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Human Reproduction Update 2015Connexins comprise a family of ~20 proteins that form intercellular membrane channels (gap junction channels) providing a direct route for metabolites and signalling... (Review)
Review
BACKGROUND
Connexins comprise a family of ~20 proteins that form intercellular membrane channels (gap junction channels) providing a direct route for metabolites and signalling molecules to pass between cells. This review provides a critical analysis of the evidence for essential roles of individual connexins in female reproductive function, highlighting implications for women's reproductive health.
METHODS
No systematic review has been carried out. Published literature from the past 35 years was surveyed for research related to connexin involvement in development and function of the female reproductive system. Because of the demonstrated utility of genetic manipulation for elucidating connexin functions in various organs, much of the cited information comes from research with genetically modified mice. In some cases, a distinction is drawn between connexin functions clearly related to the formation of gap junction channels and those possibly linked to non-channel roles.
RESULTS AND CONCLUSIONS
Based on work with mice, several connexins are known to be required for female reproductive functions. Loss of connexin43 (CX43) causes an oocyte deficiency, and follicles lacking or expressing less CX43 in granulosa cells exhibit reduced growth, impairing fertility. CX43 is also expressed in human cumulus cells and, in the context of IVF, has been correlated with pregnancy outcome, suggesting that this connexin may be a determinant of oocyte and embryo quality in women. Loss of CX37, which exclusively connects oocytes with granulosa cells in the mouse, caused oocytes to cease growing without acquiring meiotic competence. Blocking of CX26 channels in the uterine epithelium disrupted implantation whereas loss or reduction of CX43 expression in the uterine stroma impaired decidualization and vascularization in mouse and human. Several connexins are important in placentation and, in the human, CX43 is a key regulator of the fusogenic pathway from the cytotrophoblast to the syncytiotrophoblast, ensuring placental growth. CX40, which characterizes the extravillous trophoblast (EVT), supports proliferation of the proximal EVTs while preventing them from differentiating into the invasive pathway. Furthermore, women with recurrent early pregnancy loss as well as those with endometriosis exhibit reduced levels of CX43 in their decidua. The antimalaria drug mefloquine, which blocks gap junction function, is responsible for increased risk of early pregnancy loss and stillbirth, probably due to inhibition of intercellular communication in the decidua or between trophoblast layers followed by an impairment of placental growth. Gap junctions also play a critical role in regulating uterine blood flow, contributing to the adaptive response to pregnancy. Given that reproductive impairment can result from connexin mutations in mice, it is advised that women suffering from somatic disease symptoms associated with connexin gene mutations be additionally tested for impacts on reproductive function. Better knowledge of these essential connexin functions in human female reproductive organs is important for safeguarding women's reproductive health.
Topics: Animals; Cell Communication; Connexin 26; Connexin 43; Connexins; Cumulus Cells; Embryo Implantation; Embryo Loss; Female; Fertility; Gap Junctions; Humans; Ion Channels; Mefloquine; Mice; Oocytes; Oogenesis; Placenta; Pregnancy; Pregnancy Outcome; RNA, Messenger; Reproductive Health; Trophoblasts
PubMed: 25667189
DOI: 10.1093/humupd/dmv007 -
Journal of Assisted Reproduction and... Dec 2020Chronic endometritis (CE) is a frequent hysteroscopic and histological finding which affects embryo transfer implantation during IVF-ICSI cycles. In particular, CE...
PURPOSE
Chronic endometritis (CE) is a frequent hysteroscopic and histological finding which affects embryo transfer implantation during IVF-ICSI cycles. In particular, CE impairs proper decidualization and, subsequently, implantation. Although this correlation has been clearly clarified, a pathophysiological explanation assembling all the studies performed has not been elucidated yet. For this reason, we have structured a systematic review considering all the original articles that evaluated a pathological element involved in CE and implantation impairment.
