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

引用塞缪尔·巴特勒(Samuel Butler)的话来说，“老鼠是鸡蛋生成另一个鸡蛋的方式”。但是，如果我们不需要经历‘造老鼠’的阶段来生一个蛋，那会怎么样？基于干细胞的类似胚胎的模型彻底改变了发育生物学家的工具箱，提供了一套强大的、实验上容易处理的体外发育模型。使用一种被称为小鼠原肠的类似胚胎的模型，我观察到原始生殖细胞样细胞(PGCLCs)的自发出现，这是配子的早期前体。与活体中的同类细胞一样，这些原肠类PGCL细胞很早就被指定，沿内胚道定向迁移，形成离散的簇，在转录和表观遗传上成熟，达到相当于胚胎中~E12.5生殖细胞的配子发生前状态。然而，对发育真实性的真正考验将是一种功能成熟的细胞类型的形成：无性配子。在这里，我建议使用生物工程原理直接从原肠突中诱导出有组织的性腺样组织(性腺)。这将使原肠样PGCCs进一步成熟为配子。这利用了自组织原肠的独特性质来反映动态和对发展忠诚的PGC利基。胃泌素和性腺激素结合在一起，将使我能够回答该领域长期存在的问题，包括识别PGC早期创立人群，探索迁移机制，以及研究生殖细胞成熟中的生态位依赖。最后，小鼠从胃体到性腺的技术有可能像巴特勒的谚语中所隐含的那样，在培养皿中关闭胚胎发生到配子发生的循环；完全从单一的、自组织的多能干细胞聚合体获得功能配子。

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.