NOTCH3 IS A KEY REGULATOR OF HUMAN TROPHOBLAST SELF-RENEWAL AND DIFFERENIATION

Datum

23.10.2023

Zeit

11:00 - 12:00

Sprecher

Bianca Dietrich

Zugehörigkeit

the Medical University of Vienna; Dept. of Obstetrics and Gynecology Placental Development Group

Sprache

en

Hauptthema

Biologie

Host

Claudia Gerri

Beschreibung

Failures in growth and differentiation of the early human placenta are associated with severe pregnancy disorders such as preeclampsia and fetal growth restriction. However, regulatory mechanisms controlling development of its 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 signaling controls human placental expansion and differentiation. 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). Doxycyclin-inducible expression of dominant-negative MAML1 in TSC lines provoked cell fusion and upregulation of genes specific for multinucleated syncytiotrophoblasts, the differentiated hormone-producing cell type of the placenta. However, progenitor expansion and markers of trophoblast stemness and proliferation were suppressed. Accordingly, overexpression of NOTCH3-ICD in primary CTBs and TSCs showed opposite effects. In conclusion, the data suggest that canonical NOTCH3 signaling plays a key role in human placental development promoting self-renewal of CTB progenitors.

Letztmalig verändert: 24.10.2023, 07:37:45