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Journal of Cellular Physiology May 2024Spontaneous abortion is the most common complication in early pregnancy, the exact etiology of most cases cannot be determined. Emerging studies suggest that mutations...
Spontaneous abortion is the most common complication in early pregnancy, the exact etiology of most cases cannot be determined. Emerging studies suggest that mutations in ciliary genes may be associated with progression of pregnancy loss. However, the involvement of primary cilia on spontaneous abortion and the underlying molecular mechanisms remains poorly understood. We observed the number and length of primary cilia were significantly decreased in decidua of spontaneous abortion in human and lipopolysaccharide (LPS)-induced abortion mice model, accompanied with increased expression of proinflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The length of primary cilia in human endometrial stromal cell (hESC) was significantly shortened after TNF-α treatment. Knocking down intraflagellar transport 88 (IFT88), involved in cilia formation and maintenance, promoted the expression of TNF-α. There was a reverse regulatory relationship between cilia shortening and TNF-α expression. Further research found that shortened cilia impair decidualization in hESC through transforming growth factor (TGF)-β/SMAD2/3 signaling. Primary cilia were impaired in decidua tissue of spontaneous abortion, which might be mainly caused by inflammatory injury. Primary cilia abnormalities resulted in dysregulation of TGF-β/SMAD2/3 signaling transduction and decidualization impairment, which led to spontaneous abortion.
PubMed: 38704705
DOI: 10.1002/jcp.31292 -
FASEB Journal : Official Publication of... May 2024Endometriosis (EMs)-related infertility commonly has decreased endometrial receptivity and normal decidualization is the basis for establishing and maintaining...
Endometriosis (EMs)-related infertility commonly has decreased endometrial receptivity and normal decidualization is the basis for establishing and maintaining endometrial receptivity. However, the potential molecular regulatory mechanisms of impaired endometrial decidualization in patients with EMs have not been fully clarified. We confirmed the existence of reduced endometrial receptivity in patients with EMs by scanning electron microscopy and quantitative real-time PCR. Here we identified an lncRNA, named BMPR1B-AS1, which is significantly downregulated in eutopic endometrium in EMs patients and plays an essential role in decidual formation. Furthermore, RNA pull-down, mass spectrometry, RNA immunoprecipitation, and rescue analyses revealed that BMPR1B-AS1 positively regulates decidual formation through interaction with the RNA-binding protein insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Downregulation of IGF2BP2 led to a decreased stability of BMPR1B-AS1 and inhibition of activation of the SMAD1/5/9 pathway, an inhibitory effect which diminished decidualization in human endometrial stromal cells (hESCs) decidualization. In conclusion, our identified a novel regulatory mechanism in which the IGF2BP2-BMPR1B-AS1-SMAD1/5/9 axis plays a key role in the regulation of decidualization, providing insights into the potential link between abnormal decidualization and infertility in patients with EMs, which will be of clinical significance for the management and treatment of infertility in patients with EMs.
Topics: Adult; Female; Humans; Bone Morphogenetic Protein Receptors, Type I; Decidua; Endometriosis; Endometrium; Infertility, Female; RNA, Long Noncoding; RNA-Binding Proteins; Signal Transduction; Stromal Cells; Smad Proteins; Young Adult
PubMed: 38703029
DOI: 10.1096/fj.202302195R -
Endocrinology Apr 2024Recurrent spontaneous abortion (RSA) is defined as the loss of 2 or more consecutive intrauterine pregnancies with the same sexual partner in the first trimester....
CONTEXT
Recurrent spontaneous abortion (RSA) is defined as the loss of 2 or more consecutive intrauterine pregnancies with the same sexual partner in the first trimester. Despite its significance, the etiology and underlying mechanisms of RSA remain elusive. Defective decidualization is proposed as one of the potential causes of RSA, with abnormal decidualization leading to disturbances in trophoblast invasion function.
OBJECTIVE
To assess the role of bone morphogenetic protein 4 (BMP4) in decidualization and RSA.
METHODS
Decidual samples were collected from both RSA patients and healthy controls to assess BMP4 expression. In vitro cell experiments utilized the hESC cell line to investigate the impact of BMP4 on decidualization and associated aging, as well as its role in the maternal-fetal interface communication. Subsequently, a spontaneous abortion mouse model was established to evaluate embryo resorption rates and BMP4 expression levels.
RESULTS
Our study identified a significant downregulation of BMP4 expression in the decidua of RSA patients compared to the normal control group. In vitro, BMP4 knockdown resulted in inadequate decidualization and inhibited associated aging processes. Mechanistically, BMP4 was implicated in the regulation of FOXO1 expression, thereby influencing decidualization and aging. Furthermore, loss of BMP4 hindered trophoblast migration and invasion via FOXO1 modulation. Additionally, BMP4 downregulation was observed in RSA mice.
