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Prostaglandins, Leukotrienes, and... Feb 2024A pivotal event in uterine receptivity and human reproduction is the differentiation of endometrial stromal cells into decidual cells, known as decidualization....
A pivotal event in uterine receptivity and human reproduction is the differentiation of endometrial stromal cells into decidual cells, known as decidualization. Decidualization is interlinked with its inflammatory environment. Our study aimed to investigate the presence and role of pro-resolving lipid mediators in first trimester maternal tissue. We assessed the levels of LXA4 and RvD1, along with their metabolic LOX enzymes, in elective (control) and sporadic miscarriage samples. We investigated the effects of LXA4 and RvD1 on decidualization using primary endometrial stromal cells and the immortalized endometrial stromal St-T1b cell line. The upregulation of 12- and 15-LOX expression was observed in pregnancy tissue after sporadic miscarriage, suggesting an inflammatory imbalance. Furthermore, incubation with these lipid mediators led to a decrease in decidualization biomarkers PRL and IGFBP-1, accompanied by morphological changes indicative of aberrant differentiation. The expression of LOX enzymes in decidual natural killer cells suggests their involvement in regulating the inflammatory surroundings and the extent of decidualization.
Topics: Female; Humans; Pregnancy; Pregnancy Trimester, First; Abortion, Spontaneous; Decidua; Adult; Lipoxins; Arachidonate 15-Lipoxygenase; Stromal Cells; Insulin-Like Growth Factor Binding Protein 1; Prolactin; Killer Cells, Natural; Cell Line; Cell Differentiation; Endometrium; Docosahexaenoic Acids
PubMed: 38788346
DOI: 10.1016/j.plefa.2024.102619 -
Frontiers in Immunology 2024A balance between pro-inflammatory decidual CD4 T cells and regulatory T cells ( Tregs) is important for maintaining fetomaternal tolerance. Using single-cell...
A balance between pro-inflammatory decidual CD4 T cells and regulatory T cells ( Tregs) is important for maintaining fetomaternal tolerance. Using single-cell RNA-sequencing and T cell receptor repertoire analysis, we determined that diversity and clonality of decidual CD4 T cell subsets depend on gestational age. Th1/Th2 intermediate and Th1 subsets of CD4 T cells were clonally expanded in both early and late gestation, whereas Tregs were clonally expanded in late gestation. Th1/Th2 intermediate and Treg subsets showed altered gene expression in preeclampsia (PE) compared to healthy late gestation. The Th1/Th2 intermediate subset exhibited elevated levels of cytotoxicity-related gene expression in PE. Moreover, increased Treg exhaustion was observed in the PE group, and Treg subcluster analysis revealed that the effector Treg like subset drove the Treg exhaustion signatures in PE. The Th1/Th2 intermediate and effector Treg like subsets are possible inflammation-driving subsets in PE.
Topics: Humans; Female; Pre-Eclampsia; Pregnancy; Single-Cell Analysis; Gestational Age; Adult; T-Lymphocytes, Regulatory; Forkhead Transcription Factors; CD4-Positive T-Lymphocytes; Sequence Analysis, RNA; T-Lymphocyte Subsets; Th1 Cells; Decidua
PubMed: 38774869
DOI: 10.3389/fimmu.2024.1401738 -
Journal of Translational Medicine May 2024Miscarriage is a frustrating complication of pregnancy that is common among women of reproductive age. Insufficient decidualization which not only impairs embryo...
BACKGROUND
Miscarriage is a frustrating complication of pregnancy that is common among women of reproductive age. Insufficient decidualization which not only impairs embryo implantation but disturbs fetomaternal immune-tolerance, has been widely regarded as a major cause of miscarriage; however, the underlying mechanisms resulting in decidual impairment are largely unknown.
METHODS
With informed consent, decidual tissue from patients with spontaneous abortion or normal pregnant women was collected to detect the expression profile of UCHL1. Human endometrial stromal cells (HESCs) were used to explore the roles of UCHL1 in decidualization and dNK modulation, as well as the mechanisms involved. C57/BL6 female mice (7-10 weeks old) were used to construct pregnancy model or artificially induced decidualization model to evaluate the effect of UCHL1 on mice decidualization and pregnancy outcome.
