Stem Cell-Based Embryo Models: En Route to a Programmable Future.

Early-stage human embryogenesis, such as implantation, gastrulation, and neurulation, are critical for successful pregnancy. For decades, our knowledge about these stages has been limited by the inaccessibility to such embryo specimens in vivo and the difficulty in rebuilding them in vitro. Although human embryos could be cultured in vitro beyond implantation, it remains challenging for the cultured embryos to recapitulate the continuous, coordinated morphogenesis and cytodifferentiation as seen in vivo. Stem cell-based embryo models, mainly derived from human pluripotent stem cells, are organized structures mimicking essential developmental processes in the early-stage human embryos. Despite their invaluable potentials, most embryo models are based on the self-organization of human pluripotent stem cells, which are limited in controllability, reproducibility, and developmental fidelity. Recently, the integration of bioengineered tools and stem cell biology has fueled a technological transformation towards programmable, highly complex, high-fidelity stem cell-based embryo models. Given its scientific and clinical significance, we present an overview of recent paradigm-shifting advances as well as historical perspectives regarding the past, present, and future of synthetic human embryology. Following the developmental roadmap of human embryogenesis, we critically review existing stem cell-based models for implantation, gastrulation, and neurulation, respectively. We highlight the limitations encountered by autonomous self-organization strategy and discuss the concept and application of guided cell organization as a game-changer for innovating next-generation embryo models. Future endeavors in synthetic human embryology should rationally leverage both the self-organizing power and programmable microenvironmental guidance to secure faithful reconstructions of the hierarchical orders of human embryogenesis in vitro.