METHODS
The authors searched electronic databases and, after screening, collected 15 original articles. These were fully scanned and used to create a summary pathway.
RESULTS
CE is primarily caused by infections, which lead to a specific cytokine and leukocyte pattern in order to prepare the uterus to fight the noxa. In particular, the immunosuppression requested for a proper semi-allogenic embryo transfer implantation is converted into an immunoreaction, which hampers correct embryo implantation. Moreover, endometrial vascularization is affected and both irregular vessel density and luminal thickening and thrombosis reduce what we have first identified as endometrial flow reserve. Finally, incorrect uterine wave propagation could affect embryo contact with decidua.
CONCLUSION
This is the first summary of evidence on CE pathophysiology and its relationship with infertility. Understanding the CE pathophysiology could improve our knowledge in embryo transfer success.
Topics: Chronic Disease; Embryo Implantation; Endometritis; Female; Fertilization in Vitro; Humans; Infertility, Female; Pregnancy; Pregnancy Rate
PubMed: 33025403
DOI: 10.1007/s10815-020-01955-8 -
Frontiers in Immunology 2022Mesenchymal stromal cells (MSCs) possess profound immunomodulatory and regenerative properties that are of clinical use in numerous clinical indications with unmet... (Meta-Analysis)
Meta-Analysis
Mesenchymal stromal cells (MSCs) possess profound immunomodulatory and regenerative properties that are of clinical use in numerous clinical indications with unmet medical need. Common sources of MSCs include among others, bone marrow (BM), fat, umbilical cord, and placenta-derived decidua stromal cells (DSCs). We here summarize our more than 20-years of scientific experience in the clinical use of MSCs and DSCs in different clinical settings. BM-MSCs were first explored to enhance the engraftment of autografts in hematopoietic cell transplantation (HCT) and osteogenesis imperfecta around 30 years ago. In 2004, our group reported the first anti-inflammatory use of BM-MSCs in a child with grade IV acute graft-versus-host disease (GvHD). Subsequent studies have shown that MSCs appear to be more effective in acute than chronic GvHD. Today BM-MSC-therapy is registered for acute GvHD in Japan and for GvHD in children in Canada and New Zeeland. MSCs first home to the lung following intravenous injection and exert strong local and systemic immunomodulatory effects on the host immune system. Thus, they were studied for ameliorating the cytokine storm in acute respiratory distress syndrome (ARDS). Both, MSCs and DSCs were used to treat SARS-CoV-2 coronavirus-induced disease 2019 (COVID-19)-induced ARDS. In addition, they were also used for other novel indications, such as pneumomediastinum, colon perforation, and radiculomyelopathy. MSC and DSCs trigger coagulation and were thus explored to stop hemorrhages. DSCs appear to be more effective for acute GvHD, ARDS, and hemorrhages, but randomized studies are needed to prove superiority. Stromal cell infusion is safe, well tolerated, and only gives rise to a slight fever in a limited number of patients, but no major side effects have been reported in multiple safety studies and metaanalysis. In this review we summarize current evidence from studies, animal models, and importantly our clinical experience, to support stromal cell therapy in multiple clinical indications. This encloses MSC's effects on the immune system, coagulation, and their safety and efficacy, which are discussed in relation to prominent clinical trials within the field.
Topics: Animals; COVID-19; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Pregnancy; Respiratory Distress Syndrome; SARS-CoV-2
PubMed: 35371003
DOI: 10.3389/fimmu.2022.839844 -
BioMed Research International 2020Preeclampsia (PE) is termed as a systemic disease that involves multiple organs; however, the exact etiology is still quite unclear. It is believed that the poor...
