Shukla Vinay, Moreno-Irusta Ayelen, Varberg Kaela M, Kuna Marija, Iqbal Khursheed, Galligos Anna M, Aplin John D, Choudhury Ruhul H, Okae Hiroaki, Arima Takahiro, Soares Michael J
Institute for Reproductive and Developmental Sciences, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS.
Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, The University of Manchester, Manchester M13 9WL, United Kingdom.
bioRxiv. 2024 Aug 22:2024.02.13.579974. doi: 10.1101/2024.02.13.579974.
Trophoblast stem () cells have the unique capacity to differentiate into specialized cell types, including extravillous trophoblast () cells. EVT cells invade into and transform the uterus where they act to remodel the vasculature facilitating the redirection of maternal nutrients to the developing fetus. Disruptions in EVT cell development and function are at the core of pregnancy-related disease. WNT-activated signal transduction is a conserved regulator of morphogenesis of many organ systems, including the placenta. In human TS cells, activation of canonical WNT signaling is critical for maintenance of the TS cell stem state and its downregulation accompanies EVT cell differentiation. We show that aberrant WNT signaling undermines EVT cell differentiation. Notum, palmitoleoyl-protein carboxylesterase (), a negative regulator of canonical WNT signaling, was prominently expressed in first trimester EVT cells developing in situ and upregulated in EVT cells derived from human TS cells. Furthermore, NOTUM was required for optimal human TS cell differentiation to EVT cells. Activation of NOTUM in EVT cells is driven, at least in part, by endothelial PAS domain 1 (also called hypoxia-inducible factor 2 alpha). Collectively, our findings indicate that canonical WNT signaling is essential for maintenance of human trophoblast cell stemness and regulation of human TS cell differentiation. Downregulation of canonical WNT signaling via the actions of NOTUM is required for optimal EVT cell differentiation.
滋养层干细胞（TS细胞）具有独特的分化为特定细胞类型的能力，包括绒毛外滋养层（EVT）细胞。EVT细胞侵入并改造子宫，在那里它们重塑脉管系统，促进母体营养物质重新定向至发育中的胎儿。EVT细胞发育和功能的破坏是妊娠相关疾病的核心。WNT激活的信号转导是包括胎盘在内的许多器官系统形态发生的保守调节因子。在人TS细胞中，经典WNT信号的激活对于维持TS细胞的干细胞状态至关重要，其下调伴随着EVT细胞的分化。我们发现异常的WNT信号会破坏EVT细胞的分化。Notum，棕榈酰蛋白羧基酯酶，经典WNT信号的负调节因子，在孕早期原位发育的EVT细胞中显著表达，并在源自人TS细胞的EVT细胞中上调。此外，Notum是人类TS细胞向EVT细胞最佳分化所必需的。EVT细胞中Notum的激活至少部分是由内皮PAS结构域1（也称为缺氧诱导因子2α）驱动的。总之，我们的研究结果表明，经典WNT信号对于维持人滋养层细胞的干性和调节人TS细胞的分化至关重要。通过Notum的作用下调经典WNT信号是EVT细胞最佳分化所必需的。
