Developmental cell biology of human villous trophoblast: current research problems

The common gestational pathologies are placental and developmental in origin. However, much remains to be learned about the key events of morphogenesis and growth in the placenta. Metabolic settings established early in both the fetus and placenta define their capacity to respond to later challenges, as well as the quality of the response. Placental growth is exponential in the first trimester and involves coordinated events in trophoblast and mesenchyme, with early cell segregation events having a strong influence on growth potential. One of these is the differentiation of progenitor cytotrophoblasts into villous intermediate cells programmed to fuse with the syncytium, or, alternatively, into extravillous migratory cells that transform the maternal vascular supply. In the latter case, contact with decidual extracellular matrix stimulates differentiation, and therefore this decision is influenced by the number of contact sites at the placental periphery, which in turn is a function of branching in the villous tree. The villous trophoblast bilayer is the primary barrier between maternal and fetal tissues. The maternal-facing layer is syncytial and post-mitotic: this limits traffic of pathogens to the fetus and chimaerism arising by shedding of (non-proliferative) syncytial elements into maternal circulation. Conventional cell culture models fail to replicate this critical vectorial relationship. Tissue explants can overcome the problem to some extent, and have been used to show that turnover of trophoblast in the villous environment is regulated by signals from both fetal and maternal tissues. Maternally delivered insulin-like growth factors stimulate growth and might be therapeutically useful when endogenous growth pathways falter.