Harunobu Kagawa  ^# 1,  Alok Javali  ^# 1,  Heidar Heidari Khoei  ^# 1,  Theresa Maria Sommer ¹,  Giovanni Sestini ¹,  Maria Novatchkova ^1 2,  Yvonne Scholte Op Reimer ¹,  Gaël Castel ³,  Alexandre Bruneau ³,  Nina Maenhoudt ⁴,  Jenna Lammers ^3 5,  Sophie Loubersac ^3 5,  Thomas Freour ^3 5,  Hugo Vankelecom ⁴,  Laurent David ^3 6,  Nicolas Rivron ⁷

Affiliations

• 1Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria.
• 2Institute of Molecular Pathology (IMP), Vienna Biocenter, Vienna, Austria.
• 3Université de Nantes, CHU Nantes, INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.
• 4Unit of Stem Cell Research, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven, (University of Leuven), Leuven, Belgium.
• 5CHU Nantes, Service de Biologie de la Reproduction, Nantes, France.
• 6Université de Nantes, CHU Nantes, INSERM, CNRS, SFR Santé, FED 4203, INSERM UMS 016, CNRS UMS 3556, Nantes, France.
• 7Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria. nicolas.rivron@imba.oeaw.ac.at.
• #Contributed equally.

PMID: 34856602   DOI: 10.1038/s41586-021-04267-8

Abstract

One week after fertilization, human embryos implant into the uterus. This event requires the embryo to form a blastocyst consisting of a sphere encircling a cavity lodging the embryo proper. Stem cells can form a blastocyst model that we called a blastoid¹. Here we show that naive human pluripotent stem cells cultured in PXGL medium² and triply inhibited for the Hippo, TGF-β and ERK pathways efficiently (with more than 70% efficiency) form blastoids generating blastocyst-stage analogues of the three founding lineages (more than 97% trophectoderm, epiblast and primitive endoderm) according to the sequence and timing of blastocyst development. Blastoids spontaneously form the first axis, and we observe that the epiblast induces the local maturation of the polar trophectoderm, thereby endowing blastoids with the capacity to directionally attach to hormonally stimulated endometrial cells, as during implantation. Thus, we propose that such a human blastoid is a faithful, scalable and ethical model for investigating human implantation and development^3,4.