Maternal-fetal Interactions Research Articles

Anesteziyoloji ve Reanimasyon Hekimleri Arasında Sezaryen Cerrahisi ve Doğum Sonrası Ağrı Yönetiminde; Prosedüre Özgü Ağrı Yönetimi (PROSPECT) Farkındalığı Anket Çalışması

Objective: Procedure-specific pain management (PROSPECT) provides clinicians with evidence-based recommendations for postoperative pain management. It was aimed to evaluate the preferences of Anesthesiology and Reanimation physicians for postpartum analgesia management. Methods: A questionnaire consisting of 19 questions was prepared, including demographic data, cesarean surgery and postpartum analgesia practices, and whether PROSPECT recommendations were followed. This questionnaire was sent to participants via e-mail. Results: The study included 247 participants. Thirtysix percent of participants reported following PROSPECT recommendations and 55.1% of participants reported prefering opioids routinely or in combination with other techniques for cesarean surgery and postpartum analgesia. Eightyfive percent of the participants think that inadequate postpartum analgesic treatment was performed. Conclusion: Inadequate postpartum analgesia appears to be a common problem. The potential of maternofetal interaction is reported to be the most important reason for this situation. We think that training on postoperative pain management following cesarean surgery will make a significant contribution to eliminating concerns about maternal-fetal interaction. Keywords: Cesarean section, postpartum analgesia, prospect, anesthesiology and reanimation, questionnaire study

The extension of mammalian pregnancy required taming inflammation: Independent evolution of extended placentation in the tammar wallaby.

In the first live-bearing mammals, pregnancy was likely short and ended with a brief period of inflammatory maternal-fetal interaction. This mode of reproduction has been retained in many marsupials. While inflammation is key to successful implantation in eutherians, a key innovation in eutherians is the ability to switch off this inflammation after it has been initiated. This extended period, in which inflammation is suppressed, likely allowed for an extended period of placentation. Extended placentation has evolved independently in one lineage of marsupials, the macropodids (wallabies and kangaroos), with placentation lasting beyond the 2 to 4 d seen in other marsupial taxa, which allows us to investigate the role of inflammation response after attachment in the extension of placentation in mammals. By comparing gene expression changes at attachment in three marsupial species, the tammar wallaby, opossum, and fat-tailed dunnart, we show that inflammatory attachment is an ancestral feature of marsupial implantation. In contrast to eutherians, where attachment-related (quasi-) inflammatory reaction is even involved in epitheliochorial placentation (e.g., pig), this study found no evidence of a distinct attachment-related reaction in wallabies. Instead, only a small number of inflammatory genes are expressed at distinct points of gestation, including IL6 before attachment, LIF throughout placentation, and prostaglandins before birth. During parturition, a more distinct inflammatory reaction is detectable, likely involved in precipitating the parturition cascade similar to eutherians. We suggest that in wallaby, extended gestation became possible by avoiding an inflammatory attachment reaction, which is a different strategy than seen in eutherians.

Factors influencing happiness and depression in high-risk pregnant women: a cross-sectional study using the ecological systems approach.

The increasing number of high-risk pregnancies has led to a greater emphasis on psychological well-being in nursing care. However, reducing depression does not automatically equate to increasing happiness. This study aimed to systematically examine the factors influencing happiness and depression among high-risk pregnant women in South Korea. This correlational, cross-sectional study was based on the ecological systems theory. In total, 152 high-risk pregnant women completed a self-report survey questionnaire available online or offline. Data were analyzed using hierarchical regression analysis. The first model (individual system) identified pregnancy stress and mindfulness as significant factors influencing both happiness and depression. The second model (microsystem) identified medical status at the time of the survey, maternal-fetal interaction, marital intimacy, and social support as additional significant factors influencing either happiness or depression. In the third model (mesosystem), maternal-fetal interaction and paternal-fetal attachment were no longer identified as significant factors. Although the fourth model (exosystem) did not identify community service as a significant factor, individual (pregnancy stress, mindfulness) and microsystem (marital intimacy) factors were found to influence happiness and depression. Medical status at the time of survey and social support were additional factors that influenced happiness, but not depression. These factors explained 51.2% and 55.5% of the variance in happiness and depression, respectively, among high-risk pregnant women. Different factors at the individual and microsystem levels affected happiness and depression among high-risk pregnant women. Hence, efforts to reduce depression among these women should be accompanied by efforts to actively promote happiness.

