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NOTCH3 signalling controls human trophoblast stem cell expansion and differentiation

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Title
NOTCH3 signalling controls human trophoblast stem cell expansion and differentiation
Author(s)
Dietrich, Bianca; Kunihs, Victoria; Lackner, Andreas I.; Meinhardt, Gudrun; Bon-Kyoung Koo; Pollheimer, Jürgen; Haider, Sandra; Knöfler, Martin
Publication Date
2023-11
Journal
Development (Cambridge), v.150, no.22
Publisher
Company of Biologists Ltd
Abstract
Failures in growth and differentiation of the early human placenta are associated with severe pregnancy disorders such as pre-eclampsia and fetal growth restriction. However, regulatory mechanisms controlling development of placental epithelial cells, the trophoblasts, remain poorly elucidated. Using trophoblast stem cells (TSCs), trophoblast organoids (TB-ORGs) and primary cytotrophoblasts (CTBs) of early pregnancy, we herein show that autocrine NOTCH3 signalling controls human placental expansion and differentiation. The NOTCH3 receptor was specifically expressed in proliferative CTB progenitors and its active form, the nuclear NOTCH3 intracellular domain (NOTCH3-ICD), interacted with the transcriptional co-activator mastermind-like 1 (MAML1). Doxycycline-inducible expression of dominant-negative MAML1 in TSC lines provoked cell fusion and upregulation of genes specific for multinucleated syncytiotrophoblasts, which are the differentiated hormone-producing cells of the placenta. However, progenitor expansion and markers of trophoblast stemness and proliferation were suppressed. Accordingly, inhibition of NOTCH3 signalling diminished growth of TB-ORGs, whereas overexpression of NOTCH3-ICD in primary CTBs and TSCs showed opposite effects. In conclusion, the data suggest that canonical NOTCH3 signalling plays a key role in human placental development by promoting selfrenewal of CTB progenitors. © 2023. Published by The Company of Biologists Ltd.
URI
https://pr.ibs.re.kr/handle/8788114/14720
DOI
10.1242/dev.202152
ISSN
0950-1991
Appears in Collections:
Center for Genome Engineering(유전체 교정 연구단) > 1. Journal Papers (저널논문)
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