Cyclic decidualization of the human endometrium in reproductive health and failure.

Decidualization denotes the transformation of endometrial stromal fibroblasts into specialized secretory decidual cells that provide a nutritive and immunoprivileged matrix essential for embryo implantation and placental development. In contrast to most mammals, decidualization of the human endometrium does not require embryo implantation. Instead, this process is driven by the postovulatory rise in progesterone levels and increasing local cAMP production.

The motile and invasive capacity of human endometrial stromal cells: implications for normal and impaired reproductive function.

BACKGROUND Mechanisms underlying early reproductive loss in the human are beginning to be elucidated. The migratory and invasive capacity of human endometrial stromal cells (ESCs) is increasingly recognized to contribute to the intense tissue remodelling associated with embryo implantation, trophoblast invasion and endometrial regeneration. In this review, we examine the signals and mechanisms that control ESC migration and invasion and assess how deregulation of these cell functions contributes to common reproductive disorders.

Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors.

Human implantation involves extensive tissue remodeling at the fetal-maternal interface. It is becoming increasingly evident that not only trophoblast, but also decidualizing endometrial stromal cells are inherently motile and invasive, and likely contribute to the highly dynamic processes at the implantation site. The present study was undertaken to further characterize the mechanisms involved in the regulation of endometrial stromal cell motility and to identify trophoblast-derived factors that modulate migration.

Human endometrial stromal cell-trophoblast interactions: mutual stimulation of chemotactic migration and promigratory roles of cell surface molecules CD82 and CEACAM1.

We have previously shown that the presence of trophoblast cells enhances invasiveness of decidualizing human endometrial stromal cells. The metastasis suppressor CD82, which has antimigratory function in tumor cells, is up-regulated in decidualizing endometrial stromal cells. CEACAM1 is expressed in trophoblast cells at the invasion front in early placenta and is considered proinvasive.

Endometrial stromal cells of women with recurrent miscarriage fail to discriminate between high- and low-quality human embryos.

Background: The aetiology of recurrent miscarriage (RM) remains largely unexplained. Women with RM have a shorter time to pregnancy interval than normally fertile women, which may be due to more frequent implantation of non-viable embryos. We hypothesized that human endometrial stromal cells (H-EnSCs) of women with RM discriminate less effectively between high-and low-quality human embryos and migrate more readily towards trophoblast spheroids than H-EnSCs of normally fertile women.

Expansion of human trophoblastic spheroids is promoted by decidualized endometrial stromal cells and enhanced by heparin-binding epidermal growth factor-like growth factor and interleukin-1 β.

Successful pregnancy in humans depends on deep invasion of the maternal decidua by extravillous trophoblast cells (EVTs), a process regulated by autocrine and paracrine signals in the decidual-trophoblast microenvironment. Here we examined whether trophoblast invasion is affected by decidual differentiation of endometrial stromal cells (ESC) and modulated locally by cytokines and growth factors. Trophoblast spheroids were generated from the EVT-derived cell line AC-1M88 and placed onto monolayers of either undifferentiated or decidualized ESC, or directly onto tissue culture surface.

HoxA-11 and FOXO1A cooperate to regulate decidual prolactin expression: towards inferring the core transcriptional regulators of decidual genes.

During the menstrual cycle, the ovarian steroid hormones estrogen and progesterone control a dramatic transcriptional reprogramming of endometrial stromal cells (ESCs) leading to a receptive state for blastocyst implantation and the establishment of pregnancy. A key marker gene of this decidualization process is the prolactin gene. Several transcriptional regulators have been identified that are essential for decidualization of ESCs, including the Hox genes HoxA-10 and HoxA-11, and the forkhead box gene FOXO1A.

Characterization of a novel telomerase-immortalized human endometrial stromal cell line, St-T1b.

Background: Coordinated differentiation of the endometrial compartments in the second half of the menstrual cycle is a prerequisite for the establishment of pregnancy. Endometrial stromal cells (ESC) decidualize under the influence of ovarian progesterone to accommodate implantation of the blastocyst and support establishment of the placenta. Studies into the mechanisms of decidualization are often hampered by the lack of primary ESC.

