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Published June 2016 | Supplemental Material + Accepted Version
Journal Article Open

Self-organization of the human embryo in the absence of maternal tissues

Abstract

Remodelling of the human embryo at implantation is indispensable for successful pregnancy. Yet it has remained mysterious because of the experimental hurdles that beset the study of this developmental phase. Here, we establish an in vitro system to culture human embryos through implantation stages in the absence of maternal tissues and reveal the key events of early human morphogenesis. These include segregation of the pluripotent embryonic and extra-embryonic lineages, and morphogenetic rearrangements leading to generation of a bilaminar disc, formation of a pro-amniotic cavity within the embryonic lineage, appearance of the prospective yolk sac, and trophoblast differentiation. Using human embryos and human pluripotent stem cells, we show that the reorganization of the embryonic lineage is mediated by cellular polarization leading to cavity formation. Together, our results indicate that the critical remodelling events at this stage of human development are embryo-autonomous, highlighting the remarkable and unanticipated self-organizing properties of human embryos.

Additional Information

© 2016 Nature Publishing Group. Received 25 February 2016; accepted 29 March 2016; published online 4 May 2016; corrected online 17 May 2016. We are grateful to the patients donating their embryos, colleagues in the M.Z.-G. laboratory, C. Lee (Gurdon Institute), and embryologists at the CARE, Bourn Hall (K. Elder and P. Snell) and Kings College Guy's Hospital IVF clinics for help and discussions. We thank P. Braude, D. Glover and C. Ogilvie for insightful discussion and I. Bedzhov for help in a pilot experiment. This work was supported by the Wellcome Trust grant to M.Z.-G. Work in the K.K.N. laboratory was supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK, the Medical Research Council and the Wellcome Trust. M.N.S. was initially supported by a Ramon Areces Spanish Foundation Fellowship, and subsequently by an EMBO Postdoctoral Fellowship. S.V. was supported by a Post Doc Pool Grant from the Finnish Cultural Foundation. G.R. was supported by a Newton Fellowship. Marta N. Shahbazi, Agnieszka Jedrusik & Sanna Vuoristo -- These authors contributed equally to this work. Author Contributions: M.N.S., A.J. and S.V. carried out all experiments and data analyses. G.R. analysed microscopy data and generated 3D reconstructions. A.H. prepared illustrations and contributed experimentally. N.M.E.F. and K.K.N. helped with human embryo cultures and contributed experimentally, and L.G.D. helped with human embryo cultures. A.C., S.F., D.I., Y.K. and K.K.N. oversaw and provided human embryos for these studies. M.Z.-G. conceived the project and supervised the study. M.N.S. and M.Z.-G. wrote the manuscript with help from all of the authors. The authors declare no competing financial interests. Change history: 17 May 2016 --In the version of this Technical Report originally published online, in Fig. 1d (which presents pilot in vitro culture experiments) it erroneously stated that 20% HCS was used in the IVC2 medium; it should have stated that 30% KSR was used. This error arose by a miscommunication between the postdoctoral fellow who contributed to the pilot in vitro culture experiments and prepared the media, and the postdoctoral fellow who performed the experiments. The composition of the media has been verified based on the laboratory notebooks that describe the media preparation. This error has been corrected in the labels and caption of Fig. 1d, in the description of the results in the main text, and in the Methods section, in all versions of the Technical Report.

Attached Files

Accepted Version - emss-68293.pdf

Supplemental Material - ncb3347-s1.pdf

Supplemental Material - ncb3347-sf1.jpg

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