Regulation of Pregnancy: Evidence for Major Roles by the Uterine and Placental Kisspeptin/KISS1R Signaling Systems

2019 ◽  
Vol 37 (04) ◽  
pp. 182-190 ◽  
Author(s):  
Sally Radovick ◽  
Andy V. Babwah
Keyword(s):  
Stromal Cells ◽  
Pregnancy Loss ◽  
Therapeutic Agent ◽  
Recurrent Pregnancy Loss ◽  
Embryo Implantation ◽  
Extravillous Trophoblast ◽  
Migration And Invasion ◽  
Decidual Cell ◽  
Signaling Systems ◽  
Placental Invasion

AbstractSeveral studies provide strong evidence suggesting that in addition to central kisspeptin/KISS1R signaling, the peripheral uterine- and placental-based kisspeptin/KISS1R signaling systems are major regulators of pregnancy. Specifically, the evidence suggests that the uterine-based system regulates embryo implantation and decidualization, while both the uterine- and placental-based systems regulate placentation. Uterine kisspeptin and KISS1R regulate embryo implantation by controlling the availability of endometrial glandular secretions, like leukemia inhibitory factor, which are essential for embryo adhesion to the uterine epithelium. As for decidualization, the data suggest that decidualized stromal cells express KISS1R and secrete kisspeptin-inhibiting decidual cell motility and thereby indirectly regulate embryo and placental invasion of the uterus. Similarly, for placentation, placental kisspeptin and KISS1R negatively regulate extravillous trophoblast migration and invasion and thereby directly control placental invasion of the uterus. Having recognized a significant role for the uterine- and placental-based kisspeptin/KISS1R signaling systems regulating pregnancy, the future looks promising for the development of kisspeptin and KISS1R as prognostic and diagnostic markers of pregnancy disorders and the use of kisspeptin as a therapeutic agent in the prevention and treatment of conditions such as recurring implantation failure, recurrent pregnancy loss, and preeclampsia.

scholarly journals Immunoregulation of the decidualization program: focus on the endoplasmic reticulum stress

Reproduction ◽  
2020 ◽  
Vol 159 (4) ◽  
pp. R203-R211 ◽  
Author(s):  
Elizabeth Soczewski ◽  
Esteban Grasso ◽  
Lucila Gallino ◽  
Vanesa Hauk ◽  
Laura Fernández ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Inflammatory Response ◽  
Er Stress ◽  
Stromal Cells ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Embryo Implantation ◽  
Endometrial Stromal Cells ◽  
Unfolded Protein ◽  
Protein Response

Decidualization denotes the reprogramming of endometrial stromal cells that includes the secretion of different mediators like cytokines, chemokines, and the selective recruitment of immune cells. This physiological process involves changes in the secretome of the endometrial stromal cells leading to the production of immunomodulatory factors. The increased amount of protein secretion is associated with a physiological endoplasmic reticulum (ER) stress and the resulting unfolded protein response (UPR), allowing the expansion of ER and the machinery to assist the protein folding. Notably, the signaling pathways involved in the ER stress and the UPR are interconnected with the onset of a sterile inflammatory response, as well as with angiogenesis. Both of these processes have a key role in decidualization and placentation, therefore, alterations in them could lead to pregnancy complications. In this review, we will discuss how the induction of ER stress and the UPR processes that accompanies the decidualization are associated with embryo implantation and whether they might condition pregnancy outcome. The ER stress activates/triggers sensing proteins which, among others, induces kinase/RNAse-TXNIP expression, activating the NLRP3 inflammasome. This multiprotein system allows caspase-1 activation, which catalyzes the cleavage of the inactive IL-1β proform toward the mature secretory form, with pro-implantatory effects. However, the sterile inflammatory response should be later controlled in favor of a tolerogenic microenvironment to sustain pregnancy. In accordance, alterations of the ER stress and UPR processes can be reflected in recurrent implantation failures (RIF), recurrent pregnancy loss (RPL), or complications associated with deficient placentation, such as preeclampsia (PE).

