Transcriptome Analysis Reveals New Insights into the Modulation of Endometrial Stromal Cell Receptive Phenotype by Embryo-Derived Signals Interleukin-1 and Human Chorionic Gonadotropin: Possible Involvement in Early Embryo Implantation

Abstract

The presence of the conceptus in uterine cavity necessitates an elaborate network of interactions between the implanting embryo and a receptive endometrial tissue. We believe that embryo-derived signals play an important role in the remodeling and the extension of endometrial receptivity period. Our previous studies provided original evidence that human Chorionic Gonadotropin (hCG) modulates and potentiates endometrial epithelial as well as stromal cell responsiveness to interleukin 1 (IL1), one of the earliest embryonic signals, which may represent a novel pathway by which the embryo favors its own implantation and growth within the maternal endometrial host. The present study was designed to gain a broader understanding of hCG impact on the modulation of endometrial cell receptivity, and in particular, cell responsiveness to IL1 and the acquisition of growth-promoting phenotype capable of receiving, sustaining, and promoting early and crucial steps of embryonic development. Our results showed significant changes in the expression of genes involved in cell proliferation, immune modulation, tissue remodeling, apoptotic and angiogenic processes. This points to a relevant impact of these embryonic signals on the receptivity of the maternal endometrium, its adaptation to the implanting embryo and the creation of an environment that is favorable for the implantation and the growth of this latter within a new and likely hostile host tissue. Interestingly our data further identified a complex interaction between IL1 and hCG, which, despite a synergistic action on several significant endometrial target genes, may encompass a tight control of endogenous IL1 and extends to other IL1 family members.

Intrauterine infusion of human chorionic gonadotropin before embryo transfer in IVF/ET cycle: The critical review

“…44 The effect of recombinant hCG on endometrial cytokine production has been studied by using either in vitro culture model and in vivo intrauterine microdialysis in humans. 45 More recently, Akhilesh et al's study used a three-dimensional primary culture model to demonstrate that the administration of hCG resulted in significantly different cytokine secretion profiles in epithelial cells, in stromal cells and in mixed cells. 45 More recently, Akhilesh et al's study used a three-dimensional primary culture model to demonstrate that the administration of hCG resulted in significantly different cytokine secretion profiles in epithelial cells, in stromal cells and in mixed cells.…”

“…45 More recently, Akhilesh et al's study used a three-dimensional primary culture model to demonstrate that the administration of hCG resulted in significantly different cytokine secretion profiles in epithelial cells, in stromal cells and in mixed cells. 45,46 The regulation of hCG on angiogenic factors in human endometrium has been extensively characterized. The exact physiological role of hCG on endometrial cytokine profiles needs further in vivo studies since the inconsistent results have been observed previously.…”

“…39 It has been found that numerous cytokine genes involved in cell signaling, proliferation, apoptosis, immune modulation, tissue remodeling and angiogenesis were regulated directly or indirectly by hCG in human endometrial stromal cells. 45 More recently, Akhilesh et al's study used a three-dimensional primary culture model to demonstrate that the administration of hCG resulted in significantly different cytokine secretion profiles in epithelial cells, in stromal cells and in mixed cells. 46 However, these in vitro observations still cannot completely reflect the changes taking place in vivo.…”

Embryonic Diapause and Maternal Recognition of Pregnancy in Diapausing Mammals

“…These 229 genes consisted of major functional categories, including the cell cycle, cell signalling, adhesion molecules and metabolic pathways. One of the earliest genes upregulated at implantation is interleukin-1 (IL-1) of embryonic origin which modulates endometrial cell responsiveness (Bourdiec et al 2013 ). In mink, there are 123 genes differentially expressed between diapause and reactivation.…”

L’implantation embryonnaire

“…En effet, l'hCG serait responsable d'un déséquilibre dans l'expression des membres de la famille IL1 : elle favoriserait l'augmentation des récepteurs fonctionnels tout en diminuant, de façon concomitante, l'expression des récepteurs leurres et antagonistes, et modèrerait l'expression de l'IL1, de l'IL18 et de l'IL33 [19,47,48]. Il en résulterait une amplification synergique de certaines cibles moléculaires pertinentes pour la poursuite de l'implantation, telles que MCP1, VEGFC, RANTES (regulated upon activation normal T cell expressed and presumably secreted), VCAM1 (vascular cell adhesion molecule 1) et IL6 [19,47,49]. Ces facteurs sont impliqués dans la régulation de la réponse immunitaire, l'induction d'une tolérance immunitaire, le contrôle de l'angiogenèse locale et de l'immunotrophisme (voir note 2).…”