Can C-type natriuretic peptide during in vitro maturation or culture influence the development of bovine embryos?

The C-type natriuretic peptide (CNP) plays a central role in regulating the meiotic progression of oocytes into growing follicles in mammals. However, there are few reports examining the relationship between CNP and embryonic development. In our study, different concentrations (50, 100, or 150 nM) of CNP were added during in vitro maturation (IVM) of cumulus-oocyte complexes (COCs) or in vitro culture (IVC) of the bovine embryos (B. taurus indicus). The effects on embryo production and transcript abundance of the 20 genes of greatest interest that are related to metabolism, oocyte maturation, follicular development, cell signaling, oxidative and thermal stress, maternal-fetal interaction, and epigenetic regulation were evaluated. The blastocyst rate was influenced by CNP treatment (P = 0.049). Blastocyst rates were 31.05% (136/438) in the control group, 33.47% (162/484) in the 50 nM treatment group, 35.24% (179/508) in the 100 nM treatment group, and 32.53% (162/498) in the 150 nM treatment group for IVM. Furthermore, with IVC CNP supplementation, blastocyst rates were 28.49% (100/351) at 50 nM, 27.67% (119/430) at 100 nM, and 26.92% (112/416) at 150 nM. Moreover, the expression of RE1 silencing transcription factor (REST), a gene related to pluripotency and to embryonic development, was greater (P = 0.028) in response to 150 nM CNP supplementation in IVM. Finally, we observed for the first time the expression of the CNP receptor (NPR2) in embryos and the possible action of CNP at this stage. In conclusion, our data provide a reference for the improvement of IVM results in the in vitro production of bovine embryos with supplementation with 100 nM CNP, and this is the first study to demonstrate the expression of the CNP receptor (NPR2) in bovine embryos.

Unveiling the human fetal-maternal interface during the first trimester: biophysical knowledge and gaps.

The intricate interplay between the developing placenta and fetal-maternal interactions is critical for pregnancy outcomes. Despite advancements, gaps persist in understanding biomechanics, transport processes, and blood circulation parameters, all of which are crucial for safe pregnancies. Moreover, the complexity of fetal-maternal interactions led to conflicting data and methodological variations. This review presents a comprehensive overview of current knowledge on fetal-maternal interface structures, with a particular focus on the first trimester. More in detail, the embryological development, structural characteristics, and physiological functions of placental chorionic plate and villi, fetal membranes and umbilical cord are discussed. Furthermore, a description of the main structures and features of maternal and fetal fluid dynamic exchanges is provided. However, ethical constraints and technological limitations pose still challenges to studying early placental development directly, which calls for sophisticated in vitro, microfluidic organotypic models for advancing our understanding. For this, knowledge about key in vivo parameters are necessary for their design. In this scenario, the integration of data from later gestational stages and mathematical/computational simulations have proven to be useful tools. Notwithstanding, further research into cellular and molecular mechanisms at the fetal-maternal interface is essential for enhancing prenatal care and improving maternal and fetal health outcomes.

TFEB safeguards trophoblast syncytialization in humans and mice

Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent study demonstrated that the placenta adapts to nutrient insufficiency through mechanistic target of rapamycin (mTOR) inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype mediating extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. TFEB deficiency significantly impaired STB differentiation in human trophoblasts and placenta organoids. Consistently, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Mechanistically, TFEB conferred direct transcriptional activation of the fusogen ERVFRD-1 in human trophoblasts and thereby promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. Moreover, we demonstrated that TFEB directed the trophoblast syncytialization response driven by mTOR complex 1 (mTORC1) signaling. TFEB expression positively correlated with the reinforced trophoblast syncytialization in human fetal growth-restricted placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.

