Pivotal role of the transcriptional co-activator YAP in trophoblast stemness of the developing human placenta

Abstract

<jats:p>Various pregnancy complications, such as severe forms of preeclampsia or intrauterine growth restriction, are thought to arise from failures in the differentiation of human placental trophoblasts. Progenitors of the latter either develop into invasive extravillous trophoblasts, remodeling the uterine vasculature, or fuse into multinuclear syncytiotrophoblasts transporting oxygen and nutrients to the growing fetus. However, key regulatory factors controlling trophoblast self-renewal and differentiation have been poorly elucidated. Using primary cells, three-dimensional organoids, and CRISPR-Cas9 genome-edited JEG-3 clones, we herein show that YAP, the transcriptional coactivator of the Hippo signaling pathway, promotes maintenance of cytotrophoblast progenitors by different genomic mechanisms. Genetic or chemical manipulation of YAP in these cellular models revealed that it stimulates proliferation and expression of cell cycle regulators and stemness-associated genes, but inhibits cell fusion and production of syncytiotrophoblast (STB)-specific proteins, such as hCG and GDF15. Genome-wide comparisons of primary villous cytotrophoblasts overexpressing constitutively active YAP-5SA with YAP KO cells and syncytializing trophoblasts revealed common target genes involved in trophoblast stemness and differentiation. ChIP-qPCR unraveled that YAP-5SA overexpression increased binding of YAP–TEAD4 complexes to promoters of proliferation-associated genes such as<jats:italic>CCNA</jats:italic>and<jats:italic>CDK6</jats:italic>. Moreover, repressive YAP–TEAD4 complexes containing the histone methyltransferase EZH2 were detected in the genomic regions of the STB-specific<jats:italic>CGB5</jats:italic>and<jats:italic>CGB7</jats:italic>genes. In summary, YAP plays a pivotal role in the maintenance of the human placental trophoblast epithelium. Besides activating stemness factors, it also directly represses genes promoting trophoblast cell fusion.</jats:p>

Radial extracorporeal shockwave promotes subchondral bone stem/progenitor cell self-renewal by activating YAP/TAZ and facilitates cartilage repair in vivo

“…The comprehensive analysis of the results suggests that YAP/TAZ and downstream self-renewal-associated genes are involved in the biological process of radial shockwave-mediated promotion of SCB-SPC self-renewal. The results are consistent with previous studies that demonstrated that YAP correlated closely with the self-renewal of ES cells because elevated YAP maintains the potency of ES cells [ 46 , 47 ]. Meanwhile, others reported that YAP/TAZ are dispensable for ES cell fate [ 48 ].…”

Context-dependent roles of YAP/TAZ in stem cell fates and cancer

“…Like in the mouse, YAP is essential for the development of the human TE and placenta, and its expression is negatively correlated with pregnancy disorders like preeclampsia [40,41]. The YAP-TEAD4 transcriptional program was recently shown to maintain human trophoblast stemness in primary cytotrophoblasts and repress cell fusion [40].…”

A tale of two cell-fates: role of the Hippo signaling pathway and transcription factors in early lineage formation in mouse preimplantation embryos

“…Interestingly, YAP1 is expressed in the human placenta and its levels are downregulated in patients with preeclampsia ( Sun et al , 2018 ), indicating that Hippo signaling may be important for human trophoblast lineage development. In support of this notion, a recent study using human cell models revealed that YAP1 and TEAD4 promote self-renewal of cytotrophoblast progenitor cells, while inhibiting formation of differentiated syncytiotrophoblast cells ( Meinhardt et al , 2020 ). Based on the function of the Hippo signaling pathway in mouse preimplantation embryos and embryos from other large animal species such as cattle and pigs ( Negron-Perez and Hansen, 2018 ; Cao et al , 2019 ; Emura et al , 2020 ; Sharma and Madan, 2020 ), it is easy to postulate that Hippo signaling plays a fundamental role in human preimplantation embryo development and early lineage formation.…”