Modeling post-implantation human development to yolk sac blood emergence

Implantation of the human embryo commences a critical developmental stage that comprises profound events including axis formation, gastrulation, and the emergence of hematopoietic system. Our mechanistic knowledge of this window of human life remains limited due to restricted access to in vivo samples for both technical and ethical reasons. Stem cell models of human embryo have emerged to help unlock the mysteries of this stage. Here, we present heX-Embryoids, a genetically inducible stem cell model of early post-implantation human embryogenesis that captures the reciprocal co-development of embryonic tissue and extra-embryonic endoderm and mesoderm niche with early hematopoiesis. They are produced from induced pluripotent stem cells and show unanticipated self-organizing developmental programs that include formation of the amniotic cavity and bilaminar disc morphology as well as generation of an anterior hypoblast pole and posterior domain. The extra-embryonic layer in these embryoids lacks trophoblast and exhibits advanced multilineage yolk sac tissue morphogenesis that reconstitutes distinct waves of hematopoiesis, including the emergence of erythroid, megakaryocytes, myeloid, and lymphoid cells. heX-Embryoids offer an easy-to-use, high-throughput, reproducible, and scalable platform to probe multifaceted aspects of human development and blood formation at the early post-implantation stage. They will provide a tractable human-based model for drug testing, disease modeling, and a unique cell source for regenerative medicine.