Critical growth factors and signalling pathways controlling human trophoblast invasion

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.