CONCLUSION
Our findings highlighted the downregulation of BMP4 in both RSA patients and mice. BMP4 in human endometrial stromal cells was shown to modulate decidualization by regulating FOXO1 expression. Loss of BMP4 may contribute to the pathogenesis of RSA, suggesting potential avenues for abortion prevention strategies.
Topics: Female; Humans; Bone Morphogenetic Protein 4; Forkhead Box Protein O1; Stromal Cells; Animals; Mice; Decidua; Pregnancy; Endometrium; Abortion, Habitual; Adult; Trophoblasts; Case-Control Studies
PubMed: 38679470
DOI: 10.1210/endocr/bqae049 -
Medicina (Kaunas, Lithuania) Apr 2024Up to 70-80% of women of reproductive age may be affected with the most common uterine tumors, known as fibroids or myomas. These benign tumors are the second most... (Review)
Review
Up to 70-80% of women of reproductive age may be affected with the most common uterine tumors, known as fibroids or myomas. These benign tumors are the second most prevalent cause of surgery among premenopausal women. Predictions show that the occurrence of myomas in pregnancy will increase, and that the risk of having myomas during pregnancy increases with advanced maternal age. Although most women with fibroids do not experience any symptoms during pregnancy, up to 30% of women experience problems during pregnancy, childbirth, and the puerperium. The viability of myoma excision during cesarean surgery (CS) is a contentious issue raised by the rising incidence of myomas in pregnancy and CS rates. A new surgical procedure for removing fibroids using a trans-endometrial approach, which involves making an incision through the decidua itself, has put into doubt the long-standing practice of cesarean myomectomy (CM) with a trans-serosal approach. Some authors have recently advocated for this last approach, highlighting its advantages and potential uses in real-world situations. The purpose of this paper is to critique the present approach to cesarean myomectomy by analyzing the clinical and surgical distinctions between the two approaches and providing illustrations of the CM methods.
Topics: Humans; Female; Cesarean Section; Uterine Myomectomy; Pregnancy; Leiomyoma; Uterine Neoplasms; Adult; Pregnancy Complications, Neoplastic; Decidua
PubMed: 38674255
DOI: 10.3390/medicina60040609 -
Biomedicines Apr 2024This study aimed to investigate the cytotoxic activity of decidual lymphocytes and the mRNA/protein expression of cytotoxic proteins in various cell types in the context...
This study aimed to investigate the cytotoxic activity of decidual lymphocytes and the mRNA/protein expression of cytotoxic proteins in various cell types in the context of preeclampsia (PE) compared to those of healthy pregnancies. We analyzed fresh decidua basalis tissue and tissue embedded in paraffin (FFPE) from PE pregnancies (n = 15) and compared them with those of healthy pregnancies (n = 15) of the corresponding gestational age. Using double immunofluorescence staining, we observed differences in the intensity and distribution of staining for granzyme K (GZMK) and FasL in extravillous trophoblasts. RT-qPCR analysis of FFPE placental tissue showed that GZMK mRNA expression was statistically higher ( < 0.0001) in PE compared to that of healthy controls. On the contrary, there was a low expression ( < 0.001) of FasL mRNA in PE compared to controls, while there was no statistically significant difference for IFN-γ mRNA between PE and controls. Although the level of cytotoxic activity changed depending on the ratio of effector and target cells, there was no significant difference observed between PE and controls in this in vitro study. In conclusion, in PE, extravillous trophoblasts exhibited increased expression of GZMK and decreased expression of FasL. These changes may contribute to impaired trophoblast invasion. However, these alterations did not appear to affect the cytotoxic properties of decidual lymphocytes. Additionally, the possibility of cell sorter separation of decidual lymphocytes would greatly contribute to a better understanding of single cells' genetic profiles.
PubMed: 38672196
DOI: 10.3390/biomedicines12040842 -
Diagnostics (Basel, Switzerland) Apr 2024Connexins (Cx) 43 and 40 play a role in leukocytes recruitment in acute inflammation. They are expressed in the endothelial cells. They are also found in the placenta...
BACKGROUND
Connexins (Cx) 43 and 40 play a role in leukocytes recruitment in acute inflammation. They are expressed in the endothelial cells. They are also found in the placenta and involved in the placenta development. Acute chorioamnionitis is associated with an increased risk of adverse perinatal outcomes. The aim of this study was to determine the expressions of Cx43 and Cx40 in the placenta of mothers with acute chorioamnionitis, and to correlate their association with the severity of chorioamnionitis and adverse perinatal outcomes.
