Tumor suppresson protein p53 governs human trophoblast lineage development

In addition to being a potent tumor suppressor, the p53 protein (encoded by Trp53 in mouse and TP53 in human) has important functions in embryo development and stem cells. The Trp53-null mice exhibit developmental defects whereas p53 activation causes implantation failure. However, it remains unclear how p53 affects early embryonic cell lineage development. We report here that p53 is highly expressed in the trophectoderm (TE) of the blastocyst and that blocking p53 activities arrests preimplantation embryo development. We have subsequently investigated p53 using human pluripotent stem cells (hPSCs) in the generation of human trophoblast stem cells (hTSCs). Genetic ablation of TP53 or chemical inhibition of p53 activities hinders the generation of hTSCs while enhancing the generation of amniotic cells. Furthermore, p53 deficiency in hTSCs results in epigenetic dysregulation of the trophoblast regulatory network involving the generation of mature syncytiotrophoblasts (STBs). In contrast, the generation and invasiveness of extravillous trophoblasts (EVTs) is enhanced. Single-cell transcriptomics analysis and experimental investigation further revealed the importance of p53 functions at multiple stages of human trophoblast development and identify that p53-mediated cell-cycle state determines trophoblast cell fate propensity. These findings for the first time demonstrate the important functions of p53 in human early embryonic cell lineage development and implicate possible links between the role of p53 in early development and tumor suppression.