PHD Student Guangzhou National Laboratory, China (People's Republic)
Abstract: In vitro embryo-like models have emerged as transformative tools for investigating human early development, providing a controlled platform to elucidate processes such as lineage specification, morphogenesis, and body axis formation. Despite their potential, existing models are often hindered by suboptimal efficiency or limited fidelity in recapitulating these complex developmental events. We developed a novel system wherein human pluripotent stem cells (hPSCs), under precise modulation of signaling pathways, autonomously self-organize into embryo-like structures that closely resemble Carnegie Stage (CS) 6–7 human embryos. Single-cell RNA sequencing (scRNA-seq) combined with trajectory inference was employed to dissect the molecular mechanisms underlying the differentiation processes guiding hPSCs toward their terminal cell fates. These analyses revealed distinct differentiation trajectories and dynamic molecular events orchestrating cell fate transitions driven by the trajectory-dependent stepwise activation of lineage-specific genes. Collectively, these findings illuminate the molecular programming underlying transitions to distinct cellular fates. Comprehensive molecular profiling of the embryo-like structures demonstrated their remarkable fidelity to natural CS6–7 embryos, as evidenced by highly similar lineage composition and marker gene expression patterns, as well as accurate recapitulation of key intercellular signaling interactions observed in their in vivo counterparts. These findings highlight the utility of our model as a robust and faithful system for studying the molecular underpinnings of human post-implantation development.