RESULTS
The Ubiquitin C-terminal hydrolase L1 (UCHL1), as a deubiquitinating enzyme, was significantly downregulated in decidua from patients with miscarriage, along with impaired decidualization and decreased dNKs. Blockage of UCHL1 led to insufficient decidualization and resultant decreased expression of cytokines CXCL12, IL-15, TGF-β which were critical for generation of decidual NK cells (dNKs), whereas UCHL1 overexpression enhanced decidualization accompanied by increase in dNKs. Mechanistically, the promotion of UCHL1 on decidualization was dependent on its deubiquitinating activity, and intervention of UCHL1 inhibited the activation of JAK2/STAT3 signaling pathway, resulting in aberrant decidualization and decreased production of cytokines associated with dNKs modulation. Furthermore, we found that inhibition of UCHL1 also disrupted the decidualization in mice and eventually caused adverse pregnancy outcome.
CONCLUSIONS
UCHL1 plays significant roles in decidualization and dNKs modulation during pregnancy in both humans and mice. Its deficiency indicates a poor pregnancy outcome due to defective decidualization, making UCHL1 a potential target for the diagnosis and treatment of miscarriage.
Topics: Ubiquitin Thiolesterase; Female; Decidua; Animals; Pregnancy; Abortion, Spontaneous; Humans; Mice, Inbred C57BL; Killer Cells, Natural; Adult; Mice; Stromal Cells; Signal Transduction
PubMed: 38769534
DOI: 10.1186/s12967-024-05253-0 -
Research Square May 2024Preeclampsia (PEC) is a complication of pregnancy associated with hypertension and the risk of eclampsia. The pathophysiology of PEC is unknown and identifying factors...
Preeclampsia (PEC) is a complication of pregnancy associated with hypertension and the risk of eclampsia. The pathophysiology of PEC is unknown and identifying factors associated with PEC during pregnancy is crucial for placental, fetal, and maternal health. Renalase (RNLS) is an anti-inflammatory secretory flavoprotein associated with hypertension. Recent data demonstrated a correlation between maternal serum RNLS and PEC, and work from our group identified RNLS expression in the placenta. However, it remains unknown whether RNLS levels in placenta are altered by preeclampsia. Additionally, it is unclear if there is a differential effect of preterm and term PEC on RNLS. We demonstrate that serum RNLS was reduced in preterm cases of PEC. Similarly, placental RNLS was diminished in the chorion of preterm cases of PEC. However, a reduction of RNLS in the decidua was observed with all cases of PEC, while the levels of RNLS within the placental villi were similar in all cases. Overall, we demonstrate that RNLS correlates with PEC both systemically in maternal serum and locally within the placenta, with variable effects on the different layers of the placenta and more pronounced in preterm cases.
PubMed: 38765989
DOI: 10.21203/rs.3.rs-4319658/v1 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... May 2024To investigate the effect of subacute exposure of Di (2-ethylhexyl) phthalate (DEHP) on endometrial decidualization in mice.
OBJECTIVES
To investigate the effect of subacute exposure of Di (2-ethylhexyl) phthalate (DEHP) on endometrial decidualization in mice.
METHODS
CD1 mice were orally administrated with 300 mg·kg·d (low-dose group), 1000 mg·kg·d (medium-dose group), or 3000 mg·kg·d DEHP (1/10 LD, high-dose group) for 28 days, respectively. The early natural pregnancy model and artificially induced decidualization model were established, and the uterine tissues were collected on D7 of natural pregnancy and D8 of artificially induced decidualization, respectively. The effects of subacute exposure to DEHP on the decidualization of mice were detected by HE staining, Masson staining, TUNEL staining, and Western blotting, respectively. A model of spontaneous abortion was constructed in mice after subacute exposure to 300 mg·kg·d DEHP, and the effect of impaired decidualization on pregnancy was investigated by observing the pregnancy outcome on the 10th day of gestation.
RESULTS
Compared with the control group, the conception rate was significantly lower in the high-dose DEHP subacute exposure group. HE staining showed that, compared with the control group, the decidual stromal cells in the low- and medium-dose exposure groups were disorganized, the nuclei of the cells were irregular, the cytoplasmic staining was uneven, and the number of polymorphonuclear cells was significantly reduced. Masson staining showed that compared with the control group, the collagen fibers in the decidua region of the DEHP low-dose group and the medium-dose group were more distributed, more abundant and more disorderly. TUNEL staining showed increased apoptosis in the decidua area compared to the control group. Western blotting showed that the expression of BMP2, a marker molecule for endometrial decidualization, was significantly reduced. The abortion rate and embryo resorption rate were significantly higher, and the number of embryos, uterine wet weight, uterine area and placenta wet weight were significantly lower in mice exposed to 300 mg·kg·d DEHP than in control mice stimulated by mifepristone abortifacient drug.
