TEAD4 ensures postimplantation development by promoting trophoblast self-renewal: An implication in early human pregnancy loss

Abstract

Early pregnancy loss affects ∼15% of all implantation-confirmed human conceptions. However, evolutionarily conserved molecular mechanisms that regulate self-renewal of trophoblast progenitors and their association with early pregnancy loss are poorly understood. Here, we provide evidence that transcription factor TEAD4 ensures survival of postimplantation mouse and human embryos by controlling self-renewal and stemness of trophoblast progenitors within the placenta primordium. In an early postimplantation mouse embryo, TEAD4 is selectively expressed in trophoblast stem cell–like progenitor cells (TSPCs), and loss of Tead4 in postimplantation mouse TSPCs impairs their self-renewal, leading to embryonic lethality before embryonic day 9.0, a developmental stage equivalent to the first trimester of human gestation. Both TEAD4 and its cofactor, yes-associated protein 1 (YAP1), are specifically expressed in cytotrophoblast (CTB) progenitors of a first-trimester human placenta. We also show that a subset of unexplained recurrent pregnancy losses (idiopathic RPLs) is associated with impaired TEAD4 expression in CTB progenitors. Furthermore, by establishing idiopathic RPL patient-specific human trophoblast stem cells (RPL-TSCs), we show that loss of TEAD4 is associated with defective self-renewal in RPL-TSCs and rescue of TEAD4 expression restores their self-renewal ability. Unbiased genomics studies revealed that TEAD4 directly regulates expression of key cell cycle genes in both mouse and human TSCs and establishes a conserved transcriptional program. Our findings show that TEAD4, an effector of the Hippo signaling pathway, is essential for the establishment of pregnancy in a postimplantation mammalian embryo and indicate that impairment of the Hippo signaling pathway could be a molecular cause for early human pregnancy loss.

Induction of Human Trophoblast Stem Cells from Somatic Cells and Pluripotent Stem Cells

“…Differentially regulated pathways included HIPPO, NOTCH, and ERBB pathways, which are main drivers of the self-renewing state of mouse TSCs (El-Hashash et al, 2010;Home et al, 2012;Nishioka et al, 2009;Rayon et al, 2014;Rivron et al, 2018b) and PPARG that is associated with mouse trophoblast proliferation and differentiation (Parast et al, 2009). These results complete previous studies suggesting conserved mechanisms of trophoblast development across mammals (Gerri et al, 2020;Hunkapiller et al, 2011;Saha et al, 2020;Schaiff et al, 2000), while they also highlight specific features of the human trophoblast lineage such as the steroid hormone biosynthesis pathway that was specifically associated with the ST in humans (Malassiné et al, 2003). Moreover, our analysis pointed to additional pathways including MTOR, estrogen, RAP1, and JAK/STAT signaling pathways that seem to be active in h(i/c)TSCs (Figures S4 and S5).…”

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

“…The YAP-TEAD4 transcriptional program was recently shown to maintain human trophoblast stemness in primary cytotrophoblasts and repress cell fusion [40]. This was confirmed in another study using both a mouse model and human trophoblast stem cells (TSCs) derived from patients who had experienced pregnancy loss [42]. However, the precise roles of YAP in the human ICM are contested.…”

MSX2 safeguards syncytiotrophoblast fate of human trophoblast stem cells

“…TFAP2C, TFAP2A, GATA3 and GATA2 were reported to cooperatively regulate early trophoblast specification in vitro (Krendl et al 2017). Similarly, TEAD4 is a crucial controller of CT identity as its depletion in hTSC resulted in loss of self-renewal and differentiation (Saha et al 2020). Taken together, our findings highlight MSX2 as a key regulator within the TF network of human trophoblast development.…”