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

错误地引用塞缪尔·巴特勒的话：“老鼠是鸡蛋制造另一个鸡蛋的方式”。但是，如果我们不需要经过“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。使用一种被称为小鼠类原肠细胞的类胚胎模型，我观察到原始生殖细胞样细胞（pgclc）的自发出现，这是配子的早期前体。与体内同类细胞一样，这些原肠样pgclc在早期被指定，沿着内胚层束定向迁移，形成离散簇，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形成一种功能成熟的细胞类型：无核细胞。在这里，我建议使用生物工程原理直接从类胃原体诱导有组织的性腺样组织（“性腺样组织”）的发展。这将使原胃样pgclc进一步成熟为配子。这利用了自组织类胃的独特性质来反映动态和发育忠实的PGC生态位。同时，胃原体和性腺激素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过程中的生态位依赖性。最后，小鼠胃样细胞到性腺样细胞的技术有可能“闭环”，这在巴特勒的格言中是隐含的，即在培养皿中胚胎发生到配子发生；从单一的、自组织的多能干细胞集合中获得功能性配子。

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.