CONCLUSIONS
Subacute exposure to DEHP leads to impaired endometrial decidualization during early pregnancy and exacerbates the risk of adverse pregnant outcomes in mice.
PubMed: 38763769
DOI: 10.3724/zdxbyxb-2023-0583 -
Cell Reports Jun 2024The decidua plays a crucial role in providing structural and trophic support to the developing conceptus before placentation. Following embryo attachment, embryonic...
The decidua plays a crucial role in providing structural and trophic support to the developing conceptus before placentation. Following embryo attachment, embryonic components intimately interact with the decidual tissue. While evidence indicates the participation of embryo-derived factors in crosstalk with the uterus, the extent of their impact on post-implantation decidual development requires further investigation. Here, we utilize transgenic mouse models to selectively eliminate primary trophoblast giant cells (pTGCs), the embryonic cells that interface with maternal tissue at the forefront. pTGC ablation impairs decidualization and compromises decidual interferon response and lipid metabolism. Mechanistically, pTGCs release factors such as interferon kappa (IFNK) to strengthen the decidual interferon response and lipoprotein lipase (LPL) to enhance lipid accumulation within the decidua, thereby promoting decidualization. This study presents genetic and metabolomic evidence reinforcing the proactive role of pTGC-derived factors in mobilizing maternal resources to strengthen decidualization, facilitating the normal progression of early pregnancy.
Topics: Female; Animals; Trophoblasts; Lipid Metabolism; Decidua; Mice; Pregnancy; Interferons; Endometrium; Signal Transduction; Mice, Transgenic
PubMed: 38762885
DOI: 10.1016/j.celrep.2024.114246 -
Tissue & Cell Jun 2024GATA3 plays critical roles in the development and function of various tissues and organs throughout the body. Likewise, TGF-β signaling is critical for placental...
GATA3 plays critical roles in the development and function of various tissues and organs throughout the body. Likewise, TGF-β signaling is critical for placental development and can interact with GATA3. We aimed to investigate the involvement of the multifunctional cytokine and transcription factor in trophoblast development. By using immunohistochemistry, we evaluated the localization and expression level of GATA3 and TGF-β in placentas at term of normal pregnancy and with pre-eclampsia. Up-regulation of both GATA3 and TGF-β was observed in pathological placentas, with localization in the villus epithelium (syncytiotrophoblast) stroma and decidua. Our data show altered expression of TGF-β and GATA3, which downstream could lead to a cascade of events that negatively influence trophoblast development and contribute to the pathogenesis of pre-eclampsia.
Topics: Pre-Eclampsia; Humans; Pregnancy; Female; GATA3 Transcription Factor; Placenta; Transforming Growth Factor beta; Adult; Trophoblasts
PubMed: 38759523
DOI: 10.1016/j.tice.2024.102402 -
Environmental Research May 2024Triphenyl phosphate (TPhP) is an organophosphate flame retardant that is widely used in many commercial products. The United States Environmental Protection Agency has...
Triphenyl phosphate (TPhP) is an organophosphate flame retardant that is widely used in many commercial products. The United States Environmental Protection Agency has listed TPhP as a priority compound that requires health risk assessment. We previously found that TPhP could accumulate in the placentae of mice and impair birth outcomes by activating peroxisome proliferator-activated receptor gamma (PPARγ) in the placental trophoblast. However, the underlying mechanism remains unknown. In this study, we used a mouse intrauterine exposure model and found that TPhP induced preeclampsia (PE)-like symptoms, including new on-set gestational hypertension and proteinuria. Immunofluorescence analysis showed that during placentation, PPARγ was mainly expressed in the labyrinth layer and decidua of the placenta. TPhP significantly decreased placental implantation depth and impeded uterine spiral artery remodeling by activating PPARγ. The results of the in vitro experiments confirmed that TPhP inhibited extravillous trophoblast (EVT) cell migration and invasion by activating PPARγ and inhibiting the PI3K-AKT signaling pathway. Overall, our data demonstrated that TPhP could activate PPARγ in EVT cells, inhibit cell migration and invasion, impede placental implantation and uterine spiral artery remodeling, then induce PE-like symptom and impair birth outcomes. Although the exposure doses used in this study was several orders of magnitude higher than human daily intake, our study highlights the placenta as a potential target organ of TPhP worthy of further research.
