The human placenta has a vital role in ensuring a successful pregnancy. Despite the growing body of knowledge about its cellular compositions and functions, there has been limited research on the heterogeneity of the billions of nuclei within the syncytiotrophoblast (STB), a multinucleated entity primarily responsible for placental function. Here we conducted integrated single-nucleus RNA sequencing and single-nucleus ATAC sequencing analyses of human placentas from early and late pregnancy. Our findings demonstrate the dynamic heterogeneity and developmental trajectories of STB nuclei and their correspondence with human trophoblast stem cell (hTSC)-derived STB. Furthermore, we identified transcription factors associated with diverse STB nuclear lineages through their gene regulatory networks and experimentally confirmed their function in hTSC and trophoblast organoid-derived STBs. Together, our data provide insights into the heterogeneity of human STB and represent a valuable resource for interpreting associated pregnancy complications.

人类胎盘对于确保成功妊娠具有至关重要的作用。尽管关于其细胞组成和功能的知识不断增长，但对合体滋养层（STB）（主要负责胎盘功能的多核实体）内数十亿个细胞核的异质性的研究仍然有限。在这里，我们对妊娠早期和晚期的人胎盘进行了综合单核 RNA 测序和单核 ATAC 测序分析。我们的研究结果证明了 STB 核的动态异质性和发育轨迹及其与人滋养层干细胞 (hTSC) 衍生的 STB 的对应关系。此外，我们通过基因调控网络鉴定了与不同 STB 核谱系相关的转录因子，并通过实验证实了它们在 hTSC 和滋养层类器官衍生的 STB 中的功能。总之，我们的数据提供了对人类 STB 异质性的见解，并为解释相关妊娠并发症提供了宝贵的资源。