scholarly journals Environmental Pollutant Benzo[a]pyrene Induces Recurrent Pregnancy Loss through Promoting Apoptosis and Suppressing Migration of Extravillous Trophoblast

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Yang Ye ◽  
Sushi Jiang ◽  
Chao Zhang ◽  
Yanxiang Cheng ◽  
Huan Zhong ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Environmental Pollutant ◽  
Extravillous Trophoblast ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Study Results ◽  
Before And After ◽  
Dose Dependent

Objects. To investigate the effects of environmental pollutant benzo(a)pyrene (BaP) and its metabolite benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) on human trophoblasts and on murine miscarriages. Methods. The implantation sites, fetus resorption, and abnormal fetuses were studied in pregnant mice treated with different doses of BaP by oral gavage from day 1 to day 10 of gestation. Additionally, apoptosis and related signaling pathway, and the migration and invasion of trophoblasts, were assessed before and after exposure of BPDE in Swan 71 trophoblast cell. Besides, the migration and invasion, and its related signaling pathway, were assessed in villi obtained from women. Results. We observed a concentration-dependent incidence of abnormal murine fetuses, beginning with 0.1 mg/kg BaP; with a BaP concentration of 2 mg/kg, no fetuses developed. Correspondingly, a BPDE concentration-dependent apoptosis of human trophoblasts. Beginning with 0.5 μM BPDE exposure, Bax/Caspase-3 were increased and Bcl-2 decreased. Furthermore, BPDE also inhibited, in a dose-dependent manner, the migration of villous explants from elective abortion women, consistent with the reduced migration of villous explants from women with recurrent pregnancy loss (RPL), and reduced the cell immigration in Swan 71 trophoblasts, in a dose-dependent manner measured by transwell assays. Conclusions. Our study results provide mechanistic insight to the effect of BPDE on trophoblast dysfunction through enhanced cell apoptosis and inhibited migration, providing further experimental evidence to the causative links between BaP exposure and PRL.

scholarly journals Disordered IL-33/ST2 Activation in Decidualizing Stromal Cells Prolongs Uterine Receptivity in Women with Recurrent Pregnancy Loss

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e52252 ◽  
Author(s):  
Madhuri S. Salker ◽  
Jaya Nautiyal ◽  
Jennifer H. Steel ◽  
Zoe Webster ◽  
Sandra Šućurović ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Uterine Receptivity

scholarly journals Kisspeptin regulation of human decidual stromal cells motility via FAK–Src intracellular tyrosine kinases

2019 ◽  
Vol 34 (7) ◽  
pp. 1291-1301 ◽  
Author(s):  
H-M Wu ◽  
H-Y Huang ◽  
Y-K Soong ◽  
P C K Leung ◽  
H-S Wang
Keyword(s):  
Cell Motility ◽  
Stromal Cells ◽  
Tyrosine Kinases ◽  
Intracellular Signaling ◽  
Conflicts Of Interest ◽  
Embryo Implantation ◽  
Extravillous Trophoblast ◽  
Clinical Genetics ◽  
Small Interfering Rnas ◽  
Human Pregnancy

