Complete human day 14 post-implantation embryo models from naive ES cells

Bernardo Oldak, Emilie Wildschutz, Vladyslav Bondarenko, Mehmet-Yunus Comar, Cheng Zhao, Alejandro Aguilera-Castrejon, Shadi Tarazi, Sergey Viukov, Thi Xuan Ai Pham, Shahd Ashouokhi, Dmitry Lokshtanov, Francesco Roncato, Eitan Ariel, Max Rose, Nir Livnat, Tom Shani, Carine Joubran, Roni Cohen, Yoseph Addadi, Muriel Chemla, Merav Kedmi, Hadas Keren-Shaul, Vincent Pasque, Sophie Petropoulos, Fredrik Lanner, Noa Novershtern and Jacob H. Hanna ()
Additional contact information
Bernardo Oldak: Weizmann Institute of Science
Emilie Wildschutz: Weizmann Institute of Science
Vladyslav Bondarenko: Weizmann Institute of Science
Mehmet-Yunus Comar: Weizmann Institute of Science
Cheng Zhao: Karolinska Institutet
Alejandro Aguilera-Castrejon: Weizmann Institute of Science
Shadi Tarazi: Weizmann Institute of Science
Sergey Viukov: Weizmann Institute of Science
Thi Xuan Ai Pham: KU Leuven-University of Leuven
Shahd Ashouokhi: Weizmann Institute of Science
Dmitry Lokshtanov: Weizmann Institute of Science
Francesco Roncato: Weizmann Institute of Science
Eitan Ariel: Weizmann Institute of Science
Max Rose: Weizmann Institute of Science
Nir Livnat: Weizmann Institute of Science
Tom Shani: Weizmann Institute of Science
Carine Joubran: Weizmann Institute of Science
Roni Cohen: Weizmann Institute of Science
Yoseph Addadi: Weizmann Institute of Science
Muriel Chemla: Weizmann Institute of Science
Merav Kedmi: Weizmann Institute of Science
Hadas Keren-Shaul: Weizmann Institute of Science
Vincent Pasque: KU Leuven-University of Leuven
Sophie Petropoulos: Karolinska Institutet
Fredrik Lanner: Karolinska Institutet
Noa Novershtern: Weizmann Institute of Science
Jacob H. Hanna: Weizmann Institute of Science

Nature, 2023, vol. 622, issue 7983, 562-573

Abstract: Abstract The ability to study human post-implantation development remains limited owing to ethical and technical challenges associated with intrauterine development after implantation1. Embryo-like models with spatially organized morphogenesis and structure of all defining embryonic and extra-embryonic tissues of the post-implantation human conceptus (that is, the embryonic disc, the bilaminar disc, the yolk sac, the chorionic sac and the surrounding trophoblast layer) remain lacking1,2. Mouse naive embryonic stem cells have recently been shown to give rise to embryonic and extra-embryonic stem cells capable of self-assembling into post-gastrulation structured stem-cell-based embryo models with spatially organized morphogenesis (called SEMs)3. Here we extend those findings to humans using only genetically unmodified human naive embryonic stem cells (cultured in human enhanced naive stem cell medium conditions)4. Such human fully integrated and complete SEMs recapitulate the organization of nearly all known lineages and compartments of post-implantation human embryos, including the epiblast, the hypoblast, the extra-embryonic mesoderm and the trophoblast layer surrounding the latter compartments. These human complete SEMs demonstrated developmental growth dynamics that resemble key hallmarks of post-implantation stage embryogenesis up to 13–14 days after fertilization (Carnegie stage 6a). These include embryonic disc and bilaminar disc formation, epiblast lumenogenesis, polarized amniogenesis, anterior–posterior symmetry breaking, primordial germ-cell specification, polarized yolk sac with visceral and parietal endoderm formation, extra-embryonic mesoderm expansion that defines a chorionic cavity and a connecting stalk, and a trophoblast-surrounding compartment demonstrating syncytium and lacunae formation. This SEM platform will probably enable the experimental investigation of previously inaccessible windows of human early post implantation up to peri-gastrulation development.

Date: 2023
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DOI: 10.1038/s41586-023-06604-5

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