GastruloGO: From gastruloid to gonadoid: exploring germ cell development in an embryo-like system

GastruloGO：从类原肠胚到性腺：探索类胚胎系统中生殖细胞的发育

• 批准号: EP/Y009967/1
• 负责人: Naomi Moris
• 金额: $ 161.88万
• 依托单位: The Francis Crick 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%2FY009967%2F1
• 关键词: GastruloGO; gastruloid; gonadoid; exploring; germ; GastruloGO; gastruloid; gonadoid; exploring; germ

To misquote Samuel Butler, "the mouse is the egg's way of making another egg". But what if we didn't need to go through the stage of 'making a mouse' to make an egg? Stem cell-based embryo-like models have revolutionised the developmental biologist's toolbox, providing a suite of powerful, experimentally tractable models of development in vitro. Using one such embryo-like model, known as mouse gastruloids, I have observed the spontaneous emergence of Primordial Germ Cell-like cells (PGCLCs), the early precursors to gametes. Like their in vivo counterparts, these gastruloid PGCLCs are specified early, migrate directionally along the endodermal tract, form discrete clusters, and mature transcriptionally and epigenetically to reach a pre-gametogenesis state equivalent to ~E12.5 germ cells in the embryo. However, the real test of developmental authenticity would be the formation of a functional, mature cell type: agamete. Here, I propose to use bioengineering principles to elicit the development of an organised gonad-like tissue (a 'gonadoid') directly from gastruloids. This will enable the further maturation of gastruloid PGCLCs to gametes. This makes use of the unique property of self-organised gastruloids to mirror the dynamic and developmentally-faithful PGC niche. Together, gastruloids and gonadoids will allow me to answer long-standing questions in the field, including identifying the early PGC founding population, exploring the mechanisms of migration, and investigating niche-dependency in germ cell maturation. Finally, the mouse gastruloid-to-gonadoid technique has the potential to 'close the loop', implicit in Butler's adage, of embryogenesis-to-gametogenesis in a dish; deriving functional gametes entirely from a single, self-organised aggregate of pluripotent stem cells.

误以为塞缪尔·巴特勒（Samuel Butler），“老鼠是鸡蛋制作另一个鸡蛋的方式”。但是，如果我们不需要经历“制作鼠标”的阶段才能制造鸡蛋怎么办？基于干细胞的胚胎样模型已彻底改变了发育生物学家的工具箱，从而提供了一套强大的实验性开发模型的体外模型。我使用一种称为小鼠胃类的类似胚胎样模型，我观察到了原始生殖细胞样细胞（PGCLCS）的自发出现，即配子的早期前体。像它们的体内对应物一样，这些胃类PGCLC是早期指定的，沿着内胚层方向迁移，形成离散的簇，并在胚胎中与〜E12.5生殖细胞相等，在胚胎上和表观遗传上成熟。但是，发育真实性的真正检验将是形成功能性成熟的细胞类型：Agamete。在这里，我建议使用生物工程原理来引起直接从胃类似的有组织的性腺样组织（A Gonadoid'）的发展。这将使胃PGCLCs进一步成熟到配子。这利用了自组织的胃肠机的独特特性，以反映动态和发展信仰的PGC利基市场。胃底子和性腺类别一起将使我能够在现场回答长期存在的问题，包括识别早期的PGC创始人群，探索迁移的机制以及研究生殖细胞成熟中的小裂依赖性。最后，小鼠的胃胃对甲状腺素技术具有“关闭循环”的潜力，这隐含在巴特勒的格言中，对菜肴中的胚胎发生对 - 果膜发生。完全来自多能干细胞的单个自组织聚集体。