Regulation of trophoblast differentiation by the PI3-K/Akt signaling pathway

Abstract

Trophoblast cells are essential for the establishment and maintenance of pregnancy. In rodents, trophoblast giant cells are located at the maternal-embryonic interface and represent one of the major endocrine cell types of the rodent placenta. The endocrine phenotype of trophoblast giant cells includes production of peptide and steroid hormones. In this study we evaluate the role of the PI3-K/Akt signaling pathway in regulation of the endocrine phenotype of trophoblast giant cells. This study employed the Rcho-1 trophoblast cells as an in vitro trophoblast cell model system. Rcho-1 trophoblast cells can be maintained in a stem cell state or induced to differentiate along the trophoblast giant cell lineage. Inhibition of the PI3-K/Akt signaling pathway in Rcho-1 cells leads to decreased expression of peptide hormones: placental lactogen II and prolactin-like-protein A. Other peptide hormones such as placental lactogen I are unaffected. Likewise, disruption of the PI3-K/Akt signaling pathway significantly inhibited Rcho-1 trophoblast cell production of androstenedione, as measured by radioimmunoassay. Inhibition of the PI3-K/Akt pathway also significantly interfered with the expression of genes encoding key regulatory proteins controlling androstenedione biosynthesis and metabolism, including 3-beta hydroxysteroid dehydrogenase, 17-alpha hydroxylase and 17-beta hydroxysteroid dehydrogenase. The expression of other genes encoding regulatory proteins controlling steroidogenesis (StAR and cytochrome P450 side-chain cleavage) was not significantly altered by inhibition of this pathway. In summary, the PI3-K/Akt signaling pathway participates in the regulation of the trophoblast giant cell endocrine phenotype and potentially the maintenance of pregnancy.