P-300 Exosomes derived from uterine fluid in patients with repeated implantation failure inhibit embryonic adhesion, invasion, and migration to endometrium

Abstract Study question By collecting clinical samples, we focused on the effect and mechanism of exosomes derived from uterine fluid on embryo implantation during the window of implantation. Summary answer Exosomes from uterine fluid in repeated implantation failure group inhibited adhesion, invasion, and migration of trophoblast cells via MAPK, VEGF, estrogen, Rap1 signal pathways. What is known already Implantation of the embryo requires the endometrium to be in an optimal state of reception for simultaneous development of normal blastocyst. Repeated implantation failure can result from embryonic quality and disturbed crosstalk between embryo and endometrium. Exosomes are extra cellular vesicles, they can be secreted into the uterine cavity, and transfer key information to recipient cells. At present, plenty of studies have shown that exosomes derived from uterine fluid worked on the maternal-fetal interaction during the window of implantation. Whether and how exosome from uterine fluid of RIF patients caused transplantation failure remained to be explored. Study design, size, duration During 2023.2-2023.8, 6 women with repeated implantation failure (RIF) and 9 women who had successfully conceived after the first transplant were recruited as RIF and control groups. All the included women were selected strictly according to the inclusion and exclusion criteria, and confounding factors such as age, BMI, and menstrual cycle were excluded, the window of implantation was determined by artificial cycle preparation. Participants/materials, setting, methods Exosomes were identified by Transmission electron microscope(TEM), Western blot(WB) and Nanoparticle Tracking Analysis(NTA). Immunofluorescence test scratch test and transwell experiment were used to verify the effects of exosomes on cell migration and invasion, cell implantation model culture and real-time cells analysis by xCELLigence were used to verify the effect of exosomes on cell adhesion. Finally, Micro-RNA sequence was conducted on Illumina HiSeq 6000 instrumen between two groups to find out the key potential signal pathway. Main results and the role of chance a. Isolation and identification of exosomes: TEM: Exosomes derived from the uterine fluid from the two groups showed a complete disc-like structure; NTA: The average diameter of exosomes from two groups were similar; WB: CD9, CD63, TSG101, HSP70 were expressed in both groups. b. Exosomes can be taken up by trophoblast cells: Immunofluorescence assay showed that exosomes derived from uterine fluid could be taken up by trophoblast cells, and the amount of uptake increased with time. c. Exosomes affect cell migration and invasion: Scratch test and transwell experiment showed that compared with the control group, the migration ability of trophoblast cells in RIF group was reduced, and the number of migrating cells decreased(P＜0.05). d. Exosomes affect cell adhesion: cell implantation model culture and real-time cells analysis by xCELLigence showed that compared with the control group, the adhesion ability of trophoblast cells decreased in the RIF group(P＜0.05). e. miRNA profile between RIF and control group: Before and during the implantation window period, there were significant differences in 43 genes between two groups, these genes regulate embryo implantation by mediating the MAPK, VEGF, estrogen, Rap1, mucin type O-glycan biosynthesis pathway. Limitations, reasons for caution 1.Due to the strict recruitment criteria, the number of women enrolled in the study was limited. 2.Through the analysis of differentially expressed micro-RNAs, relevant downstream pathways have been found. However, there is a lack of corresponding mechanism studies on how gene expression affects maternal-fetal interaction. Wider implications of the findings Through in vitro cell experiment and biological information data analysis, this study allows us to better understand the mechanism of action of exosomes in the embryo implantation process, detect and diagnose RIF populations at an early stage, and provide new ideas for promoting the treatment of infertility and implantation failure. Trial registration number Not applicable.

Endocytosis at the maternal-fetal interface: balancing nutrient transport and pathogen defense.

Endocytosis represents a category of regulated active transport mechanisms. These encompass clathrin-dependent and -independent mechanisms, as well as fluid phase micropinocytosis and macropinocytosis, each demonstrating varying degrees of specificity and capacity. Collectively, these mechanisms facilitate the internalization of cargo into cellular vesicles. Pregnancy is one such physiological state during which endocytosis may play critical roles. A successful pregnancy necessitates ongoing communication between maternal and fetal cells at the maternal-fetal interface to ensure immunologic tolerance for the semi-allogenic fetus whilst providing adequate protection against infection from pathogens, such as viruses and bacteria. It also requires transport of nutrients across the maternal-fetal interface, but restriction of potentially harmful chemicals and drugs to allow fetal development. In this context, trogocytosis, a specific form of endocytosis, plays a crucial role in immunological tolerance and infection prevention. Endocytosis is also thought to play a significant role in nutrient and toxin handling at the maternal-fetal interface, though its mechanisms remain less understood. A comprehensive understanding of endocytosis and its mechanisms not only enhances our knowledge of maternal-fetal interactions but is also essential for identifying the pathogenesis of pregnancy pathologies and providing new avenues for therapeutic intervention.

