NOTUM- mediated WNT silencing drives extravillous trophoblast cell lineage development

• 成果类型: Article
• 署名作者: 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.
• 署名单位: University System of Maryland; University of Maryland Baltimore; Children's Mercy Hospital; Oklahoma State University System; Oklahoma State University - Stillwater; Stowers Institute for Medical Research; University of Kansas; University of Kansas Medical Center; University of Manchester; University of Manchester; Kumamoto University; Tohoku University; Children's Mercy Hospital; University of Kansas; University of Kansas Medical Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9064
• DOI: 10.1073/pnas.2403003121
• 发表日期: 2024-10-01
• 关键词: differentiation; induction; placenta; invasion

摘要

Trophoblast stem (TS) cells have the unique capacity to differentiate into specialized cell types, including extravillous trophoblast (EVT) 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 differlator of canonical WNT signaling, was prominently expressed in first- trimester EVT cells developing in situ and up- regulated 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 our findings indicate that canonical Wingless- related integration site (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.