occurs and identify supplements for the culture medium that may restrain it.

我们对哺乳动物发育的了解的大多数通过研究小鼠胚胎而获得了。但是，尽管在子宫中植入之前的早期阶段似乎在物种之间似乎非常相似，但植入方法可能会发生巨大变化。受精后，所有哺乳动物的胚胎都会发生几轮细胞分裂，形成球形结构。这包括外部的滋养剂，一个“内部细胞质量”（ICM）将分离成胎儿的创始人（胎儿的创始人），而肌细胞则将形成内部的蛋黄囊。 ICM通过扩展的腔（“胚托克尔”）将其置于一侧，该腔将此阶段定义为“胚泡”。整个结构被保护性的“ Zona pellucida”包围，以使其沿着输卵管传播到子宫。关于如何报道了不同哺乳动物形式的胚泡的细节，但随后的植入过程可能会发生巨大变化。从Zona pellucida孵化后，小鼠胚胎被子宫分泌的决结构组织包裹，在整个组织规格的早期阶段一直持续存在，并且直到头三个月之后才与母体组织直接接触。相反，人类胚泡通过覆盖ICM的滋养剂的快速侵袭直接植入子宫壁。这种入侵对于确保子宫内的胚胎并建立与母亲交换营养和浪费以发育胎儿的联系至关重要。在我们在HFEA许可下使用人类胚泡的研究期间，我们注意到将ICM（称为“极性”滋养剂）上覆盖的滋养剂变成了几层层，因为胚胎成熟以准备植入。尚未研究极性滋养外胚层扩展的机制，因此我们开发了用于外部细胞进行顺序标记的方法，以确定人滋养外胚层的快速扩展是通过复制滋养外胚层细胞的复制，通过募集和通过固定ICM募集和转化从基础ICM转化的，以满足植入植入的培训的需求。我们怀疑人滋养剂的扩展容易失控，导致异常发育，因为我们观察到滋养外胚层的过度生长，而牺牲了ICM的衍生物为牺牲了大约1/3的胚胎，该胚胎约有1/3的胚胎从IVF治疗中剩下的胚胎中，由多个临床治疗，捐赠给了我们的项目。我们假设人类滋养剂的这种异常过度生长可能是快速依附和入侵子宫进化的结果，而小鼠在小鼠中并非如此。此外，在人类早期妊娠期间引起的一些已知问题，例如异位植入，早期植入后失败或完全由滋养外胚层组织组成的氢化摩尔的形成，可能是造成人类滋养性人体所需的快速下游的异常下游结果。这些故障在植入小鼠胚胎期间很少发生（如果有的话）。我们将使用各种分子分析来研究滋养外的形成和生长。该项目的输出不仅会进一步了解我们对某些非型哺乳动物的胚胎如何准备植入的胚胎，还将提供一个离散且可拖延的系统，以研究如何从单个上皮中形成多层，这可能与人体中其他系统共享特征。可以使用可以诱导的干细胞系来对胚泡的发育阶段进行建模，以组装成类似于滋养外胚层，层细胞和低均质细胞的组织。我们将利用我们了解指定每个血统所需的指导性信号，以构建滋养剂过度生长的模型，从而仔细检查其发生的机制并确定可能限制其培养基的补充。