Combining engineered post-implantation embryoid and xenotransplantation for improved modeling of early human organogenesis

• Human post-implantation embryoid is generated from human embryonic stem cells in 3D. • Human post-implantation embryoid recapitulates formation of all three germ layers. • Cell fate determination events underpinning construction of an early human post-implantation embryoid is depicted via single cell transcriptomic analyses. • Human post-implantation embryoid develops into well-patterned multiple organ systems after xenotransplantation. After implantation, the human embryo undergoes gastrulation and organogenesis, crucial stages for early development. Given the limited accessibility, the cell lineage developmental trajectory in an early human embryo remains largely elusive. Derivation of organoids in vitro via 3D culture or teratomas in vivo via xenotransplantation of human pluripotent stem cells (hPSCs) has shed new light on this respect. Here, we report a new system to model human gastrulation and early organogenesis by engineering hPSCs into a self-developed early human embryoid. Single-cell transcriptomic analyses uncovered molecular features of cell populations organized in early human embryoid. Remarkably, xenotransplantation of the engineered early human embryoid in mice generated well-patterned human organ systems, such as muscle and bone from the mesoderm, gut from the endoderm and neural tissues from the ectoderm, which showed more sophisticated morphology than those generated from teratomas. Engineering of hPSCs into early human embryoids, followed by xenotransplantation, therefore represents an improved model for studying cellular and molecular features underlying early human embryogenesis.