METHODS
This study comprised a total of 81 cases, consisting of 39 placenta samples of mothers with acute chorioamnionitis and 42 non-acute chorioamnionitis controls. Cx43 and Cx40 immunohistochemistry were performed on all cases and their expressions were evaluated on cytotrophoblasts, syncytiotrophoblasts, chorionic villi endothelial cells, stem villi endothelial cells, maternal endothelial cells and decidua of the placenta.
RESULTS
Primigravida has a significantly higher risk of developing acute chorioamnionitis ( < 0.001). Neonates of mothers with a higher stage of fetal inflammatory response was significantly associated with lung complications ( = 0.041) compared to neonates of mothers with a lower stage. The expression of Cx40 was significantly higher in fetal and maternal vascular endothelial cells in acute chorioamnionitis ( < 0.001 and = 0.037, respectively) compared to controls. Notably, Cx43 was not expressed in most of the types of cells in the placenta, except for decidua. Both Cx43 and Cx40 expressions did not have correlation with the severity of acute chorioamnionitis and adverse perinatal outcomes.
CONCLUSION
Cx40 was overexpressed in the fetal and maternal vascular endothelial cells in the placenta of mothers with acute chorioamnionitis, and it may have a role in the development of inflammation in placenta.
PubMed: 38667457
DOI: 10.3390/diagnostics14080811 -
Developmental Cell Apr 2024Placental ischemia, resulting from inadequate remodeling of uterine spiral arteries, is a factor in the development of preeclampsia. However, the effect of endothelial...
Placental ischemia, resulting from inadequate remodeling of uterine spiral arteries, is a factor in the development of preeclampsia. However, the effect of endothelial progenitor cells that play a role in the vascular injury-repair program is largely unexplored during remodeling. Here, we observe that preeclampsia-afflicted uterine spiral arteries transition to a synthetic phenotype in vascular smooth muscle cells and characterize the regulatory axis in endothelial progenitor cells during remodeling in human decidua basalis. Excessive sEng, secreted by AMP-activated protein kinase (AMPK)-deficient endothelial progenitor cells through the inhibition of HO-1, damages residual endothelium and leads to the accumulation of extracellular matrix produced by vascular smooth muscle cells during remodeling, which is further confirmed by animal models. Collectively, our findings suggest that the impaired functionality of endothelial progenitor cells contributes to the narrowing of remodeled uterine spiral arteries, leading to reduced utero-placental perfusion. This mechanism holds promise in elucidating the pathogenesis of preeclampsia.
PubMed: 38663400
DOI: 10.1016/j.devcel.2024.04.009 -
Drug Discoveries & Therapeutics Jun 2024Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder characterized by a complex pathogenesis and limited treatment options. Yishen Huatan and...
Yishen Huatan Huoxue decoction and quercetin ameliorate decidualization dysfunction in polycystic ovary syndrome: A comprehensive investigation combining clinical trial and experimental studies.
Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder characterized by a complex pathogenesis and limited treatment options. Yishen Huatan and Huoxue decoction (YHHD), as a traditional Chinese Medicine formula, has shown effectiveness in treating PCOS. However, the specific mechanisms by which YHHD exerts its therapeutic effects remain unclear. In this study, we performed to investigate the therapeutic effects of YHHD and quercetin on dehydroepiandrosterone-induced PCOS mice, and examine the effect of quercetin on the decidualization of T-HESCs under hyperinsulinemic conditions. The results showed that YHHD could reduce early miscarriage rates in PCOS patients and significantly improved glucose metabolism disorders, sex hormone levels, and the estrous cycles in PCOS mice. Quercetin could alleviate effect of high insulin levels and restore the low expression of insulin receptor substrate1/2 (IRS1/2) and glucose transporte 4 (GLUT4) in T-HESCs, demonstrating its potential to mitigate hyperinsulin-induced decidualization dysfunction via the GLUT4 signaling pathway mediated by IRS1/2. This study provides valuable molecular insights of YHHD and highlight the therapeutic potential of quercetin in treating decidualization dysfunction in PCOS.
Topics: Polycystic Ovary Syndrome; Female; Quercetin; Animals; Drugs, Chinese Herbal; Mice; Humans; Disease Models, Animal; Glucose Transporter Type 4; Insulin Receptor Substrate Proteins; Signal Transduction; Adult; Abortion, Spontaneous; Insulin; Dehydroepiandrosterone; Decidua; Estrous Cycle; Pregnancy
PubMed: 38644207
DOI: 10.5582/ddt.2024.01003 -
Cell Communication and Signaling : CCS Apr 2024Recurrent pregnancy loss (RPL) patients have higher absolute numbers of decidual natural killer (dNK) cells with elevated intracellular IFN-γ levels leading to a...
Increased levels of villus-derived exosomal miR-29a-3p in normal pregnancy than uRPL patients suppresses decidual NK cell production of interferon-γ and exerts a therapeutic effect in abortion-prone mice.
