TY - JOUR
T1 - Blastocyst-like structures generated solely from stem cells
AU - Rivron, Nicolas C.
AU - Frias-Aldeguer, Javier
AU - Vrij, Erik J.
AU - Boisset, Jean Charles
AU - Korving, Jeroen
AU - Vivié, Judith
AU - Truckenmüller, Roman K.
AU - Van Oudenaarden, Alexander
AU - Van Blitterswijk, Clemens A.
AU - Geijsen, Niels
N1 - Funding Information:
Acknowledgements We would like to thank J. Deschamps for providing the Cdx2-eGFP mice; M. Creyghton for providing V6.5 mouse ES cells; V. Prideaux, J. Garner and J. Rossant for providing the F4 mouse TS cell lines; A.-K. Hadjantonakis for providing the PDGFRα-H2B-GFP mouse ES cells; N. Schelling for helping with logistics; S. van der Elst for helping with FACS assays; A. de Graaf for helping with microscopes; L. Yvernogeau for helping with the imaging of embryos; B. El Haddouti for helping with uterus injections; H. Begthel for helping with histology; W. de Lau for helping with the TCF luciferase assay; C. Rabouille and H. Clevers for commenting on the manuscript. N.C.R. is grateful for support from The Netherlands Organisation for Scientific Research (NWO-ZonMw) Translational Adult Stem Cell grant (116005008). We apologize that all relevant publications could not be cited.
Publisher Copyright:
© 2018 Macmillan Publishers Ltd., part of Springer Nature.
PY - 2018/5/3
Y1 - 2018/5/3
N2 - The blastocyst (the early mammalian embryo) forms all embryonic and extra-embryonic tissues, including the placenta. It consists of a spherical thin-walled layer, known as the trophectoderm, that surrounds a fluid-filled cavity sheltering the embryonic cells 1 . From mouse blastocysts, it is possible to derive both trophoblast 2 and embryonic stem-cell lines 3, which are in vitro analogues of the trophectoderm and embryonic compartments, respectively. Here we report that trophoblast and embryonic stem cells cooperate in vitro to form structures that morphologically and transcriptionally resemble embryonic day 3.5 blastocysts, termed blastoids. Like blastocysts, blastoids form from inductive signals that originate from the inner embryonic cells and drive the development of the outer trophectoderm. The nature and function of these signals have been largely unexplored. Genetically and physically uncoupling the embryonic and trophectoderm compartments, along with single-cell transcriptomics, reveals the extensive inventory of embryonic inductions. We specifically show that the embryonic cells maintain trophoblast proliferation and self-renewal, while fine-Tuning trophoblast epithelial morphogenesis in part via a BMP4/Nodal-KLF6 axis. Although blastoids do not support the development of bona fide embryos, we demonstrate that embryonic inductions are crucial to form a trophectoderm state that robustly implants and triggers decidualization in utero. Thus, at this stage, the nascent embryo fuels trophectoderm development and implantation.
AB - The blastocyst (the early mammalian embryo) forms all embryonic and extra-embryonic tissues, including the placenta. It consists of a spherical thin-walled layer, known as the trophectoderm, that surrounds a fluid-filled cavity sheltering the embryonic cells 1 . From mouse blastocysts, it is possible to derive both trophoblast 2 and embryonic stem-cell lines 3, which are in vitro analogues of the trophectoderm and embryonic compartments, respectively. Here we report that trophoblast and embryonic stem cells cooperate in vitro to form structures that morphologically and transcriptionally resemble embryonic day 3.5 blastocysts, termed blastoids. Like blastocysts, blastoids form from inductive signals that originate from the inner embryonic cells and drive the development of the outer trophectoderm. The nature and function of these signals have been largely unexplored. Genetically and physically uncoupling the embryonic and trophectoderm compartments, along with single-cell transcriptomics, reveals the extensive inventory of embryonic inductions. We specifically show that the embryonic cells maintain trophoblast proliferation and self-renewal, while fine-Tuning trophoblast epithelial morphogenesis in part via a BMP4/Nodal-KLF6 axis. Although blastoids do not support the development of bona fide embryos, we demonstrate that embryonic inductions are crucial to form a trophectoderm state that robustly implants and triggers decidualization in utero. Thus, at this stage, the nascent embryo fuels trophectoderm development and implantation.
UR - http://www.scopus.com/inward/record.url?scp=85046452156&partnerID=8YFLogxK
U2 - 10.1038/s41586-018-0051-0
DO - 10.1038/s41586-018-0051-0
M3 - Article
AN - SCOPUS:85046452156
SN - 0028-0836
VL - 557
SP - 106
EP - 111
JO - Nature
JF - Nature
IS - 7703
ER -