Human placental trophoblast invasion and differentiation: a particular focus on Wnt signaling

Abstract

Wingless ligands, a family of secreted proteins, are critically involved in organ development and tissue homeostasis by ensuring balanced rates of stem cell proliferation, cell death and differentiation. Wnt signaling components also play crucial roles in murine placental development controlling trophoblast lineage determination, chorioallantoic fusion and placental branching morphogenesis. However, the role of the pathway in human placentation, trophoblast development and differentiation is only partly understood. Here, we summarize our present knowledge about Wnt signaling in the human placenta and discuss its potential role in physiological and aberrant trophoblast invasion, gestational diseases and choriocarcinoma formation. Differentiation of proliferative first trimester cytotrophoblasts into invasive extravillous trophoblasts is associated with nuclear recruitment of β -catenin and induction of Wnt-dependent T-cell factor 4 suggesting that canonical Wnt signaling could be important for the formation and function of extravillous trophoblasts. Indeed, activation of the pathway was shown to promote trophoblast invasion in different in vitro trophoblast model systems as well as trophoblast cell fusion. Methylation-mediated silencing of inhibitors of Wnt signaling provided evidence for epigenetic activation of the pathway in placental tissues and choriocarcinoma cells. Similarly, abundant nuclear expression of β -catenin in invasive trophoblasts of complete hydatidiform moles suggested a role for hyper-activated Wnt signaling. In contrast, upregulation of Wnt inhibitors was noticed in placentae of women with preeclampsia, a disease characterized by shallow trophoblast invasion and incomplete spiral artery remodeling. Moreover, changes in Wnt signaling have been observed upon cytomegalovirus infection and in recurrent abortions. In summary, the current literature suggests a critical role of Wnt signaling in physiological and abnormal trophoblast function.

Keywords: Wnt; human; invasion; placenta; trophoblast.

FIGURE 1

Critical steps of human placental development. (A) After implantation stems cells of the trophectoderm give rise to the primitive syncytium by cell fusion. In this region lacunae, the ancestor of the intervillous space, are formed. Some of the lacunae erode uterine vessels. (B) At a subsequent stage, proliferative cytotrophoblasts (CTBs) emanate from the trophectoderm, break through the primitive syncytium and contact the basal plate thereby forming primary villi. (C) Tertiary villi are built upon migration of extraembryonic mesodermal cells into the primary structures and vascularization. At distal sites, proliferative cell columns are formed which give rise to different invasive extravillous trophoblast subtypes. iCTBs migrate into decidual stroma approach vessels from outside and eventually form giant cells as the end stage of the invasive differentiation pathway. Endovascular trophoblasts migrate into spiral arteries and contribute to uNK cell-initiated remodeling within the decidua and the upper part of the myometrium. AE, amniotic epithelium; CCT, cell column trophoblast; DF, decidual fibroblast; EB, embryoblast; EM, extraembryonic mesoderm; eCTB, endovascular cytotrophoblast; GC, giant cell; ICM, inner cell mass, iCTB, interstitial cytotrophoblast; LUE, luminal uterine epithelium; L, lacunae, pF, placental fibroblast; PS, primitive syncytium; pV, placental vessel; SA, spiral artery; S, syncytium; TE, trophectoderm; UG, uterine gland; uNK, uterine NK cell; UV, uterine vessel; vCTB, villous cytotrophoblast.

FIGURE 2

Schematic illustration of transcript levels encoding Wnt ligands and Fzd receptors in isolated human first trimester CTBs and EVTs measured by semi-quantitative RT-PCR as published elsewhere (Sonderegger et al., 2007). Low, medium and high levels of expression are indicated by one, two and three black squares, respectively.

FIGURE 3

Color-coded mRNA expression (GDS3523) in non-invasive CTBs (5 pools) and invasive EVTs (6 pools) analyzed by GEO DataSet Cluster Analysis online tool (). Markers of EVT differentiation, Fzd receptors, putative TCF-4/β -catenin target genes as well as biomarkers of EMT are depicted.

FIGURE 4

Model system for the role of Wnt signaling in function and differentiation of the human anchoring villus. Wnt ligands and Fzd receptors expressed in vCTBs/CCTs and EVTs are shown. During EVT formation, Wnt7b, Wnt9b, Wnt10a, Wnt10b, Fzd5, and Fzd10 are down-regulated suggesting a role in trophoblast proliferation. However, interstitial cytotrophoblasts (iCTBs) upregulate TCF-4 and nuclear β -catenin to promote trophoblast motility and possibly EVT differentiation.