Dissecting the regulatory mechanisms driving trophoblast cell fate

剖析驱动滋养层细胞命运的调节机制

• 批准号: EP/Y009924/1
• 负责人: Roser Vento Tormo
• 金额: $ 164.36万
• 依托单位: Wellcome Sanger Institute
• 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=EP%2FY009924%2F1
• 关键词: Dissecting; regulatory; mechanisms; driving; trophoblast

Interactions between the placenta and uterus are essential for reproductive success in humans, and defects in this communication underlie common pregnancy complications such as pre-eclampsia. During placentation, trophoblast cells of the placenta infiltrate the uterus, transforming the maternal arteries into high conductance vessels. This process is largely unexplored in humans due to poor accessibility of this tissue during early pregnancy and, until recently, a lack of faithful in vitro models. Our single-cell transcriptomic census of the first-trimester human placental-uterine interface (Nature 2018) described novel maternal and fetal cells, and potential interactions between them. Here, we will develop and use state-of-the-art genomics, computational, cellular and bioengineering tools to investigate how trophoblast cells differentiate, invade the uterus, and interact with maternal cells with a focus on cell-intrinsic mechanisms and environmental cues. In Aim 1, we will build a roadmap of the early human placental-uterine interface by mapping the uncharacterised spatial and open chromatin landscape of the placental cells and accurately reconstructing their gene regulatory programmes and cell-cell communication events. In Aim 2, we will validate the main transcription factors predicted to be involved in trophoblast identity by recording the in vitro differentiation trajectories of trophoblast organoids with lineage tracing and using gene-editing approaches to perturb them. Our experiments will be guided by a novel computational framework to compare in vivo and in vitro systems. In Aim 3, we will bioengineer advanced co-culture models of the placental-uterine interface. The development of these platforms will enable us to mechanistically dissect the influence of maternal uterine cells on trophoblast identity. Our proposal will reconstruct the early events of human placentation and provide fundamental knowledge on the regulation of cell identity during development.

胎盘和子宫之间的相互作用对于人类生殖成功至关重要，这种交流的缺陷是先兆子痫等常见妊娠并发症的基础。在胎盘植入期间，胎盘的滋养层细胞浸润子宫，将母体动脉转变为高电导血管。由于妊娠早期这种组织的可及性较差，并且直到最近还缺乏可靠的体外模型，因此这一过程在人类中很大程度上尚未被探索。我们对妊娠早期人类胎盘-子宫界面的单细胞转录组普查（Nature 2018）描述了新的母体和胎儿细胞以及它们之间的潜在相互作用。在这里，我们将开发和使用最先进的基因组学、计算、细胞和生物工程工具来研究滋养层细胞如何分化、侵入子宫以及与母体细胞相互作用，重点关注细胞内在机制和环境线索。在目标 1 中，我们将通过绘制胎盘细胞未表征的空间和开放染色质景观并准确重建其基因调控程序和细胞间通讯事件来构建早期人类胎盘-子宫界面的路线图。在目标 2 中，我们将通过谱系追踪记录滋养层类器官的体外分化轨迹，并使用基因编辑方法扰乱它们，从而验证预测与滋养层身份有关的主要转录因子。我们的实验将在一个新颖的计算框架的指导下进行比较体内和体外系统。在目标 3 中，我们将对胎盘-子宫界面的先进共培养模型进行生物工程设计。这些平台的开发将使我们能够机械地剖析母体子宫细胞对滋养层身份的影响。我们的提案将重建人类胎盘的早期事件，并提供发育过程中细胞身份调节的基础知识。