Abstract STUDY QUESTION Can of Clinical Genetics, Maastricht University Medical Centre, Maastricht kisspeptin and its analogues regulate the motility of human decidual stromal cells and what intracellular signaling pathways are involved? SUMMARY ANSWER Kisspeptin analogue–mediated cell motility in human decidual stromal cells via the focal adhesion kinase (FAK)–steroid receptor coactivator (Src) pathway suggesting that kisspeptin may modulate embryo implantation and decidual programming in human pregnancy. WHAT IS KNOWN ALREADY The extravillous trophoblast invades the maternal decidua during embryo implantation and placentation. The motile behavior and invasive potential of decidual stromal cells regulate embryo implantation and programming of human pregnancy. STUDY DESIGN, SIZE, DURATION Human decidual stromal cells were isolated from healthy women undergoing elective termination of a normal pregnancy at 6- to 12-week gestation, after informed consent. PARTICIPANTS/MATERIALS, SETTING, METHODS Kisspeptin analogues were synthetic peptides. Cell motility was estimated by an invasion and migration assay. Immunoblot analysis was performed to investigate the expression of kisspeptin receptor and the effects of kisspeptin analogues on the phosphorylation of FAK and Src. Small interfering RNAs (siRNAs) were used to knock down the expression of kisspeptin receptor, FAK, Src, matrix metallo-proteinases (MMPs) 2 and 9, and extracellular signal-regulated protein kinase (ERK) 1/2. MAIN RESULTS AND THE ROLE OF CHANCE The kisspeptin receptor was expressed in human decidual stromal cells. Kisspeptin agonist decreased, but antagonist increased, cell motility. Kisspeptin agonist decreased the phosphorylation of FAK and Src tyrosine kinases, whereas antagonist increased it. These effects on phosphorylation were abolished by kisspeptin receptor siRNA. The activation of cell motility by kisspeptin analogues was suppressed by siRNA knockdown of endogenous FAK (decreased 66%), Src (decreased 60%), kisspeptin receptor (decreased 26%), MMP-2 (decreased 36%), MMP-9 (decreased 23%), and ERK 1/2 inhibitor (decreased 27%). LIMITATIONS, REASONS FOR CAUTION Human decidual stromal cells were obtained from women having terminations after 6–12 weeks of pregnancy and differences in timing could affect their properties. WIDER IMPLICATIONS OF THE FINDINGS Kisspeptin acting within the endometrium has a potential modulatory role on embryo implantation and decidual programming of human pregnancy. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grant NSC-104-2314-B-182A-146-MY2 (to H.-M.W.) from the Ministry of Science and Technology, Taiwan, and grants CMRPG3E0401 and CMRPG3E0402 (to H.-M.W.). This work was also supported by grants from the Canadian Institutes of Health Research to P.C.K.L. P.C.K.L. is the recipient of a Child & Family Research Institute Distinguished Investigator Award. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER N/A.

scholarly journals Expression of ADAMTS13 in human endometrium and its potential role in recurrent pregnancy loss

2021 ◽  
Author(s):  
Yun Feng ◽  
Xueyin Li ◽  
Xi Chen ◽  
Mengling Zhao ◽  
Qian Wang ◽  
...  
Keyword(s):  
Pregnancy Loss ◽  
Molecular Mechanisms ◽  
Recurrent Pregnancy Loss ◽  
Gene Knockout ◽  
Embryo Implantation ◽  
Human Endometrium ◽  
Control Group ◽  
Expression Levels ◽  
Knockout Animal ◽  
Mrna And Protein Expression

IntroductionThe mechanisms underlying the pathogenesis of recurrent pregnancy loss (RPL) and the effective approaches to treat this disease still remain vague and absent. Proteinases of ADAMTS family play important roles in embryonic growth and development. Our previous study suggest a role of ADAMTS13 during pregnancy. Current Study was to determine the expression of ADAMTS13 in human endometrium and its association with RPL.Material and methodsThe spatiotemporal expression of ADAMTS13 in human endometrium was examined by immunohistochemistry. real-time PCR sand western blot were then employed to determine the mRNA and protein expression levels of ADAMTS13 in human endometrium. Proteolytic cleavage of FRETS-VWF73 were performed to determine the activity of ADAMTS13 in plasma and that secreted by human endometrium. ELISA was carried out to measure plasma VWF antigen.ResultsWe show that proteolytically active ADAMTS13 is expressed in human endometrium throughout the menstrual cycle and pregnancy. The decidual expression levels of mRNA and protein in women with RPL were significantly lower compared with women with uncomplicated pregnancies (P<0.01, P<0.05, respectively). Furthermore, significantly reduced plasma ADAMTS13 activity (median [range] 69.09 [65.2–93.7]% versus 93.62 [88.1–115.6]%, P<0.001) and elevated plasma VWF antigen levels (median [range] of 125.5 [54.2–262.8]% versus 91.9[80.4–138.7]%, P < 0.01) were detected in RPL patients compared with the control group.ConclusionsThese findings suggest that ADAMTS13 may play a role in embryo implantation and the pathogenesis of recurrent pregnancy loss. Further investigation on ADAMTS13 gene knockout animal models is necessary for understanding the molecular mechanisms of the biological roles of ADAMTS13 during gestation.

