Abstract
Infertility is constantly increasing in Canada, where 16% of Canadian couples are experiencing difficulty conceiving. It is thought that infertility can emanate from the dysregulated communication between the embryo and the maternal endometrium. In order to allow for this window of implantation to be open at the right moment, endometrial stromal cells proliferate and differentiate by a mechanism called decidualization. Intracellular and molecular mechanisms involved in the regulation of apoptosis and cell proliferation during decidualization of the endometrium are yet to be fully understood. It has been well demonstrated previously that Akt is importantly involved in cell survival and glycogen synthesis. Akt1, Akt2 and Akt3 isoforms have distinct physiological roles; this could also be the case during decidualization and pregnancy. The aim of this study is to investigate the regulation of PI3K/Akt pathway during the decidualization process of endometrial stromal cells. Expression of Akt isoforms, Akt activity (phospho-Akt), pIκB and substrates of Akt during decidualization were measured. To our knowledge, these results are the first to suggest a decrease in levels of Akt isoforms as well as a downregulation of Akt activity in the process of decidualization of human endometrial stromal cells. We also uncovered that decidualization induced nuclear localization of p65 through the phosphorylation of IκB, its inhibitory subunit; however, Par-4, a recently uncovered regulator of cell differentiation, was displaced from the nucleus upon decidualization. Our results also suggest that HIESC cells exhibit decreased motility during decidualization and that PI3K pathway inhibition could be involved in this process. Finally, we demonstrate that specific Akt isoforms present unique effects on the successful induction of decidualization. Further analyses will involve investigations to understand the precise signaling mechanisms by which this pathway is regulated.
Highlights
Infertility is a problem that increasingly afflicts Canadian; in 2012, 16% of Canadian couples were found to have difficulties conceiving, a number that has doubled in the last 30 years[1]
Densitometric analyses of qRT-PCR analysis revealed a significant increased expression of insulin growth factor binding protein-1 (IGFBP1) (Fig 1B) mRNA following cAMP+medroxyprogesterone acetate (MPA) treatments; on the other hand, the decidualization treatment significantly stimulated the secretion of PRL, a decidual marker of crucial importance, to its maximum on day 6 (12,69 ± 2.07 ng/mL) PRL decreased to reach 5,55 ± 2,04 ng/mL on day 9 (Fig 1C)
In order to ascertain that the increased expression of PRL and IGFBP1 mRNA was truly caused by the concomitant use of both cAMP and MPA and not their singular use, further RT-qPCR experiments were conducted
Summary
Infertility is a problem that increasingly afflicts Canadian; in 2012, 16% of Canadian couples were found to have difficulties conceiving, a number that has doubled in the last 30 years[1]. During the late secretory phase of the menstrual cycle, endometrial stromal cells proliferate and differentiate by undergoing decidualization, a fundamental mechanism responsible for major changes in those cell phenotypes; morphological transformations occur to the fibroblast-like endometrial stromal cells that differentiate into polygonal, epithelial-like cells, becoming enlarged with lipids and glycogen secretions [2, 3]. This process of cellular differentiation is characteristic of mesenchymal to epithelial transition (MET) [4] and is confirmable by the decreased expression of mesenchymal markers such as Slug, Snail or Vimentin[5]. It allows the endometrium to become receptive to embryonic signaling that precedes and favorize implantation [9]
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