Abstract
BackgroundWnt signaling is a critical determinant for the maintenance and differentiation of stem/progenitor cells, including trophoblast stem cells during placental development. Hyperactivation of Wnt signaling has been shown to be associated with human trophoblast diseases. However, little is known about the impact and underlying mechanisms of excessive Wnt signaling during placental trophoblast development.ResultsIn the present work, we observed that two inhibitors of Wnt signaling, secreted frizzled-related proteins 1 and 5 (Sfrp1 and Sfrp5), are highly expressed in the extraembryonic trophoblast suggesting possible roles in early placental development. Sfrp1 and Sfrp5 double knockout mice exhibited disturbed trophoblast differentiation in the placental ectoplacental cone (EPC), which contains the precursors of trophoblast giant cells (TGCs) and spongiotrophoblast cells. In addition, we employed mouse models expressing a truncated β-catenin with exon 3 deletion globally and trophoblast-specifically, as well as trophoblast stem cell lines, and unraveled that hyperactivation of canonical Wnt pathway exhausted the trophoblast precursor cells in the EPC, resulting in the overabundance of giant cells at the expense of spongiotrophoblast cells. Further examination uncovered that hyperactivation of canonical Wnt pathway disturbed trophoblast differentiation in the EPC via repressing Ascl2 expression.ConclusionsOur investigations provide new insights that the homeostasis of canonical Wnt-β-catenin signaling is essential for EPC trophoblast differentiation during placental development, which is of high clinical relevance, since aberrant Wnt signaling is often associated with trophoblast-related diseases.
Highlights
Wnt signaling is a critical determinant for the maintenance and differentiation of stem/progenitor cells, including trophoblast stem cells during placental development
Sfrp1 and Sfrp5 deficiency leads to excessive Trophoblast giant cell (TGC) differentiation and compromised placental development Secreted frizzled-related proteins (SFRPs), containing a cysteine-rich domain (CRD) that is 30 to 50% similar in sequence to that of the frizzled protein while lacking the transmembrane domain, serve mainly as extracellular inhibitors of Wnt signaling by directly blocking the interactions between the Wnt and Frizzled receptors [20]
Further examination of the placental sections at E7.5-E9.5 showed that the expression of Sfrp1 and Sfrp5 was abundant in extraembryonic trophoblast, including trophoblast cells in the chorion and ectoplacental cone (EPC), as well as the subsequent spongiotrophoblast layer (Additional file 1: Fig. S1B)
Summary
Wnt signaling is a critical determinant for the maintenance and differentiation of stem/progenitor cells, including trophoblast stem cells during placental development. Hyperactivation of Wnt signaling has been shown to be associated with human trophoblast diseases. Little is known about the impact and underlying mechanisms of excessive Wnt signaling during placental trophoblast development. A mature placenta consists of three trophoblast layers: the outermost giant cell layer, the intermediate spongiotrophoblast layer, and the innermost labyrinth layer. Ascl is located in the EPC and diminishes as trophoblast cells differentiate into TGCs. Ablation of Ascl led to embryonic lethality owing to defective spongiotrophoblast formation [5]. ASCL2 is reported to be expressed in human freshly isolated cytotrophoblasts [6] and proximal column extravillous trophoblasts [7], corresponding to the EPC and/or spongiotrophoblast layer in mice. The signals that affect EPC trophoblast differentiation and how they interact with Ascl remain largely unknown
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