The development of a platform mimicking the human placental barrier
Overview: The placenta is a highly specialized organ that plays an integral role in the development and maintenance of pregnancy. Its most important function is exchange of endogenous and exogenous substances, which enables adequate supply of oxygen and nutrients, excretion of fetal metabolic waste, and protection against potentially harmful agents, such as pathogens, including the recently identified vertical transmission of Zika virus (ZIKV) as a cause of microcephaly and other birth defects in neonates. Transfer of substances between the intervillous space and fetal capillaries takes place across a multilayered structure often called the “placenta barrier”, which is composed of trophoblasts, connective tissue, basal lamina and fetal endothelium. The other major functions of placenta include the production of hormones and a key immunological mediator during pregnancy. The major hormones it produces are progesterone, estrogen, and chorionic gonadotropin (hCG)21 which serve to maintain a healthy pregnancy, to uphold an optimal environment within the physiology of the mother, and to prepare the mother for birth.
Studying the biology of the human placenta represents a major experimental challenge. Previous studies on placenta transport have used a wide range of experimental systems including in vivo animal models, ex vivo placental perfusion systems and in vitro cell cultures. A limitation of animals to model human pregnancy is that placental structure and function vary considerably among species, and current in vitro models have limited ability to dissect the process of placental transfer and to reveal mechanistic insights into its biological underpinnings. It is urgent to develop new models for real-time assessment of placental development and function during normal and abnormal pregnancies. Recently, a novel platform “placenta-on-a-chip” was developed using human cells which recapitulate the critical fetal maternal interface in the villous tree of the human placenta. This model mimics structural characteristics of the human placental barrier and some aspects of physiology. This model has potential to serve as a low-cost experimental platform with a broad range of applications. However, major limitations of this model are (1) use of JEG-3 or BeWo cell line to represent placental trophoblast cells, (2) limited characterization of its endocrine and immunologic function, (3) limited characterization of transport functions and effects of shear stress. JEG-3 and BeWo are human choriocarcinoma cell lines which still keep tumor properties, and, unlike primary cultures, do not spontaneously form syncytia without addition of forskolin27. These cell lines have limited capacity to model changes in placental barrier function during pregnancy. Using these cells raises questions about their ability to represent normal human cytotrophoblasts.
Objectives/Aims: Our study objectives are to develop a platform mimicking the human placental barrier based on the existing “placenta-on-a-chip” model using representative human trophoblasts and fetal capillary endothelial cells. Taking a step further, we will test this model for ZIKV transmission after complete characterization and validation of the developed model.