In vitro mRNA-S maternal vaccination induced altered immune regulation at the maternal-fetal interface.

Maternal-fetal immunology is intricate, and the effects of mRNA-S maternal vaccination on immune regulation at the maternal-fetal interface require further investigation. Our study endeavors to elucidate these immunological changes, enhancing our comprehension of maternal and fetal health outcomes. By analyzing immune profiles and cytokine responses, we aim to provide valuable insights into the impact of mRNA-S vaccination on the delicate balance of immune regulation during pregnancy, addressing critical questions in the field of reproductive pharmacology. This investigation sought to examine the prospective influence of mRNA-S-based vaccines and extracellular vesicles (EVs) containing the Spike (S) protein at the maternal-fetal interface. Our primary emphasis was on evaluating their effects on maternal decidua cells and fetal chorion trophoblast cells (hFM-CTCs). We validated the generation of EVs containing the S protein from small human airway epithelial cell lines (HSAECs) following mRNA-S vaccine exposure. We assessed the expression of angiotensin-converting enzyme 2 (ACE2) gene and protein in fetal membranes and the placenta, with specific attention to decidual cells and fetal membrane chorion cells. To assess cellular functionality, these cells were exposed to both recombinant S protein and EVs loaded with S proteins (eSPs). Our findings revealed that cells and EVs subjected to mRNA-S-based vaccination exhibited altered protein expression levels of S proteins. At the feto-maternal interface, both placental and fetal membrane tissues demonstrated similar ACE-2 expression levels. Among individual cellular layers, syncytiotrophoblast cells in the placenta and chorion cells in the fetal membrane exhibited elevated ACE-2 expression. Notably, EVs derived from HSAECs activated the MAPK pathway in decidual cells. Additionally, decidual cells displayed a substantial increase in gene expression of chemokines like CXCL-10 and CXCL-11, as well as proinflammatory cytokines such as IL-6 in response to eSPs. However, the levels of Ccl-2 and IL-1β remained unchanged in decidual cells under the same conditions. Conversely, hFM-CTCs demonstrated significant alterations in the proinflammatory cytokines and chemokines with respect to eSPs. In conclusion, our study indicates that mRNA-S-based maternal vaccination during pregnancy may influence the maternal-fetal interface's COVID-19 interaction and immune regulation. Further investigation is warranted to assess safety and implications.

HLA allele frequency of HLA-A, -B, -C, -DRB1 and -DQB1 in Indian recurrent implantation failure and recurrent pregnancy loss couples – A retrospective study

The maternal-fetal interaction has been hypothesized to involve the human leucocyte antigen (HLA). It has been suggested that excessive HLA antigen sharing between spouses is a mechanism causing maternal hyporesponsiveness to paternal antigens encountered during pregnancy and thus leading to a miscarriage. Participants in this retrospective study are RIF and RPL couples who visited Gunasheela Surgical and Maternity Hospital, Bangalore, India from November 2019 to September 2022. A total of 40 couples with RIF and 195 couples with RPL are included in the study. We observed that the DQB1*02:01:01 allele is associated with an increase in risk of both RIF and RPL, while the C*12:02:01 allele increases risk of only RPL. On the contrary, DQB1*02:02:01 and DQB1*06:03 alleles appear to be protective against both RPL and RIF. In addition, the C*07:02:01 allele was observed to be protective against RPL. In conclusion, C*12:02:01 and DQB1*02:01:01 could play a major role in RPL which is consistent with other studies, while DQB1*02:01:01 is the risk allele in our RIF group. The protective alleles C*07:02:01 in the RPL group, DQB1*02:02:01, and DQB1*06:03 in both RIF and RPL, were discovered for the first time. Allele frequencies will vary in population-based studies depending on the ethnicities of the cohort. Meta-analysis and antibody testing will provide additional insights on whether and how this data can be adopted into clinical practices.

Dysregulation of CREB5 Impairs Decidualization and Maternal-Fetal Interactions by Inhibiting Autophagy in Recurrent Spontaneous Abortion.

