Abstract

Pluripotent Human Stem Cells as Models For Creating Placental Syncytiotrophoblast, The Major Cellular Barrier that Limits Fetal Exposure to Xenobiotics

Toshihiko Ezashi, Research Associate Professor, The University of Missouri

The placenta provides the interface between the separate blood circulations of the mother and the fetus and has roles in controlling the movement of a variety of compounds, including dissolved nutrients and gases, between the two systems. It is also the barrier that limits direct exposure of the fetus to foreign chemicals circulating in maternal blood. The surface of the human placenta that makes direct contact with maternal blood, even in the earliest stages of pregnancy, is comprised of syncytiotrophoblast (STB), a multi-nucleated cell layer formed by fusion of underlying, proliferating cytotrophoblast. Pluripotent human stem cells can be differentiated efficiently towards placental trophoblast by exposure to BMP4 in presence of low molecular weight inhibitors of FGF2 and AVTIVIN/TGFB signaling. Within 48 h, the cells have lost their pluripotent phenotype and display marker features of trophoblast. By 5 days they begin to release hCG and progesterone and demonstrate the initiation of STB formation at discrete regions within the colonies. By day 7-8 it becomes possible to isolate sheets of syncytium. Transcriptome profiling reveals that these cells express a full complement of marker genes for STB, as well as an up-regulation of many others known to be involved in the metabolism, transport, and sequestering of xenobiotics, drugs and heavy metals. The model will provide a means of assessing how STB responds to exposure to xenobiotics and other foreign chemicals through changes in its normal developmental phenotype, including gene expression patterns.