Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Nature. 2022 Oct;610(7930):143-153. doi: 10.1038/s41586-022-05246-3. Epub 2022 Aug 25.
Embryonic stem (ES) cells can undergo many aspects of mammalian embryogenesis in vitro, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem (TS) cells, extraembryonic endoderm stem (XEN) cells and inducible XEN (iXEN) cells. Here we assembled stem cell-derived embryos in vitro from mouse ES cells, TS cells and iXEN cells and showed that they recapitulate the development of whole natural mouse embryo in utero up to day 8.5 post-fertilization. Our embryo model displays headfolds with defined forebrain and midbrain regions and develops a beating heart-like structure, a trunk comprising a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. This complete embryo model develops within an extraembryonic yolk sac that initiates blood island development. Notably, we demonstrate that the neurulating embryo model assembled from Pax6-knockout ES cells aggregated with wild-type TS cells and iXEN cells recapitulates the ventral domain expansion of the neural tube that occurs in natural, ubiquitous Pax6-knockout embryos. Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse cell lineages and genes in development. Our results demonstrate the self-organization ability of ES cells and two types of extraembryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis.
胚胎干细胞 (ES) 可以在体外经历哺乳动物胚胎发生的许多方面,但它们的发育潜力通过与胚胎外干细胞的相互作用得到了实质性的扩展,包括滋养层干细胞 (TS) 细胞、胚胎外内胚层干细胞 (XEN) 细胞和诱导性 XEN (iXEN) 细胞。在这里,我们从小鼠 ES 细胞、TS 细胞和 iXEN 细胞体外组装了干细胞衍生的胚胎,并表明它们再现了整个自然小鼠胚胎在子宫内发育到受精后 8.5 天的过程。我们的胚胎模型显示出具有定义的前脑和中脑区域的头褶,并发育出类似心跳的结构、包含神经管和体节的躯干、含有神经嵴和中胚层祖细胞的尾芽、肠道管和原始生殖细胞。这个完整的胚胎模型在一个起始血液岛发育的胚胎外卵黄囊中发育。值得注意的是,我们证明了由 Pax6 敲除 ES 细胞聚集与野生型 TS 细胞和 iXEN 细胞组装而成的神经胚模型再现了在自然、普遍的 Pax6 敲除胚胎中发生的神经管腹侧区域扩张。因此,这些完整的类胚胎是一种强大的体外模型,可以用于剖析不同细胞谱系和基因在发育中的作用。我们的结果表明 ES 细胞和两种类型的胚胎外干细胞具有自我组织能力,能够通过原肠胚形成并超越原肠胚形成到神经胚形成和早期器官发生来重建哺乳动物发育。