Adaptive changes in the transcription factor HoxA-11 are essential for the evolution of pregnancy in mammals.

Evolutionary change in gene regulation can result from changes in cis-regulatory elements, leading to differences in the temporal and spatial expression of genes or in the coding region of transcription factors leading to novel functions or both. Although there is a growing body of evidence supporting the importance of cis-regulatory evolution, examples of protein-mediated evolution of novel developmental pathways have not been demonstrated. Here, we investigate the evolution of prolactin (PRL) expression in endometrial cells, which is essential for placentation/pregnancy in eutherian mammals and is a direct regulatory target of the transcription factor HoxA-11.

Systematic expression analysis and antibody screening do not support the existence of naturally occurring progesterone receptor (PR)-C, PR-M, or other truncated PR isoforms.

Functional progesterone withdrawal associated with human parturition has been ascribed to various mechanisms modulating the function of the classical progesterone receptors (PRs), B and A, in utero. These include up-regulation of the inhibitory PR-C isoform, described as a 60-kDa protein occurring from translation initiation at codon 595. Our initial attempts to detect PR-C yielded uninterpretable results.

Honey, we need to talk about the membrane progestin receptors.

The recent discovery of three closely related cell surface receptors that bind to progesterone and mediate its actions on various cytoplasmic signalling cascades has been heralded as a major break-through. The reason for this is all too obvious. Progesterone is an essential regulator of all major reproductive events and progestins and antiprogestins are widely used in the treatment of many different gynaecological and obstetrical disorders.

Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives.

The fetomaternal interface, consisting of the maternal decidua and the invading fetal trophoblast, critically regulates placental function and the growth and development of the conceptus. In its broadest sense, decidualization could be viewed as the postovulatory process of endometrial remodeling in preparation for pregnancy, which includes secretory transformation of the uterine glands, influx of specialized uterine natural killer cells, and vascular remodeling. A more restricted definition of the decidual process denotes the morphological and biochemical reprogramming of the endometrial stromal compartment.

Expression of the metastasis suppressor KAI1 in decidual cells at the human maternal-fetal interface: Regulation and functional implications.

At the human maternal-fetal interface, the decidua forms a dense matrix that is believed to limit trophoblast invasion. We investigated whether the metastasis suppressor KAI1 (CD82) is expressed at the maternal-fetal interface. Immunohistochemistry showed strong expression of KAI1 in decidual cells, whereas trophoblast cells were negative for KAI1.

Human homologs of the putative G protein-coupled membrane progestin receptors (mPRalpha, beta, and gamma) localize to the endoplasmic reticulum and are not activated by progesterone.

The steroid hormone progesterone exerts pleiotrophic functions in many cell types. Although progesterone controls transcriptional activation through binding to its nuclear receptors, it also initiates rapid nongenomic signaling events. Recently, three putative membrane progestin receptors (mPRalpha, beta, and gamma) with structural similarity to G protein-coupled receptors have been identified.

Functional characterization of male germ cell-specific CREM isoforms.

Due to alternative promoter usage, splicing, and translational initiation, expression of the cAMP-responsive element modulator (CREM) gene results in the production of functionally different CREM proteins with either activating or repressing potential on target gene expression. Recently, we demonstrated 2 novel isoforms (CREM-2-F-G-H-Ib and CREM-2-G-H-Ib) in various germ cell types during normal and impaired human spermatogenesis. In contrast to known isoforms, these exhibit a transactivation domain but lack a kinase-inducible domain (KID) domain resulting in a disruption of the open reading frame.

Physical interaction and mutual transrepression between CCAAT/enhancer-binding protein beta and the p53 tumor suppressor.

The tumor suppressor protein p53 is not only involved in defending cells against genotoxic insults but is also implicated in differentiation processes, a function that it shares with the CCAAT/enhancer-binding protein beta (C/EBPbeta). We previously reported an up-regulation of both factors in the cycle-dependent differentiation process of human endometrial stromal cells, termed decidualization. C/EBPbeta-mediated activation of a decidualization marker, the decidual prolactin promoter, was antagonized by p53.