Clinically, recurrent spontaneous abortion (RSA) is a pregnancy illness that is difficult to treat. Impaired decidualization is a documented cause of RSA, but the etiology and mechanism are still unknown. cAMP-responsive element binding protein 5 (CREB5) is a member of the ATF/CREB family. CREB5 has been reported to be related to pathological pregnancy, but there are few related studies on this topic in patients with RSA, and the underlying mechanism is unclear. We collected decidual tissues from RSA patients and healthy pregnant women to measure the expression level of CREB5, PRL, IGFBP1, ATG5, LC3B, and SQSTM/p62. Then, the changes in CREB5 expression and autophagy levels were measured in human endometrial stromal cells (hESCs) during decidualization. The expression levels of PRL and IGFBP1 were tested in sh-CREB5/ov-CREB5 hESCs after decidualization induction, and the autophagy level in sh-CREB5/ov-CREB5 hESCs was measured without decidualization induction. The decidualization ability of sh-CREB5 and ov-CREB5 hESCs treated with an autophagy inducer or inhibitor was measured. To investigate the effect of CREB5 in hESCs on the invasion and migration of HTR8/SVneo cells, we performed a coculture experiment. Finally, we examined the expression of CREB5 and autophagy key proteins in mouse decidual tissues by constructing an abortion mouse model. In our study, we found that the expression of CREB5 was unusually elevated in the uterine decidua of RSA patients, but the expression of PRL, IGFBP1, and autophagy were decreased. During the decidualization of hESCs, the expression of CREB5 gradually decreases in a time-dependent manner with increasing autophagy. Moreover, by knocking down or overexpressing CREB5 in hESCs, it was found that CREB5 can impair decidualization and reduce autophagy in hESCs. Furthermore, the damage caused by CREB5 in terms of decidualization can be reversed by the addition of an autophagy inducer (rapamycin). In addition, CREB5 can increase the secretion of proteins (IL-1β and TGF-β1) in hESCs to inhibit trophoblast invasion and migration. Our data support the supposition that CREB5 disturbs the decidualization of endometrial stromal cells and interactions at the maternal-fetal interface by inhibiting autophagy and that its abnormal upregulation and dysfunction may lead to RSA. It may function as a diagnostic and therapeutic target for RSA. Similarly, we found that in the spontaneous abortion mouse model, the expression of CREB5 in the decidual tissue of the abortion group was significantly increased, and autophagy was decreased.

MiR-124-3p negatively impacts embryo implantation via suppressing uterine receptivity formation and embryo development

During embryo implantation, blastocyst interacts with the receptivity endometrium and the endometrial epithelium secretes nurturing fluid to support embryonic development. Interferon-λ (IFN-λ) is a novel, non-redundant regulator that participates in the fetal–maternal interaction; however, the precise molecular mechanism underlying its impact on uterine receptivity remains elusive. Here, microarray profiling revealed that 149 specific miRNAs were differentially expressed in the human endometrial cells following IFN-λ treatment. In particular, miR-124-3p expression was significantly reduced after IFN-λ treatment (p < 0.05). An in vivo mouse pregnancy model showed that miR-124-3p overexpression notably decreased embryo implantation rate and led to an aberrant epithelial phenotype. Furthermore, miR-124-3p negatively impacted the migration and proliferation of endometrial cells, and hindered embryonic developmental competence in terms of blastocyst formation and global DNA re-methylation. Downstream analysis showed that LIF, MUC1 and BCL2 are potential target genes for miR-124-3p, which was confirmed using western blotting and immunofluorescence assays. In conclusion, IFN-λ-driven downregulation of miR-124-3p during embryo implantation modulates uterine receptivity. The dual functional role of miR-124-3p suggests a cross-talk model wherein, maternal endometrial miRNA acts as a transcriptomic modifier of the peri-implantation endometrium and embryo development.

Transitions in development - an interview with Berna Sozen.

Berna Sozen is an Assistant Professor in the Department of Genetics at Yale University, USA. Berna's lab studies early mammalian development, metabolism, and maternal-fetal interactions using mouse and human embryos, as well as stem cell-derived embryo-like models. In 2022, Berna received the NIH Director's New Innovator Award. We spoke to Berna over Zoom to learn more about her journey to becoming a group leader and the importance of making science careers accessible.

