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

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.

塞缪尔·巴特勒（Samuel Butler）曾说过：“老鼠是鸡蛋制造另一个鸡蛋的方式。但是，如果我们不需要通过“制造老鼠”的阶段来制造鸡蛋呢？基于干细胞的胚胎样模型已经彻底改变了发育生物学家的工具箱，提供了一套强大的，实验上易于处理的体外发育模型。使用一个这样的胚胎样模型，被称为小鼠gastruloids，我观察到原始生殖细胞样细胞（PGCLC），配子的早期前体的自发出现。与其体内对应物一样，这些胃状PGCLC在早期被指定，沿内胚层道沿着定向迁移，形成离散簇，并在转录和表观遗传上成熟，以达到相当于胚胎中~E12.5生殖细胞的配子发生前状态。然而，发育真实性的真实的检验是一种功能性的成熟细胞类型的形成：配子。在这里，我建议使用生物工程的原则，直接从gastruloids引出一个有组织的性腺样组织（“性腺”）的发展。这将使胃状PGCLC进一步成熟为配子。这利用了自组织胃状体的独特性质来反映动态和发育忠实的PGC生态位。总之，gastruloids和gonadoids将使我能够回答该领域长期存在的问题，包括确定早期PGC创始人群，探索迁移机制，以及研究生殖细胞成熟中的生态位依赖性。最后，小鼠类性腺到类性腺的技术有可能“关闭循环”，隐含在巴特勒的格言中，在培养皿中胚胎发生到配子发生;完全从一个单一的、自组织的多能干细胞聚集体中获得功能性配子。