OBJECTIVE
Recurrent pregnancy loss (RPL) patients have higher absolute numbers of decidual natural killer (dNK) cells with elevated intracellular IFN-γ levels leading to a pro-inflammatory cytokine milieu, which contributes to RPL pathogenesis. The main objective of this study was twofold: first to explore the regulatory effects and mechanisms of villus-derived exosomes (vEXOs) from induced abortion patients or RPL patients at the level of intracellular IFN-γ in dNK cells; second to determine the validity of application of vEXOs in the treatment of unexplained RPL (uRPL) through in vitro experiments and mouse models.
METHODS
Exosomes were isolated from villus explants by ultracentrifugation, co-cultured with dNK cells, and purified by enzymatic digestion and magnetically activated cell sorting. Flow cytometry, enzyme-linked immunosorbent assays, and RT-qPCR were used to determine IFN-γ levels. Comparative miRNA analysis of vEXOs from induced abortion (IA) and uRPL patients was used to screen potential candidates involved in dNK regulation, which was further confirmed by luciferase reporter assays. IA-vEXOs were electroporated with therapeutic miRNAs and encapsulated in a China Food and Drug Administration (CFDA)-approved hyaluronate gel (HA-Gel), which has been used as a clinical biomaterial in cell therapy for > 30 years. In vivo tracking was performed using 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyaine iodide (DiR) labelling. Tail-vein and uterine horn injections were used to evaluate therapeutic effects of the engineered exosomes in an abortion-prone mouse model (CBA/J × DBA/2 J). Placental growth was evaluated based on placental weight. IFN-γ mRNA levels in mouse placentas were measured by RT-qPCR.
RESULTS
IFN-γ levels were significantly higher in dNK cells of uRPL patients than in IA patients. Both uRPL-vEXOs and IA-vEXOs could be efficiently internalized by dNK cells, whereas uRPL-vEXOs could not reduce the expression of IFN-γ by dNK cells as much as IA-vEXOs. Mechanistically, miR-29a-3p was delivered by vEXOs to inhibit IFN-γ production by binding to the 3' UTR of IFN-γ mRNA in dNK cells. For in vivo treatment, application of the HA-Gel effectively prolonged the residence time of vEXOs in the uterine cavity via sustained release. Engineered vEXOs loaded with miR-29a-3p reduced the embryo resorption rate in RPL mice with no signs of systemic toxicity.
CONCLUSION
Our study provides the first evidence that villi can regulate dNK cell production of IFN-γ via exosome-mediated transfer of miR-29a-3p, which deepens our understanding of maternal-fetal immune tolerance for pregnancy maintenance. Based on this, we developed a new strategy to mix engineered vEXOs with HA-Gel, which exhibited good therapeutic effects in mice with uRPL and could be used for potential clinical applications in uRPL treatment.
Topics: Animals; Female; Humans; Mice; Pregnancy; Abortion, Induced; Abortion, Spontaneous; Decidua; Interferon-gamma; Killer Cells, Natural; Mice, Inbred CBA; Mice, Inbred DBA; MicroRNAs; Placenta; RNA, Messenger
PubMed: 38627796
DOI: 10.1186/s12964-024-01610-0 -
Reproductive Sciences (Thousand Oaks,... Apr 2024Mucin 16 (MUC16) participates in the process of embryo implantation, but few studies have examined the association between MUC16 and pregnancy loss. To investigate this...
Mucin 16 (MUC16) participates in the process of embryo implantation, but few studies have examined the association between MUC16 and pregnancy loss. To investigate this association, the expression of MUC16 in serum and decidua was compared between women with pregnancy loss and ongoing pregnancies. In vitro experiments and animal models were used to explore the role and underlying mechanisms of MUC16 in pregnancy loss. In human study, the expression of MUC16 in serum and decidua was both consistently lower in the women with pregnancy loss compared with those in women with ongoing pregnancies. In vitro experiments revealed the interaction of MUC16 with peripheral blood natural killer (pNK) cells. MUC16 changed the phenotype and reduced the pro-inflammation ability of pNK cells. MUC16 also inhibited the cytotoxicity of pNK cells through the Src homology region 2 domain-containing phosphatase-1/extracellular signal-regulated kinase (SHP-ERK) pathway. Furthermore, MUC16 promoted the migration, invasion and tube formation of trophoblast cells by co-culturing together with pNK cells. In vivo experiments, the mouse model of abortion was used to further confirm that intraperitoneal administration of MUC16 could rescue the pregnancy loss. This study reveals the still-unknown connection between MUC16 and pNK cells and indicates that MUC16 provides a novel method for future prediction and treatment of unfavorable pregnancy outcomes.
PubMed: 38622477
DOI: 10.1007/s43032-024-01550-7