research highlights

DEVELOPMENT Human embryogenesis in a dish A 3D culture system recapitulates human development prior to gastrulation and enables transcriptomic studies.

uman embryogenesis has been 68 10 12 14 d.p.f. modeled in 2D cultures up to days Extravillous cytotrophoblast Primitive Basement membrane (laminin) Syncytiotrophoblast 12–13. “However, these embryos streak anlage H Primitive endoderm (GATA6) grown in a dish only recapitulate some Amniotic Cytotrophoblast epithelium developmental landmarks and form Epiblast (OCT4) Extraembryonic mesenchyme some simple structures,” says Tianqing Li from Kunming University of Science and Anterior Technology and from Yunnan Provincial AC AC Academy of Science and Technology. PYS Anterior SYS Cytotrophoblast visceral Structures or processes such as amniotic endoderm PYS Visceral Syncytiotrophoblast Extravillous cytotrophoblast epithelium–epiblast separation, basement Squamous parietal endoderm endoderm membrane, secondary yolk sac, anterior visceral endoderm, anterior–posterior Schematic overview of early human development. AC, amniotic cavity; PYS, primary yolk sac; polarity initiation and primitive streak SYS, secondary yolk sac; d.p.f., days post-fertilization; GATA6 and OCT4, transcription factors. anlage are not present in human embryos Adapted with permission from Xiang, L. et al. A developmental landscape of 3D-cultured human grown in 2D culture conditions, making it pre-gastrulation embryos. Nature https://doi.org/10.1038/s41586-019-1875-y (2019). difficult to study spatial self-organization and cell lineages. Thus, better models for studying human pregastrulation embryogenesis are needed. sac. Moreover, a clear difference between the has a high similarity with human, these Li, his colleague Weizhi Ji and their amniotic epithelium and the epiblast arose, differences indicate monkey embryos teams addressed this limitation by growing which had not been observed in embryos cannot completely replace human embryos human embryos in a 3D environment. cultured under 2D conditions. Additional in uncovering human development, They found that supplementing media features that had previously not been and human embryo studies are very used for 2D cultures with 10% Matrigel observed were the appearance of anterior– necessary,” says Li. This is one of the reasons allowed human embryos to develop posterior polarity in the embryo and the why Li thinks that — after a thorough from the blastocyst stage at 5–6 days formation of the primitive streak anlage. ethical discussion and evaluation by the post-fertilization until day 14 in culture. Having a suitable model for human international community — extending “Of course, because of a lack of in vivo embryogenesis in hand allows Li, Ji and human embryo culture beyond the reference, we cannot guarantee that their teams “to systematically reveal internationally agreed upon 14-day limit this 3D embryo is 100% similar to an the molecular and morphogenetic is necessary for a better understanding of in vivo embryo,” says Li. Nevertheless, developmental landscape of pregastrulation events during human gastrulation. these embryos appear to recapitulate key human embryos [and to] delineate specific In the meantime, Li and his colleagues morphological processes. The researchers pathways and transcription factors for plan to follow up on their work. They achieved a success rate of about 25%, epiblast, amniotic epithelium, hypoblast and want to understand why three-quarters meaning that a quarter of the embryos trophoblast separation and development.” of embryos fail to develop in culture. survived and developed until day 14. To do so, the researchers performed In addition, they want to gain a deeper While it is difficult to compare this rate to single-cell RNA-seq experiments on understanding of the mechanisms of human human development in vivo, Li says that the seven different stages of embryogenesis, embryo development. Current studies pregnancy rate after intrauterine transfer of which allowed them to identify additional have only scratched the surface. This is an in vitro-fertilized embryos, which is affected markers for embryonic tissues and to exciting time for understanding how our by the uterine environment also, is similar. describe crucial signaling pathways involved species develops. The researchers could observe that the in the various developmental processes, blastocysts initially expressed markers for such as amniotic epithelium emergence Nina Vogt the inner cell mass, epiblast and primitive and trophoblast differentiation. endoderm. After 1–2 days in culture, a Furthermore, the transcriptomic analysis Published online: 4 February 2020 trophoblast marker appeared, and epiblast, revealed key differences between human https://doi.org/10.1038/s41592-020-0740-0 primitive endoderm and trophoblast and macaque embryos in, for example, Research paper fates were well defined. Then the epiblast the epiblast, where bone morphogenetic Xiang, L. et al. A developmental landscape of started to polarize and the primary yolk sac protein (BMP) signaling patterns differed 3D-cultured human pre-gastrulation embryos. Nature developed, followed by the secondary yolk between the two species. “Although monkey https://doi.org/10.1038/s41586-019-1875-y (2019).

Nature Methods | VOL 17 | February 2020 | 125–131 | www.nature.com/naturemethods 125