Preeclampsia (PE) is termed as a systemic disease that involves multiple organs; however, the exact etiology is still quite unclear. It is believed that the poor remodeling of uterine spiral arteries triggers PE, thereby causing failed placentation and producing inflammatory factors. The decline of blood flow results in lowering the nutrients and oxygen received by the fetus and augmenting the placental pressure in PE. Decidual immune cells, especially uterine natural killer (uNK) cells, are involved in the process of placentation. Decidual NK (dNK) cells significantly contribute to the vascular remodeling through the secretion of cytokines and angiogenic mediators in normal placental development. The abnormal activation of NK cells in both the peripheral blood and the decidua was counted among the causes leading to PE. The correlation existing between maternal killer cell immunoglobulin-like receptor (KIR) and HLA-C in trophoblast cells constitutes a robust evidence for the genetic etiology of PE. The combinations of the two kinds of gene systems, together with the KIR genotype in the mother and the HLA-C group in her fetus, are likely to exactly decide the pregnancy outcome. The women, who have the inappropriate match of KIR/HLA-C, are likely to be prone to the augmented risk of PE. However, the combinations of KIR/HLA-C in PE undergo ethnic changes. The extensive prospective research works in Europe, Asia, and Africa are required for providing more findings in PE patients.
Topics: Animals; Female; Fetus; Genotype; HLA-C Antigens; Humans; Killer Cells, Natural; Pre-Eclampsia; Pregnancy; Receptors, KIR; Trophoblasts; Uterine Artery; Uterus
PubMed: 32309433
DOI: 10.1155/2020/4808072 -
Frontiers in Immunology 2021The success of pregnancy relies on the fine adjustment of the maternal immune system to tolerate the allogeneic fetus. Trophoblasts carrying paternal antigens are the...
The success of pregnancy relies on the fine adjustment of the maternal immune system to tolerate the allogeneic fetus. Trophoblasts carrying paternal antigens are the only fetal-derived cells that come into direct contact with the maternal immune cells at the maternal-fetal interface. The crosstalk between trophoblasts and decidual immune cells (DICs) via cell-cell direct interaction and soluble factors such as chemokines and cytokines is a core event contributing to the unique immunotolerant microenvironment. Abnormal trophoblasts-DICs crosstalk can lead to dysregulated immune situations, which is well known to be a potential cause of a series of pregnancy complications including recurrent spontaneous abortion (RSA), which is the most common one. Immunotherapy has been applied to RSA. However, its development has been far less rapid or mature than that of cancer immunotherapy. Elucidating the mechanism of maternal-fetal immune tolerance, the theoretical basis for RSA immunotherapy, not only helps to understand the establishment and maintenance of normal pregnancy but also provides new therapeutic strategies and promotes the progress of immunotherapy against pregnancy-related diseases caused by disrupted immunotolerance. In this review, we focus on recent progress in the maternal-fetal immune tolerance mediated by trophoblasts-DICs crosstalk and clinical application of immunotherapy in RSA. Advancement in this area will further accelerate the basic research and clinical transformation of reproductive immunity and tumor immunity.
Topics: Abortion, Habitual; Animals; Decidua; Female; Humans; Immune Privilege; Immunotherapy; Pregnancy; Trophoblasts
PubMed: 33717198
DOI: 10.3389/fimmu.2021.642392 -
International Journal of Molecular... Jun 2021Placental abruption is the separation of the placenta from the lining of the uterus before childbirth. It is an infrequent perinatal complication with serious...
Placental abruption is the separation of the placenta from the lining of the uterus before childbirth. It is an infrequent perinatal complication with serious after-effects and a marked risk of maternal and fetal mortality. Despite the fact that numerous placental abruption risk factors are known, the pathophysiology of this issue is multifactorial and not entirely clear. The aim of this review was to examine the current state of knowledge concerning the molecular changes on the maternal-fetal interface occurring in placental abruption. Only original research articles describing studies published in English until the 15 March 2021 were considered eligible. Reviews, book chapters, case studies, conference papers and opinions were excluded. The systematic literature search of PubMed/MEDLINE and Scopus databases identified 708 articles, 22 of which were analyzed. The available evidence indicates that the disruption of the immunological processes on the maternal-fetal interface plays a crucial role in the pathophysiology of placental abruption. The features of chronic non-infectious inflammation and augmented immunological cytotoxic response were found to be present in placental abruption samples in the reviewed studies. Various molecules participate in this process, with only a few being examined. More advanced research is needed to fully explain this complicated process.