Mechanism of prostaglandin (PG)E2-induced prolactin expression in human T cells: cooperation of two PGE2 receptor subtypes, E-prostanoid (EP) 3 and EP4, via calcium- and cyclic adenosine 5'-monophosphate-mediated signaling pathways.

We previously reported that prolactin gene expression in the T-leukemic cell line Jurkat is stimulated by PGE(2) and that cAMP acts synergistically with Ca(2+) or protein kinase C on the activation of the upstream prolactin promoter. Using the transcription inhibitor actinomycin D, we now show that PGE(2)-induced prolactin expression requires de novo prolactin mRNA synthesis and that PGE(2) does not influence prolactin mRNA stability. Furthermore, PGE(2)-induced prolactin expression was inhibited by protein kinase inhibitor fragment 14-22 and BAPTA-AM, which respectively, inhibit protein kinase A- and Ca(2+)-mediated signaling cascades.

Wild-type p53 protein is up-regulated upon cyclic adenosine monophosphate-induced differentiation of human endometrial stromal cells.

Decidualization of the endometrial stromal compartment is critical for embryo implantation. Initiation of this differentiation process requires elevated intracellular cAMP levels. We now report a massive and sustained up-regulation of p53 tumor suppressor protein during cAMP-induced decidualization of cultured endometrial stromal cells.

Expression pattern of the CCAAT/enhancer-binding proteins C/EBP-alpha, C/EBP-beta and C/EBP-delta in the human placenta.

The human trophoblast has the capacity to invade maternal tissue in a controlled fashion and to produce a wide range of hormones. The transcription factors belonging to the CCAAT/enhancer-binding protein (C/EBP) family are regulators of intracellular processes and mediators of hormone action. C/EBP binding sites have been described in the promoters of several placenta-expressed target genes.

Promyelocytic leukaemia zinc finger protein (PLZF) is a glucocorticoid- and progesterone-induced transcription factor in human endometrial stromal cells and myometrial smooth muscle cells.

The promyelocytic leukaemia zinc finger (PLZF) protein belongs to the family of Krüppel-like zinc finger proteins. It is a transcriptional repressor involved in cell cycle control and has been implicated in limb development, differentiation of myeloid cells, and spermatogenesis. Little is known about the regulation of PLZF expression.

Novel leader exons of the cyclic adenosine 3',5'-monophosphate response element modulator (CREM) gene, transcribed from promoters P3 and P4, are highly testis-specific in primates.

Testicular expression of CREM is essential for spermatogenesis in the mouse. From a monkey testis cDNA library we isolated a CREM transcript isoform with a novel 5' exon theta2 which provides at its 3'-end an in-frame ATG to the downstream reading frame. 5'-RACE on human testis cDNA indicated that exon theta2 is > or = 113 bp in size.

Cyclic AMP-induced forkhead transcription factor, FKHR, cooperates with CCAAT/enhancer-binding protein beta in differentiating human endometrial stromal cells.

Decidual transformation of human endometrial stromal (ES) cells requires sustained activation of the protein kinase A (PKA) pathway. In a search for novel transcriptional mediators of this process, we used differential display PCR analysis of undifferentiated primary ES cells and cells stimulated with 8-bromo-cAMP (8-Br-cAMP). We now report on the role of forkhead homologue in rhabdomyosarcoma (FKHR), a recently described member of the forkhead/winged-helix transcription factor family, as a mediator of endometrial differentiation.

Functional association of PR and CCAAT/enhancer-binding protein beta isoforms: promoter-dependent cooperation between PR-B and liver-enriched inhibitory protein, or liver-enriched activatory protein and PR-A in human endometrial stromal cells.

Activation of the decidual PRL (dPRL) promoter, a major differentiation marker in human endometrial stromal (ES) cells, by cAMP is effected through the induction and binding of CCAAT/enhancer-binding protein-beta (C/EBPbeta) to two overlapping cognate response elements in the promoter region dPRL-332/-270. Progesterone is essential for decidualization and potently enhances cAMP-dependent dPRL promoter activity. We now demonstrate that both liganded PR isoforms, PR-A and PR-B, are capable of trans-activating the dPRL-332/-270 region.