title: Notch1 controls development of the extravillous trophoblast lineage in the human placenta.
abstract: 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 RBPJκ 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.
authors.affiliation: Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Haider
authors.affiliation: Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Meinhardt
authors.affiliation: Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Leila
authors.initials: L
authors.lastname: Saleh
authors.affiliation: Gynmed Clinic, 1150 Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Fiala
authors.affiliation: Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pollheimer
authors.affiliation: Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, 1090 Vienna, Austria; martin.knoefler@meduniwien.ac.at.
authors.forename: Martin
authors.initials: M
authors.lastname: Knöfler
mesh_terms: D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D010920:Placenta / Q000166:cytology; D010929:Placentation; D011247:Pregnancy; D051881:Receptor, Notch1 / Q000502:physiology*; D014327:Trophoblasts / Q000502:physiology*
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1
keywords: Notch1; cell fusion; extravillous trophoblast; human placenta; trophoblast progenitors