PubMed: 38754605
DOI: 10.1016/j.envres.2024.119159 -
Frontiers in Endocrinology 2024Nutritional deficiency occurs frequently during pregnancy and breastfeeding. Tryptophan (Trp), an essential amino acid which is critical for protein synthesis, serves as...
INTRODUCTION
Nutritional deficiency occurs frequently during pregnancy and breastfeeding. Tryptophan (Trp), an essential amino acid which is critical for protein synthesis, serves as the precursor for serotonin, melatonin, and kynurenine (Kyn). The imbalance between serotonin and kynurenine pathways in Trp metabolism is closely related to inflammation and depression. This study assessed the effects of Trp deficiency on mouse early pregnancy.
METHODS
Embryo implantation and decidualization were analyzed after female mice had been fed diets containing 0.2% Trp (for the control group), 0.062% Trp (for the low Trp group) and 0% Trp (for the Trp-free group) for two months. The uteri of the mice were collected on days 4, 5, and 8 of pregnancy for further analysis.
RESULTS
On day 8 of pregnancy, the number of implantation sites were found to be similar between the control and the low Trp groups. However, no implantation sites were detected in the Trp-free group. On day 5 of pregnancy, plane polarity- and decidualization-related molecules showed abnormal expression pattern in the Trp-free group. On day 4 of pregnancy, there was no significant difference in uterine receptivity molecules between the low-Trp group and the control group, but uterine receptivity was abnormal in the Trp-free group. At implantation sites of the Trp-free group, IDO and AHR levels were markedly elevated. This potentially increased levels of Kyn, 2-hydroxy estradiol, and 4-hydroxy estradiol to affect decidualization.
CONCLUSIONS
Trp-free diet may impair decidualization via the IDO-KYN-AHR pathway.
Topics: Animals; Female; Embryo Implantation; Tryptophan; Mice; Pregnancy; Decidua; Diet; Kynurenine
PubMed: 38752181
DOI: 10.3389/fendo.2024.1356914 -
American Journal of Physiology. Cell... Jul 2024During the process of decidualization, the stromal cells of the endometrium change dynamically to create a favorable environment for embryo implantation. Lysosome...
During the process of decidualization, the stromal cells of the endometrium change dynamically to create a favorable environment for embryo implantation. Lysosome activity has often been associated with physiological changes in the endometrium during the preimplantation period and early pregnancy. In this study, the effect of para-nonylphenol (p-NP), an endocrine disruptor, on human immortalized endometrial stromal cells (tHESCs) was investigated. After exposure to p-NP (1 nM and 1 pM), the cells were examined for the decidualization markers connexin-43, insulin like growth factor binding protein 1 (IGFBP1), and prolactin. In addition, the effect of p-NP on lysosome biogenesis and exocytosis was investigated by examining the expression and localization of the transcription factor EB (TFEB) and that of the lysosomal-associated membrane protein 1 (LAMP-1). Finally, we evaluated the effect of p-NP on extracellular matrix (ECM) remodeling using a fibronectin assay. Our results showed that p-NP reduced the expression of prolactin protein, increased the nuclear localization of TFEB, and induced the increase and translocation of the lysosomal protein LAMP-1 to the membrane of tHESCs. The data indicate an impairment of decidualization and suggest an increase in lysosomal biogenesis and exocytosis, which is supported by the higher release of active cathepsin D by tHESCs. Given the importance of cathepsins in the processing and degradation of the ECM during trophoblast invasiveness and migration into the decidua, our results appear to be clear evidence of the negative effects of p-NP on endometrial processes that are fundamental to reproductive success and the establishment of pregnancy. Endocrine disruptors, such as para-nonylphenol, affect the decidualization of human endometrial stromal cells with an impact on decidualization itself, lysosome biogenesis and exocytosis, and extracellular matrix remodeling. All these alterations may negatively impact embryo implantation with the success of reproduction and the establishment of pregnancy.
Topics: Humans; Female; Lysosomes; Stromal Cells; Phenols; Endometrium; Prolactin; Decidua; Exocytosis; Embryo Implantation; Endocrine Disruptors; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Insulin-Like Growth Factor Binding Protein 1; Extracellular Matrix; Pregnancy; Lysosomal-Associated Membrane Protein 1
PubMed: 38738312
DOI: 10.1152/ajpcell.00604.2023