The human placenta and its role in reproductive outcomes revisited

The placenta performs many key tasks which are essential for healthy growth and development of the human fetus. Placental dysfunction has multiple manifestations but they share the common property of lacking mechanistic understanding of etiology. The clinical consequences of placental dysfunction are a major determinant of the global burden of disease. Currently, the primary clinical method for assessing placental function is ultrasonic Doppler flow velocimetry of the umbilical and uterine arteries. More recently, some biomarkers have emerged which can predict or diagnose placentally-related complications of pregnancy. However, methods for identifying and characterizing placental dysfunction have developed relatively little over the last 20 years and perform poorly, and there remains an absence of disease modifying therapies targeted at the placenta. Understanding disease mechanisms is made more difficult due to the profound differences in pregnancy and placentation comparing humans and the most commonly used laboratory animals, limiting the utility of animal models. Use of omics methods in human samples may yield progress: omics analyses of maternal blood shows promise in identifying better predictors of disease and single cell analyses, including spatial omics of healthy and abnormal placentas, could identify therapeutic targets. Limitations in cellular models of the placenta have been significantly overcome in the last five to ten years by the development of human cell models, including human trophoblast stem cells and organoids, and use of these model systems may allow hypothesis testing experiments in a more clinically relevant context than animal models or immortalized cell lines.