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 1,2 . 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 3-5 . Stem cell models of human embryo have emerged to help unlock the mysteries of this stage 6-16 . Here, we present a genetically inducible stem cell-derived embryoid 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. This model is produced from induced pluripotent stem cells and shows unanticipated self-organizing cellular programs similar to those that occur in embryogenesis, including the formation of amniotic cavity and bilaminar disc morphologies as well as the 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-like morphogenesis that harbors a process similar to distinct waves of hematopoiesis, including the emergence of erythroid-, megakaryocyte-, myeloid-, and lymphoid-like cells. This model presents 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. It will provide a tractable human-based model for drug testing, and disease modeling.