An in vitro model of the interaction between the extra-embryonic lineages of the peri-implantation human embryo

围植入期人类胚胎的胚胎外谱系之间相互作用的体外模型

• 批准号: 1943755
• 金额: --
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1943755
• 关键词: vitro; model; interaction; between; extra

Theme: Bioscience for HealthThe signalling pathways that govern peri-implantation morphogenesis in the primate embryo are not fully understood. In the mouse embryo, a signalling centre known as the Anterior Visceral endoderm (AVE) secretes a number of Nodal and Wnt antagonists (e.g Lefty, Dkk1, Cer1), leading to the formation of a gradient of Nodal and Wnt activity across the AP axis of the embryo. Interestingly, AVE-like cells have been identified in the cynomolgus monkey hypoblast. These AVE-like cells secrete WNT and BMP antagonists, whereas cytotrophoblast and amniotic cells secrete WNT3A and BMP4, respectively. This suggests that the two extraembryonic lineages of the primate embryo may act to create a gradient of WNT and BMP gradient across the epiblast, which may in turn orchestrate amnion formation and also even gastrulation. Given the technical and ethical hurdles associated with the culture of human embryos post-implantation, this project seeks to model the interaction between the human extraembryonic and the embryonic lineages in vitro using stem cell lines representative of each. Via Activin A, WNT and LIF treatment of human pluripotent stem cells (hPSCs), we sought to derive a human hypoblast-like stem cell line from hPSCs representative of a pre-implantation pluripotent state: a "naïve" pluripotent state. This is because the hypoblast is specified from the pre-implantation ICM. For this, both the "Rset" cell line and the human extended potential pluripotent stem cell (hEPSC) line were used. We also sought to determine whether a hypoblast-like cell could be derive from the conventional human embryonic stem cell (hESC), which have a "primed" pluripotent state more similar to the post-implantation epiblast, and thus ascertain the influence that different pluripotent states has on amenability of a hPSC towards hypoblast-specification. We also seek to model the interaction between these ACL-treated hPSCs and hESCs in an attempt to model epiblast-hypoblast crosstalk, finding that ACL-treated hESCs act to prevent hESC differentiation via both WNT and BMP signalling inhibition.

主题：健康的生物科学在灵长类动物胚胎中控制围着床期形态发生的信号通路尚未完全了解。在小鼠胚胎中，称为前内脏内胚层（AVE）的信号中心分泌许多Nodal和Wnt拮抗剂（例如Lefty、Dkk 1、Cer 1），导致形成跨越胚胎AP轴的Nodal和Wnt活性梯度。有趣的是，已在食蟹猴下胚层中鉴定出AVE样细胞。这些AVE样细胞分泌WNT和BMP拮抗剂，而细胞滋养层和羊膜细胞分别分泌WNT 3A和BMP 4。这表明灵长类动物胚胎的两个胚外谱系可能起作用以在整个上胚层中产生WNT和BMP梯度的梯度，这反过来可能协调羊膜形成甚至原肠胚形成。考虑到与植入后人类胚胎培养相关的技术和伦理障碍，该项目试图使用代表各自的干细胞系在体外模拟人类胚胎外和胚胎谱系之间的相互作用。通过激活素A、WNT和LIF处理人多能干细胞（hPSC），我们试图从代表植入前多能状态（“幼稚”多能状态）的hPSC衍生人成低幼细胞样干细胞系。这是因为下胚层是从植入前ICM中指定的。为此，使用“Rset”细胞系和人扩展潜能多能干细胞（hEPSC）系。我们还试图确定是否可以从传统的人胚胎干细胞（hESC），它具有一个“引发”多能状态更类似于植入后的上胚层，并因此确定不同的多能状态的hPSC对成下胚层的顺从性的影响，样细胞。我们还试图对这些ACL处理的hPSC和hESC之间的相互作用进行建模，试图对上胚细胞-下胚细胞串扰进行建模，发现ACL处理的hESC通过WNT和BMP信号传导抑制来阻止hESC分化。

项目成果

Author Correction: PANDORA-seq expands the repertoire of regulatory small RNAs by overcoming RNA modifications.

作者更正：PANDORA-seq 通过克服 RNA 修饰扩展了调控小 RNA 的库。

• DOI: 10.1038/s41556-021-00687-w
• 发表时间: 2021
• 期刊: Nature cell biology
• 影响因子: 21.3
• 作者: Shi J

An in vitro stem cell model of human epiblast and yolk sac interaction

人外胚层和卵黄囊相互作用的体外干细胞模型

• DOI: 10.17863/cam.74338
• 发表时间: 2021
• 作者: Mackinlay K

An in vitro stem cell model of human epiblast and yolk sac interaction.

人育细胞和蛋黄囊相互作用的体外干细胞模型。

• DOI: 10.7554/elife.63930
• 发表时间: 2021-08-17
• 期刊: eLife
• 影响因子: 7.7
• 作者: Mackinlay KM;Weatherbee BA;Souza Rosa V;Handford CE;Hudson G;Coorens T;Pereira LV;Behjati S;Vallier L;Shahbazi MN;Zernicka-Goetz M
• 通讯作者: Zernicka-Goetz M

An in vitro model of human yolk sac and epiblast crosstalk

人卵黄囊和外胚层串扰的体外模型

• DOI: 10.17863/cam.87212
• 发表时间: 2022
• 作者: Mackinlay K