Towards an in vitro model of human hypoblast

建立人类下胚层的体外模型

• 批准号: BB/T007044/1
• 负责人: Jennifer Nichols
• 金额: $ 70.88万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT007044%2F1
• 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，绝大多数在辅助受孕计划后开始的妊娠在植入时很早就失败了。尽管许多失败可归因于与母亲子宫的不相容，但大约三分之一是由发育中的胚胎缺陷引起的。植入时，胚胎必须由三种组织组成：滋养外胚层，将与子宫首次连接并产生胎盘；下胚层对于确定胎儿的前部和后部以及形成卵黄囊至关重要；以及产生胎儿所有组织的外胚层。为了正常发育，每个早期胚胎谱系都必须适当且成比例地代表。根据我们的观察，我们假设未能指定足够的外胚层或下胚层或两者的细胞可能是产生可行妊娠的主要问题。然而，人们对调节这些谱系的适当分配的过程知之甚少。很难获得统计能力来回答有关胚胎这一过程的问题。同样，不可能将谱系的分配与最终成功的子宫着床联系起来。因此，为了了解早期胚胎谱系是如何分配的，有必要从代表早期胚胎谱系的细胞系构建模型人工胚胎。有代表外胚层和滋养层的经过验证的细胞系，但不代表下胚层。我们使用了专门配制的支持性凝胶和培养方案，可以从小鼠胚胎中捕获下胚层细胞，并在它们扩展到细胞系时将其保持在早期胚胎状态。在这项研究中，我们将专门优化机械和化学条件，以从人类胚胎中产生自我更新的下胚层细胞系。配备代表所有三个胚胎谱系的细胞系，我们将使用专门构建的 3D 水凝胶来构建人工胚胎。利用我们的人造胚胎模型，结合我们的合作者 Margherita Turco 开发的新子宫内膜类器官，我们可以量化测试有关启动正常发育（包括植入）所需的每个谱系的细胞数量等预测。我们的研究将为扩大人类下胚层种群的特定因素的要求提供有价值的信息，这可能有助于改进辅助受孕计划的培养制度。

项目成果

8C-like cells capture the human zygotic genome activation program in vitro.

8C 样细胞在体外捕获人类合子基因组激活程序。

• DOI: http://dx.10.1016/j.stem.2022.01.014
• 发表时间: 2022
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Taubenschmid

Naive stem cell blastocyst model captures human embryo lineage segregation.

幼稚干细胞囊胚模型捕获人类胚胎谱系分离。

• DOI: http://dx.10.1016/j.stem.2021.04.031
• 发表时间: 2021
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Yanagida A

Cell surface fluctuations regulate early embryonic lineage sorting.

细胞表面波动调节早期胚胎谱系排序。

• DOI: http://dx.10.17863/cam.80952
• 发表时间: 2022
• 作者: Yanagida A

insideOutside: an accessible algorithm for classifying interior and exterior points, with applications in embryology

insideOutside：一种用于对内部和外部点进行分类的易于理解的算法，在胚胎学中的应用

• DOI: http://dx.10.1101/2021.11.15.468285
• 发表时间: 2021
• 作者: Strawbridge S

Cell surface fluctuations regulate early embryonic lineage sorting.

细胞表面波动调节早期胚胎谱系排序。

• DOI: http://dx.10.1016/j.cell.2022.01.022
• 发表时间: 2022
• 期刊: Cell
• 影响因子: 64.5
• 作者: Yanagida A