Topics: Abruptio Placentae; Female; Humans; Placenta; Pregnancy; Thrombin
PubMed: 34205566
DOI: 10.3390/ijms22126612 -
The Cochrane Database of Systematic... Jul 2019Fetal fibronectin (FFN) is an extracellular matrix glycoprotein localized at the maternal-fetal interface of the amniotic membranes, between chorion and decidua, where...
BACKGROUND
Fetal fibronectin (FFN) is an extracellular matrix glycoprotein localized at the maternal-fetal interface of the amniotic membranes, between chorion and decidua, where it is concentrated in this area between decidua and trophoblast. In normal conditions, FFN is found at very low levels in cervicovaginal secretions. Levels greater than or equal to 50 ng/mL at or after 22 weeks have been associated with an increased risk of spontaneous preterm birth. In fact, FFN is one of the best predictors of preterm birth in all populations studied so far, and can help in selecting which women are at significant risk for preterm birth. This is an update of a review first published in 2008.
OBJECTIVES
To assess the effectiveness of management based on knowledge of FFN testing results for preventing preterm birth.
SEARCH METHODS
For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register (7 September 2018), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (7 September 2018), and reference lists of retrieved studies.
SELECTION CRITERIA
Randomized controlled trials of pregnant women screened with FFN for risk of preterm birth. Studies included are based exclusively on knowledge of FFN results versus no such knowledge, and we have excluded studies including women with only positive or only negative FFN results.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach.
MAIN RESULTS
We identified 16 trials, of which six were eligible for inclusion. The six included studies randomized 546 women with singleton gestations and threatened preterm labor (PTL) at 23 0/7 to 34 6/7 weeks. A total of 277 women were randomized to knowledge and 269 to no knowledge of FFN. No trials were identified on asymptomatic women or multiple gestations.The risk of bias of included studies was mixed. For selected important outcomes, preterm birth before 37, 34, and 32 weeks, and maternal hospitalization, we graded the quality of the evidence and created a 'Summary of findings' table. For these outcomes, the evidence was graded as mainly low quality due to the imprecision of effect estimates.Management based on knowledge of FFN results may reduce preterm birth before 37 weeks (21.6%) versus controls without such knowledge (29.2%) (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.52 to 1.01; 4 trials; 357 women; low-quality evidence). However, management based on knowledge of FFN results may make little or no difference to preterm birth before 34 (RR 1.09, 95% CI 0.54 to 2.18; 4 trials; 357 women; low-quality evidence) or maternal hospitalization (RR 1.06, 95% CI 0.79 to 1.43; 5 trials; 441 women; low-quality evidence). The evidence for preterm birth before 32 weeks is uncertain because the quality was found to be very low (average RR 0.79, 95% CI 0.16 to 3.96; 4 trials; 357 women; very low-quality evidence).For all other outcomes, for which there were available data (preterm birth less than 28 weeks; gestational age at delivery (weeks); birthweight less than 2500 g; perinatal death; tocolysis; steroids for fetal lung maturity; time to evaluate; respiratory distress syndrome; neonatal intensive care unit (NICU) admission; and NICU days), knowledge of FFN results may make little or no difference to the outcomes.
AUTHORS' CONCLUSIONS
The evidence from this review suggests that management based on knowledge of FFN results may reduce preterm birth before 37 weeks. However, our confidence in this result is limited as the evidence was found to be of low quality. Effects on other substantive outcomes are uncertain due to serious concerns in study design, inconsistency, and imprecision of effect estimates. No trials were identified on asymptomatic women, or multiple gestations.Future studies are needed that include specific populations (e.g. singleton gestations with symptoms of preterm labor), a study group managed with a protocol based on the FFN results, and that report not only maternal but also important perinatal outcomes. Cost-effectiveness analyses are also needed.
