Angelova Dafina M, Tsolova Aleksandra, Prater Malwina, Ballasy Noura, Bacon Wendi, Hamilton Russell S, Blackwell Danielle, Yu Ziyi, Li Xin, Liu Xin, Hemberger Myriam, Charnock-Jones D Stephen
Department of Obstetrics and Gynaecology, University of Cambridge, NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
Loke Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
Nat Commun. 2025 Jan 2;16(1):142. doi: 10.1038/s41467-024-55597-w.
The placenta is the critical interface between mother and fetus, and consequently, placental dysfunction underlies many pregnancy complications. Placental formation requires an adequate expansion of trophoblast stem and progenitor cells followed by finely tuned lineage specification events. Here, using single-cell RNA sequencing of mouse trophoblast stem cells during the earliest phases of differentiation, we identify gatekeepers of the stem cell state, notably Nicol1, and uncover unsuspected trajectories of cell lineage diversification as well as regulators of lineage entry points. We show that junctional zone precursors and precursors of one of the two syncytial layers of the mouse placental labyrinth, the Syncytiotrophoblast-I lineage, initially share similar trajectories. Importantly, our functional analysis of one such lineage precursor marker, CXADR, demonstrates that this cell surface protein regulates the differentiation dynamics between the two syncytial layers of the mouse labyrinth, ensuring the correct establishment of the placental exchange surface. Deciphering the mechanisms underlying trophoblast lineage specification will inform our understanding of human pregnancy in health and disease.
胎盘是母体与胎儿之间的关键界面，因此，胎盘功能障碍是许多妊娠并发症的根本原因。胎盘形成需要滋养层干细胞和祖细胞充分扩增，随后是精细调节的谱系特化过程。在这里，我们在分化的最早阶段对小鼠滋养层干细胞进行单细胞RNA测序，确定了干细胞状态的守门人，特别是Nicol1，并揭示了细胞谱系多样化的意外轨迹以及谱系进入点的调节因子。我们发现，小鼠胎盘迷路的两个合胞体层之一即合体滋养层-I谱系的连接区前体和前体最初具有相似的轨迹。重要的是，我们对一种这样的谱系前体标记物CXADR的功能分析表明，这种细胞表面蛋白调节小鼠迷路两个合胞体层之间的分化动态，确保胎盘交换表面的正确建立。破解滋养层谱系特化的潜在机制将有助于我们理解健康和疾病状态下的人类妊娠。
