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标题：Notch1 controls development of the extravillous trophoblast lineage in the human placenta
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作者：Sandra Haider ; Gudrun Meinhardt ; Leila Saleh 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：48
页码：E7710-E7719
DOI：10.1073/pnas.1612335113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceProgenitor trophoblast cells of the human placenta either fuse to form a syncytium or develop into invasive trophoblasts invading the maternal uterus. However, regulatory pathways controlling their development and distinct differentiation programs are poorly understood. In the present study, we demonstrate that Notch1 is a critical regulator of early pregnancy, promoting development of the invasive, extravillous trophoblast lineage and survival of its progenitors. In vivo, Notch1 is detected in extravillous trophoblast progenitors and clusters of villous trophoblast initiating the invasive differentiation program. In vitro, Notch1 repressed genes involved in self-renewal of fusogenic precursors, but induced genes specifically expressed by extravillous trophoblast progenitors. Our data delineate Notch1 as a key regulator promoting development of the human extravillous trophoblast lineage. Development of the human placenta and its different epithelial trophoblasts is crucial for a successful pregnancy. Besides fusing into a multinuclear syncytium, the exchange surface between mother and fetus, progenitors develop into extravillous trophoblasts invading the maternal uterus and its spiral arteries. Migration into these vessels promotes remodelling and, as a consequence, adaption of blood flow to the fetal-placental unit. Defects in remodelling and trophoblast differentiation are associated with severe gestational diseases, such as preeclampsia. However, mechanisms controlling human trophoblast development are largely unknown. Herein, we show that Notch1 is one such critical regulator, programming primary trophoblasts into progenitors of the invasive differentiation pathway. At the 12th wk of gestation, Notch1 is exclusively detected in precursors of the extravillous trophoblast lineage, forming cell columns anchored to the uterine stroma. At the 6th wk, Notch1 is additionally expressed in clusters of villous trophoblasts underlying the syncytium, suggesting that the receptor initiates the invasive differentiation program in distal regions of the developing placental epithelium. Manipulation of Notch1 in primary trophoblast models demonstrated that the receptor promotes proliferation and survival of extravillous trophoblast progenitors. Notch1 intracellular domain induced genes associated with stemness of cell columns, myc and VE-cadherin, in Notch1- fusogenic precursors, and bound to the myc promoter and enhancer region at RBPJ{kappa} cognate sequences. In contrast, Notch1 repressed syncytialization and expression of TEAD4 and p63, two regulators controlling self-renewal of villous cytotrophoblasts. Our results revealed Notch1 as a key factor promoting development of progenitors of the extravillous trophoblast lineage in the human placenta.
关键词：human placenta ; trophoblast progenitors ; Notch1 ; extravillous trophoblast ; cell fusion