Tumor suppressor protein p53 governs human trophoblast lineage development

Tumor suppressor protein p53 (encoded by Trp53 in mice and TP53 in humans) has important functions in normal development. Dysregulated Trp53 expression in mice causes multiple embryonic developmental defects or even implantation failure. However, how p53 affects these development processes is not entirely clear. Here, we report that p53 is highly expressed in preimplantation embryos. p53 inhibition arrests preimplantation embryonic development with defective trophectoderm (TE) development. Genetic knockout of p53 in human pluripotent stem cells (hPSCs) compromises human trophoblast development. Single-cell transcriptomic analysis further reveals the critical requirement of p53 in trophoblast cell lineage segregation and identifies that the p53-mediated cell cycle state determines trophoblast cell fate propensity. Together, our findings demonstrate that p53 is a potential master regulator in human trophoblast cell fate determination and lineage development, which has important implications for p53 functions in human fertility, reproduction, and tumor suppression.