Towards an in vitro model of human hypoblast

建立人类下胚层的体外模型

• 批准号: BB/T007044/2
• 负责人: Jennifer Nichols
• 金额: $ 34.94万
• 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: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT007044%2F2
• 关键词: Towards; vitro; model; human; hypoblast

It is widely known that the vast majority of pregnancies initiated following assisted conception programmes fail very early, at around the time of implantation. Although many of these failures can be attributed to incompatibility with the mother's uterus, around one third are caused by defects in the developing embryo. At the time of implantation, the embryo must consist of three tissues: the trophectoderm that will make the first connection with the uterus and give rise to the placenta; the hypoblast that is essential for specifying the anterior and posterior of the foetus and forming the yolk sac; and the epiblast that produces all the tissues of the foetus. In order for normal development to ensue, each early embryonic lineage must be appropriately and proportionately represented. Based on our observations, we hypothesise that failure to specify enough cells of either epiblast or hypoblast, or both, is likely to be a major problem for generating a viable pregnancy. However, the process by which appropriate allocation of these lineages is regulated is poorly understood. It is difficult to attain statistical power to answer questions about this process from embryos. Similarly, it is not possible to correlate apportionment of the lineages with eventual successful uterine implantation. Therefore, in order to understand how early embryonic lineages are allocated, it is essential to have model artificial embryos constructed from cell lines representing the early embryonic lineages. There are validated cell lines representing the epiblast and trophoblast, but not the hypoblast. We have used specially formulated supportive gels and a culture regime that can capture hypoblast cells from mouse embryos and keep them in an early embryonic state as they expand into cell lines. In this study, we will optimise the mechanical and chemical conditions specifically to generate self-renewing hypoblast cell lines from human embryos. Armed with cell lines representing all three embryonic lineages, we will use purpose-built 3D hydrogels to construct artificial embryos. With our model artificial embryos, in combination with the new endometrial organoids developed by our collaborator Margherita Turco, we can quantifiably test predictions concerning, for example, the number of cells of each lineage needed to initiate normal development, including implantation. Our study will provide valuable information on the requirements for specific factors for expanding the human hypoblast population that may enable improvement of culture regimes for assisted conception programmes.

众所周知，在植入时，辅助构想计划很早就失败了。尽管其中许多失败可以归因于母亲子宫不兼容，但大约三分之一是由发育中的胚胎缺陷引起的。在植入时，胚胎必须由三个组织组成：将与子宫建立第一连接并产生胎盘的滋养剂；对于指定胎儿的前和后部并形成蛋黄囊所必需的小细胞；以及产生胎儿所有组织的尤过生成细胞。为了使正常发育随后，每个早期的胚胎谱系必须适当和成比例地表示。根据我们的观察结果，我们假设未能指定足够的层细胞或成年细胞或两者兼而有之的细胞可能是产生可行妊娠的主要问题。但是，对这些谱系的适当分配的过程尚不清楚。很难获得统计能力来回答胚胎的问题。同样，不可能将谱系的分配与最终成功的子宫植入相关联。因此，为了了解如何分配早期的胚胎谱系，必须由代表早期胚胎谱系的细胞系构建的模型人工胚胎。有经过验证的细胞系，代表培育细胞和滋养细胞，但没有造成细胞。我们已经使用了特殊配制的支持性凝胶和一种培养状态，可以从小鼠胚胎中捕获成细胞细胞，并在它们扩展到细胞系时使其处于早期的胚胎状态。在这项研究中，我们将优化专门的机械和化学条件，以从人类胚胎产生自我更新的低成质细胞细胞系。用代表所有三个胚胎谱系的细胞系武装，我们将使用专用的3D水凝胶来构建人造胚胎。借助我们的模型人工胚胎，结合我们的合作者玛格丽塔·图科（Margherita Turco）开发的新的子宫内膜器官，我们可以量化有关启动正常发育所需的每个谱系所需的细胞数量，包括植入，包括植入。我们的研究将提供有关扩大人类低成效人群的特定因素要求的有价值的信息，这些信息可能能够改善辅助构想计划的文化制度。

项目成果

Entropy sorting of single-cell RNA sequencing data reveals the inner cell mass in the human pre-implantation embryo.

• DOI: 10.1016/j.stemcr.2022.09.007
• 发表时间: 2023-01-10
• 期刊: STEM CELL REPORTS
• 影响因子: 5.9
• 作者: Radley, Arthur;Corujo-Simon, Elena;Nichols, Jennifer;Smith, Austin;Dunn, Sara-Jane
• 通讯作者: Dunn, Sara-Jane

Entropy sorting of single cell RNA sequencing data reveals the inner cell mass in the human pre-implantation embryo

单细胞RNA测序数据的熵排序揭示了人类植入前胚胎的内细胞团

• DOI: 10.1101/2022.04.08.487653
• 发表时间: 2022
• 作者: Radley A

Evidence implicating sequential commitment of the founder lineages in the human blastocyst by order of hypoblast gene activation

暗示人类囊胚中创始人谱系按下胚层基因激活顺序顺序定向的证据

• DOI: 10.1101/2022.12.08.519626
• 发表时间: 2022
• 作者: Corujo-Simon E

Human naive epiblast cells possess unrestricted lineage potential.

• DOI: 10.1016/j.stem.2021.02.025
• 发表时间: 2021-06-03
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Guo G;Stirparo GG;Strawbridge SE;Spindlow D;Yang J;Clarke J;Dattani A;Yanagida A;Li MA;Myers S;Özel BN;Nichols J;Smith A
• 通讯作者: Smith A