Department of Cell Biology, University of Virginia, Charlottesville, VA, USA.
Institute of Genetics and Department of Genetics, School of Medicine, Zhejiang University, Hangzhou, China.
Nat Commun. 2021 Jun 2;12(1):3277. doi: 10.1038/s41467-021-23653-4.
Generating properly differentiated embryonic structures in vitro from pluripotent stem cells remains a challenge. Here we show that instruction of aggregates of mouse embryonic stem cells with an experimentally engineered morphogen signalling centre, that functions as an organizer, results in the development of embryo-like entities (embryoids). In situ hybridization, immunolabelling, cell tracking and transcriptomic analyses show that these embryoids form the three germ layers through a gastrulation process and that they exhibit a wide range of developmental structures, highly similar to neurula-stage mouse embryos. Embryoids are organized around an axial chordamesoderm, with a dorsal neural plate that displays histological properties similar to the murine embryo neuroepithelium and that folds into a neural tube patterned antero-posteriorly from the posterior midbrain to the tip of the tail. Lateral to the chordamesoderm, embryoids display somitic and intermediate mesoderm, with beating cardiac tissue anteriorly and formation of a vasculature network. Ventrally, embryoids differentiate a primitive gut tube, which is patterned both antero-posteriorly and dorso-ventrally. Altogether, embryoids provide an in vitro model of mammalian embryo that displays extensive development of germ layer derivatives and that promises to be a powerful tool for in vitro studies and disease modelling.
从多能干细胞体外生成适当分化的胚胎结构仍然是一个挑战。在这里,我们展示了通过实验工程化的形态发生素信号中心对小鼠胚胎干细胞进行指导,该中心作为组织者,可导致类胚胎实体(胚状体)的发育。原位杂交、免疫标记、细胞追踪和转录组分析表明,这些胚状体通过原肠胚形成过程形成三个胚层,并表现出广泛的发育结构,与神经胚期的小鼠胚胎高度相似。胚状体围绕轴向脊索中胚层组织,具有背侧神经板,其组织学特性类似于小鼠胚胎神经上皮,并从前脑中部向后延伸到尾部尖端折叠成具有前后模式的神经管。在脊索中胚层的侧面,胚状体显示出体节和中间中胚层,前部有搏动的心肌组织,并形成血管网络。在腹侧,胚状体分化出原始的肠道管,其在前后和背腹方向上均有模式化。总的来说,胚状体提供了一种哺乳动物胚胎的体外模型,显示出广泛的胚层衍生物发育,并有望成为体外研究和疾病建模的有力工具。