NOTCH3 signalling controls human trophoblast stem cell expansion and differentiation

• DOI: 10.1242/dev.202152
• Publication Date: 2023-10-31T09:03:07Z
• Authors: Bianca Dietrich; Victoria Kunihs; Andreas I. Lackner; Gudrun Meinhardt; Bon-Kyoung Koo; Jürgen Pollheimer; Sandra Haider; Martin Knöfler
• Keywords: Trophoblast; Cytotrophoblast; Syncytiotrophoblasts; Placentation; Syncytiotrophoblasts; CTBS

Failures in growth and differentiation of the early human placenta are associated with severe pregnancy disorders such as pre-eclampsia fetal restriction. However, regulatory mechanisms controlling development placental epithelial cells, trophoblasts, remain poorly elucidated. Using trophoblast stem cells (TSCs), organoids (TB-ORGs) primary cytotrophoblasts (CTBs) pregnancy, we herein show that autocrine NOTCH3 signalling controls expansion differentiation. The receptor was specifically expressed proliferative CTB progenitors its active form, nuclear intracellular domain (NOTCH3-ICD), interacted transcriptional co-activator mastermind-like 1 (MAML1). Doxycycline-inducible expression dominant-negative MAML1 TSC lines provoked cell fusion upregulation genes specific for multinucleated syncytiotrophoblasts, which differentiated hormone-producing placenta. progenitor markers stemness proliferation were suppressed. Accordingly, inhibition diminished TB-ORGs, whereas overexpression NOTCH3-ICD CTBs TSCs showed opposite effects. In conclusion, data suggest canonical plays a key role by promoting self-renewal progenitors.