A human cytotrophoblast-villous endothelium-fetal organ multi-cell model and the impact on gene and protein expression in placenta cytotrophoblast, fetal hepatocytes and fetal kidney epithelial cells

Appropriate fetal growth during pregnancy requires multi-directional communication from the maternal, placental and fetal systems. Disruption in any of these signaling arms can have deleterious consequences for fetal growth and initiate developmental adaptations within fetal tissues and organs that are associated with both short- and long-term morbidities. In this proof-of-concept translational, human cell model study we aimed to identify the impacts of altered trophoblast stress response mechanisms and human insulin-like 1 growth factor ( hIGF1 ) nanoparticle gene therapy on gene and protein expression in fetal liver hepatocytes and fetal kidney epithelial cells. We utilized human cell lines: BeWo choriocarcinoma cells (trophoblast), Human Placental Micro-Vascular Endothelial Cells, and WRL68 (hepatocytes) or HEK293T/17 (kidney epithelium), in a co-culture model designed to mimic cytotrophoblast-villous endothelium-fetal organ communication. Trophoblast stress response mechanisms were increased by culturing BeWo cells in growth media without FBS. Stressed BeWo cells were also treated with a hIGF1 nanoparticle gene therapy known to mitigate cellular stress mechanisms. Stressed BeWo cells had increased expression of cellular stress mechanisms but not when IGF1 was over-expressed with a transient hIGF1 nanoparticle gene therapy. Stressed and Stressed+ hIGF1 BeWo cells had increased expression of gluconeogenesis and glycolysis rate-limiting enzymes. Gene and protein expression in fetal liver and kidney cells was not impacted by increased trophoblast stress or hIGF1 nanoparticle gene therapy. In conclusion, our data demonstrated that cytotrophoblast under stress turn on mechanisms involved in glucose production. Whether this is reflected in vivo remains uninvestigated but may represent a placental compensation mechanism in complicated pregnancies.