Villous trophoblast of human placenta: a coherent view of its turnover, repair and contributions to villous development and maturation.

A coherent view of human villous trophoblast as a continuously renewing epithelium is presented. Epithelia undergoing continuous renewal (e.g. intestinal mucosa, epidermis) display clonogenic cells which pass through several transit divisions before migrating out of proliferation zones and into zones of maturation/differentiation. Quantitative relations (e.g. relative numbers of cells) between proliferation and differentiation zones help to define the steady state and this may vary in response to physiological and pathological circumstances. From the differentiation compartment, cells or cell fragments are eventually extruded by mechanisms which may involve apoptosis. All these features are seen in trophoblastic epithelium. Cytotrophoblast cells (CT, proliferation zone) divide continuously throughout gestation and post-mitotic cells are recruited into syncytiotrophoblast (ST, differentiation zone) after membrane fusion. Evidence of fusion events includes localised confluence of CT and ST cytoplasms, and intrasyncytial plasma membrane segments bearing desmosomal remnants. During differentiation, nuclei undergo changes in shape, chromatin condensation and packing density. Densely-clustered nuclei are associated with cytokeratin intermediate filaments and annulate lamellae. Both clustered and non-clustered nuclei show ultrastructural features of pre-apoptosis and apoptosis. Normally, apoptosis is triggered only when nuclei are in the syncytium. Some (pre-)apoptotic nuclear aggregates are sequestered in syncytial knots, extruded as trophoblast fragments into the intervillous space and then deported into the maternal circulation to be phagocytosed at extraplacental sites. During gestation, there is some constancy in the numerical ratios between CT and ST nuclei pointing to a normal steady state. The steady state may be perturbed when the epithelium is damaged locally. Where the epithelium is denuded, fibrin-type fibrinoid from the intervillous space plugs the discontinuity and, with CT proliferation, facilitates reepithelialisation. Features of normal villous development (e.g. sprouting, intervillous bridge formation, bridge abruption, syncytial knot formation) are explicable in the context of trophoblast turnover with early CT proliferation being mainly for growth and later proliferation for renewal and repair. Adaptive re-settings of the epithelial steady state may also occur in abnormal pregnancies.