Critical growth factors and signalling pathways controlling human trophoblast invasion

Abstract

Invasion of placental trophoblasts into uterine tissue and vessels is an essential process of human pregnancy and fetal development. Due to their remarkable plasticity invasive trophoblasts fulfil numerous functions, i.e. anchorage of the placenta, secretion of hormones, modulation of decidual angiogenesis/lymphangiogenesis and remodelling of maternal spiral arteries. The latter is required to increase blood flow to the placenta, thereby ensuring appropriate transfer of nutrients and oxygen to the developing fetus. Since failures in vascular changes of the placental bed are associated with pregnancy diseases such as preeclampsia or intrauterine growth restriction, basic research in this particular field focuses on molecular mechanisms controlling trophoblast invasion under physiological and pathological conditions. Throughout the years, an increasing number of growth factors, cytokines and angiogenic molecules controlling trophoblast motility have been identified. These factors are secreted from numerous cells such as trophoblast, maternal epithelial and stromal cells, as well as uterine NK cells and macrophages, suggesting that a complex network of cell types, mediators and signalling pathways regulates trophoblast invasiveness. Whereas essential features of the invasive trophoblast such as expression of critical proteases and adhesion molecules have been well characterised, the interplay between different cell types and growth factors and the cross-talk between distinct signalling cascades remain largely elusive. Similarly, key-regulatory transcription factors committing and differentiating invasive trophoblasts are mostly unknown. This review will summarise our current understanding of growth factors and signal transduction pathways regulating human trophoblast invasion/migration, as well as give insights into novel mechanisms involved in the particular differentiation process.

Fig. 1. Invasive differentiation of human trophoblast

After anchorage of a mesenchymal villus (formation of anchoring villi, AV) at the uterine basement membrane villous cytotrophoblast (vCTB) precursor cells give rise to proliferative cell columns (CC). At distal sites non-proliferating, extravillous trophoblasts are formed which detach from the cell columns and migrate into stromal areas of the maternal decidua (D), i.e. formation of interstitial cytotrophoblasts (iCTB). iCTB differentiate into giant cells (GC) in deeper areas of the placental bed. Endovascular trophoblasts (eCTB) migrate into spiral arteries (SA) within the decidua and inner third of the myometrium (M), replace maternal endothelial cells (EC) and acquire endothelial characteristics. In floating villi (FV) surrounded by maternal blood of the intervillous space (IS), CTB progenitors fuse to build the multinucleated syncytium (S).

Fig. 2. Interplay between growth factors expressed at the fetal-maternal interface

Growth factor expression/secretion is stimulated by paracrine interactions of diverse maternal and placental cell types. Predominant growth factors of the fetal-maternal interface as well as their mutual stimulations published so far are summarised. With the exception of TGFβ all factors depicted were shown to positively influence trophoblast proliferation and/or migration/invasion. Some soluble ligands such as hCG may play key roles in trophoblast motility since several growth factors trigger their secretion. On the other hand, hCG for example may also promote trophoblast migration through elevation of vEGF and LIF secretion. Hence, when studying effects of a particular growth factor on trophoblast migration direct as well as indirect effects must be considered. Stimulating (arrows) as well as inhibitory effects on expression / secretion are depicted.

Fig. 3. Schematic presentation of signalling pathways stimulating trophoblast migration and/or invasion

Growth factors acting through these pathways are indicated. Sequential signalling steps resulting in phosphorylation (arrows) or dephosphorylation of downstream kinases or other protein targets (STAT, β-catenin) are depicted. Several critical factors such as EGF, IGFs, hCG or WNT signal through more than one pathway.