scholarly journals A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system

Reproduction ◽  
2011 ◽  
Vol 141 (6) ◽  
pp. 715-724 ◽  
Author(s):  
J C Warning ◽  
S A McCracken ◽  
J M Morris
Keyword(s):  
Immune Cells ◽  
Vascular Remodeling ◽  
Pregnancy Loss ◽  
Extravillous Trophoblast ◽  
Successful Pregnancy ◽  
Temporal Regulation ◽  
Maternal Immune System ◽  
Inflammatory Processes ◽  
Maternal Immune Response ◽  
Placental Invasion

Successful pregnancy requires strict temporal regulation of maternal immune function to accommodate the growing fetus. Early implantation is facilitated by inflammatory processes that ensure adequate vascular remodeling and placental invasion. To prevent rejection of the fetus, this inflammation must be curtailed; reproductive immunologists are discovering that this process is orchestrated by the fetal unit and, in particular, the extravillous trophoblast. Soluble and particulate factors produced by the trophoblast regulate maternal immune cells within the decidua, as well as in the periphery. The aim of this review is to discuss the action of recently discovered immunomodulatory factors and mechanisms, and the potential effects of dysregulation of such mechanisms on the maternal immune response that may result in pregnancy loss or preeclampsia.

scholarly journals Rapamycin Corrects T Regulatory Cell Depletion and Improves Embryo Implantation and Live Birth Rates in a Murine Model

2019 ◽  
Vol 26 (12) ◽  
pp. 1545-1556 ◽  
Author(s):  
Greene Donald Royster ◽  
Justine C. Harris ◽  
Amanda Nelson ◽  
Yessenia Castro ◽  
R. Patrick Weitzel ◽  
...  
Keyword(s):  
Murine Model ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Embryo Implantation ◽  
Mammalian Target Of Rapamycin ◽  
Unexplained Infertility ◽  
Implantation Failure ◽  
T Regulatory Cell ◽  
Recurrent Implantation Failure ◽  
Regulatory Cell

There are few treatments for patients with recurrent pregnancy loss (RPL) or recurrent implantation failure (RIF). Women with RPL and unexplained infertility have lower T regulatory cell (Treg) expression when compared to fertile controls. A murine model has been developed with depletion of regulatory T cells (DEREG) after administration of diphtheria toxin (DT), resulting in smaller litter sizes, secondary to embryo implantation failure. Numerous murine studies have shown that adoptive transfer of CD4+CD25+FoxP3+ Tregs from donors improves litter sizes in DEREG mice with depleted Tregs. Our hypothesis is that DEREG mice treated with a single dose of DT will deplete Tregs and subsequently decrease litter sizes and that treatment with rapamycin (sirolimus; Pfizer) during the time of embryo implantation will increase Tregs and restore litter sizes nearly back to normal levels. Syngeneic mating of DEREG mice after depletion of Tregs resulted in smaller litter sizes and this defect was reversed when these DEREG mice were treated with rapamycin at the time of embryo implantation. The importance of Tregs at the time of embryo implantation has been well established and immunotherapy treatments, such as rapamycin (mammalian target of rapamycin inhibitor), may prove to be an effective treatment for patients with RPL, RIF, or unexplained infertility with low Treg.

scholarly journals Single-cell profiling of the human decidual immune microenvironment in patients with recurrent pregnancy loss