Topics: Biomarkers; Female; Fibronectins; Gestational Age; Humans; Infant, Newborn; Obstetric Labor, Premature; Pregnancy; Premature Birth; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome, Newborn
PubMed: 31356681
DOI: 10.1002/14651858.CD006843.pub3 -
Biology of Reproduction Aug 2023The fallopian tubes (FTs) are part of the female upper genital tract. The healthy FT provides the biological environment for successful fertilization and facilitates the...
The fallopian tubes (FTs) are part of the female upper genital tract. The healthy FT provides the biological environment for successful fertilization and facilitates the subsequent movement of the conceptus to the endometrial cavity. However, when the FT is damaged, as with salpingitis, pyosalpinx, and hydrosalpinx, it may increase the risk of an ectopic pregnancy, a life-threatening condition. Decidualization refers to a multifactorial process by which the endometrium changes to permit blastocyst implantation. The decidualization reaction is vital for endometrial receptivity during the window of implantation. To date, no comprehensive review that collates evidence on decidualization in the human FT has been conducted. Therefore, the aim of this review is to compile the current evidence on cellular decidualization occurring in the healthy and pathological FT in women of reproductive age. A literature search was conducted using five databases and identified 746 articles, 24 of which were analyzed based on inclusion and exclusion criteria. The available evidence indicates that the FT are able to undergo decidual changes under specific circumstances; however, the exact mechanism by which this occurs is poorly understood. Further research is needed to elucidate the mechanism by which decidualization can occur in the FT.
Topics: Pregnancy; Female; Humans; Fallopian Tubes; Endometrium; Embryo Implantation; Uterus; Decidua; Stromal Cells
PubMed: 37265359
DOI: 10.1093/biolre/ioad062 -
Journal of Reproductive Immunology Nov 2019Immunoinflammatory response by innate immunity components is a field with increasing interest in understanding the mechanisms behind preterm labor (PTL).
BACKGROUND
Immunoinflammatory response by innate immunity components is a field with increasing interest in understanding the mechanisms behind preterm labor (PTL).
OBJECTIVES
Systematic review of the role of innate immunity in spontaneous PTL.
STUDY DESIGN
PubMed, Scopus, ClinicalTrials.gov and Web of Science were searched using pregnancy AND innate OR toll-like OR natural-killer OR dendritic AND delivery OR premature OR rupture of membranes.
MAIN OUTCOME MEASURES
All article titles and abstracts were evaluated by two individuals, based in strict predefined inclusion criteria. For relevant studies, title, abstract, and full text were assessed to identify PTL and innate immunity studies, excluding multiple pregnancies, cervical insufficiency and indicated PTL.
RESULTS
From 894 articles evaluated, 101 full texts articles were assessed independently. For this systematic review 44 studies were finally included. Toll-like receptors 2 and 4 mediated immune dysfunction and inflammation can result in PTL. Moreover, PTL is linked to high levels of CD14 monocytes; neutrophils seem important in inflammation-associated PTL and in pathological preterm premature rupture of membranes. Besides, decidual natural-killer cells and premature activation of dendritic cells may also participate in the etiology of PTL. Finally, dysregulation of maternal complement might increase the risk of PTL, characterized by high levels of innate lymphoid cells 2 and 3.
CONCLUSIONS
Further research is warranted to ascertain the precise role of innate immunity in PTL. Nonetheless, our results indicate that Toll-like receptors, monocytes, natural-killer cells, dendritic cells and complement have significant roles in PTL.
Topics: Decidua; Female; Fetal Membranes, Premature Rupture; Humans; Immunity, Innate; Inflammation; Pregnancy; Premature Birth
PubMed: 31581042
DOI: 10.1016/j.jri.2019.102616