Endometrial BMP2 Deficiency Impairs ITGB3-Mediated Trophoblast Invasion in Women With Repeated Implantation Failure.

Repeated implantation failure (RIF) leads to a waste of high-quality embryos and remains a challenge in assisted reproductive technology. During early human placentation, the invasion of trophoblast cells into the decidua is an essential step for the establishment of maternal-fetal interactions and subsequent successful pregnancy. Bone morphogenetic protein 2 (BMP2) has been reported to regulate endometrial receptivity and promote trophoblast invasion. However, whether there is dysregulation of endometrial BMP2 expression in patients with RIF remains unknown. Additionally, the molecular mechanisms underlying the effects of BMP2 on human trophoblast invasion and early placentation remain to be further elucidated. Midluteal phase endometrial samples were biopsied from patients with RIF and from routine control in vitro fertilization followed by quantitative polymerase chain reaction and immunoblotting analyses. Human trophoblast organoids, primary human trophoblast cells, and an immortalized trophoblast cell line (HTR8/SVneo) were used as study models. We found that BMP2 was aberrantly low in midluteal phase endometrial tissues from patients with RIF. Recombinant human BMP2 treatment upregulated integrin β3 (ITGB3) in a SMAD2/3-SMAD4 signaling-dependent manner in both HTR8/SVneo cells and primary trophoblast cells. siRNA-mediated integrin β3 downregulation reduced both basal and BMP2-upregulated trophoblast invasion and vascular mimicry in HTR8/SVneo cells. Importantly, shRNA-mediated ITGB3 knockdown significantly decreased the formation ability of human trophoblast organoids. Our results demonstrate endometrial BMP2 deficiency in patients with RIF. ITGB3 mediates both basal and BMP2-promoted human trophoblast invasion and is essential for early placentation. These findings broaden our knowledge regarding the regulation of early placentation and provide candidate diagnostic and therapeutic targets for RIF clinical management.

Infection of Fetal Membranes with Mycobacterium tuberculosis and Tissue Processing to Isolate RNA for Expression Analysis.

This chapter outlines the methodology employed to infectthe chorionic and amniotic membranes with Mycobacterium tuberculosis during pregnancy. Particularly, congenital tuberculosis, a rare and serious condition associated with cases in neonates and reactivation of latent tuberculosis in pregnant mothers, is interesting to study. Understanding the mechanisms of infection and the response of fetal membranes is crucial for developing effective treatments in these cases, which will promote better neonatal and maternal health in situations of tuberculosis during pregnancy. Establishing a standardized infection model in the chorioamniotic membranes is imperative, followed by a treatment protocol for isolating both cellular and mycobacterial RNA. This will enable the expression analysis during the maternal-fetal interface interaction with M. tuberculosis. The proposed methodology might be invaluable for qRT-PCR, microarrays, and sequencing research.

Immunological Aspects of Infertility-The Role of KIR Receptors and HLA-C Antigen.

The mechanisms of immune tolerance of a mother against an antigenically foreign fetus without a concomitant loss of defense capabilities against pathogens are the factors underlying the success of a pregnancy. A significant role in human defense is played by killer immunoglobulin-like receptor (KIR) receptors, which regulate the function of the natural killer (NK) cells capable of destroying antigenically foreign cells, virus-infected cells, or tumor-lesioned cells. A special subpopulation of NK cells called uterine NK cells (uNK) is found in the uterus. Disruption of the tolerance process or overactivity of immune-competent cells can lead to immune infertility, a situation in which a woman's immune system attacks her own reproductive cells, making it impossible to conceive or maintain a pregnancy. Since the prominent role of the inflammatory response in infertility, including KIR receptors and NK cells, has been postulated, the process of antigen presentation involving major histocompatibility complex (MHC) molecules (HLA) appears to be crucial for a successful pregnancy. Proper interactions between KIR receptors on female uNK cells and HLA class I molecules, with a predominant role for HLA-C, found on the surface of germ cells, are strategically important during embryo implantation. In addition, maintaining a functional balance between activating and inhibitory KIR receptors is essential for proper placenta formation and embryo implantation in the uterus. A disruption of this balance can lead to complications during pregnancy. The discovery of links between KIR and HLA-C has provided valuable information about the complexity of maternal-fetal immune interactions that determine the success of a pregnancy. The great diversity of maternal KIR and fetal HLA-C ligands is associated with the occurrence of KIR/HLA-C combinations that are more or less favorable for reproductive success.