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Chuang Guo ◽  
Pengfei Cai ◽  
Liying Jin ◽  
Qing Sha ◽  
Qiaoni Yu ◽  
...  
Keyword(s):  
Single Cell ◽  
Immune Cells ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Immune Cell ◽  
Recurrent Miscarriage ◽  
Extravillous Trophoblast ◽  
Cellular Interactions ◽  
Immune Microenvironment ◽  
Immune Cell Subsets

AbstractMaintaining homeostasis of the decidual immune microenvironment at the maternal–fetal interface is essential for placentation and reproductive success. Although distinct decidual immune cell subpopulations have been identified under normal conditions, systematic understanding of the spectrum and heterogeneity of leukocytes under recurrent miscarriage in human deciduas remains unclear. To address this, we profiled the respective transcriptomes of 18,646 primary human decidual immune cells isolated from patients with recurrent pregnancy loss (RPL) and healthy controls at single-cell resolution. We discovered dramatic differential distributions of immune cell subsets in RPL patients compared with the normal decidual immune microenvironment. Furthermore, we found a subset of decidual natural killer (NK) cells that support embryo growth were diminished in proportion due to abnormal NK cell development in RPL patients. We also elucidated the altered cellular interactions between the decidual immune cell subsets in the microenvironment and those of the immune cells with stromal cells and extravillous trophoblast under disease state. These results provided deeper insights into the RPL decidual immune microenvironment disorder that are potentially applicable to improve the diagnosis and therapeutics of this disease.

scholarly journals Proteomic analysis of decidua in patients with recurrent pregnancy loss (RPL) reveals mitochondrial oxidative stress dysfunction

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiang-Jie Yin ◽  
Wei Hong ◽  
Fu-Ju Tian ◽  
Xiao-Cui Li
Keyword(s):  
Oxidative Stress ◽  
Western Blotting ◽  
Pregnancy Loss ◽  
Molecular Mechanisms ◽  
Recurrent Pregnancy Loss ◽  
Differentially Expressed ◽  
Decidual Cell ◽  
Differentially Expressed Proteins ◽  
Absolute Quantitation ◽  
Cox 2

Abstract Background Pregnancy is a complicated physiological process. The multifaceted regulation of maternal–fetal interface is of great importance for maintaining normal pregnancy and avoiding fetal rejection and secondary abortion. Previous studies have focused on the clinical features or pathological biomarkers of fetal rejection and abortion. However, no significant breakthrough has been made. Therefore, it is important to understand the molecular mechanisms of recurrent pregnancy loss (RPL) to identify potential therapeutic strategies. The aim of this study was to investigate the pathogenesis of RPL. Methods In this study, Relative and absolute quantitation (iTRAQ) technology integrated with liquid chromatography-tandem mass spectrometry (LC–MS/MS) analysis was used to identify differentially expressed proteins in decidual from RPL patients and matched normal controls. Further, Molecules NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3 (ndufb3) and cyclooxygenase-2 (COX-2) were validated by immunohistochemistry (IHC), Western blotting, CCK8 and mitochondrial red fluorescent probe (Mito-Tracker Red CMXRos). Results A total of 456 proteins reached the threshold of a 1.5-fold change were identified for further bioinformatics analysis. Upon mapping the differentially expressed proteins using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways database, iTRAQ results were confirmed by assessing NDUFB3 and COX-2 protein levels in specimens of decidual tissue by Western blotting. Our study indicates that the level of COX-2 and NDUFB3 were significantly increased in decidual cell from RPL patients. Overexpression of NDUFB3 inhibited cell vitality and oxidative stress of decimal cell. Further, our found that overexpression NDUFBD3 in decidual cell decreased the mitochondrial membrane potential expression levels. These results suggest that NDUFB3 might play an important role in promote the pathological process of RPL. Conclusions This comprehensive analysis of RPL proteomics reveals novel candidate: NDUFB3, which could be further investigated for explanation of the pathological mechanism of RPL.

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