Autophagy Inhibition in Trophoblasts Induces Aberrant Shift in CXCR4+ Decidual NK Cell Phenotype Leading to Pregnancy Loss

Background: Pregnancy, a complex biological phenomenon, relies on intricate maternal–fetal interactions for success. Decidual natural killer (dNK) cells and trophoblasts are pivotal in establishing immune tolerance at the maternal–fetal interface. The chemokine receptor CXCR4 plays a crucial role in NK cell development and immune tolerance during early placental development. Methods: Primary decidual immune cells from 42 women with normal pregnancies and 20 patients experiencing recurrent spontaneous abortions (RSAs) were studied. Gene transcription in NK cells was assessed using real-time polymerase chain reaction. In a co-culture system, we examined the influence of trophoblasts on CXCR4 expression in dNK cells, with subsequent analysis conducted via flow cytometry. The proportion of CXCR4+ NK cells was assessed using flow cytometry after co-culture with trophoblasts pre-treated with 3-MA or a p53 activator. Results: Our study confirmed a diminished presence of decidual CXCR4+ NK cells in RSA patients during early pregnancy. Co-culturing with a trophoblast-derived supernatant increased CXCR4 expression in dNK cells. In addition, trophoblast autophagy plays an educative role in regulating the dNK landscape via the IGF2-TP53-CXCR4 axis. Conclusion: Autophagy inhibition in trophoblasts induces an aberrant shift in the CXCR4+ dNK phenotype, potentially contributing to pregnancy loss. This sheds light on the nuanced behavior of dNK cells during pregnancy, offering promising therapeutic avenues to mitigate pregnancy complications.

Pathophysiological impact of CXC and CX3CL1 chemokines in preeclampsia and gestational diabetes mellitus.

Diabetes-related pathophysiological alterations and various female reproductive difficulties were common in pregnant women with gestational diabetes mellitus (GDM), who had 21.1 million live births. Preeclampsia (PE), which increases maternal and fetal morbidity and mortality, affects approximately 3%-5% of pregnancies worldwide. Nevertheless, it is unclear what triggers PE and GDM to develop. Therefore, the development of novel moderator therapy approaches is a crucial advancement. Chemokines regulate physiological defenses and maternal-fetal interaction during healthy and disturbed pregnancies. Chemokines regulate immunity, stem cell trafficking, anti-angiogenesis, and cell attraction. CXC chemokines are usually inflammatory and contribute to numerous reproductive disorders. Fractalkine (CX3CL1) may be membrane-bound or soluble. CX3CL1 aids cell survival during homeostasis and inflammation. Evidence reveals that CXC and CX3CL1 chemokines and their receptors have been the focus of therapeutic discoveries for clinical intervention due to their considerable participation in numerous biological processes. This review aims to give an overview of the functions of CXC and CX3CL1 chemokines and their receptors in the pathophysiology of PE and GDM. Finally, we examined stimulus specificity for CXC and CX3CL1 chemokine expression and synthesis in PE and GDM and preclinical and clinical trials of CXC-based PE and GDM therapies.

Organoid systems for investigating trophoblast biology and maternal-fetal interactions in human pregnancy

Organoid systems for investigating trophoblast biology and maternal-fetal interactions in human pregnancy

Histone modifications in embryo implantation and placentation: insights from mouse models.

Embryo implantation and placentation play pivotal roles in pregnancy by facilitating crucial maternal-fetal interactions. These dynamic processes involve significant alterations in gene expression profiles within the endometrium and trophoblast lineages. Epigenetics regulatory mechanisms, such as DNA methylation, histone modification, chromatin remodeling, and microRNA expression, act as regulatory switches to modulate gene activity, and have been implicated in establishing a successful pregnancy. Exploring the alterations in these epigenetic modifications can provide valuable insights for the development of therapeutic strategies targeting complications related to pregnancy. However, our current understanding of these mechanisms during key gestational stages remains incomplete. This review focuses on recent advancements in the study of histone modifications during embryo implantation and placentation, while also highlighting future research directions in this field.