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JCI Insight Nov 2023CXCR4 is a key regulator of the development of NK cells and DCs, both of which play an important role in early placental development and immune tolerance at the...
CXCR4 is a key regulator of the development of NK cells and DCs, both of which play an important role in early placental development and immune tolerance at the maternal-fetal interface. However, the role of CXCR4 in pregnancy is not well understood. Our study demonstrates that adult-induced global genetic CXCR4 deletion, but not uterine-specific CXCR4 deletion, was associated with increased pregnancy resorptions and decreased litter size. CXCR4-deficient mice had decreased NK cells and increased granulocytes in the decidua, along with increased leukocyte numbers in peripheral blood. We found that CXCR4-deficient mice had abnormal decidual NK cell aggregates and NK cell infiltration into trophoblast areas beyond the giant cell layer. This was associated with low NK cell expression of granzyme B, a NK cell granule effector, indicative of NK cell dysfunction. Pregnancy failure in these mice was associated with abnormalities in placental vascular development and increased placental expression of inflammatory genes. Importantly, adoptive BM transfer of WT CXCR4+ BM cells into CXCR4-deficient mice rescued the reproductive deficits by normalizing NK cell function and mediating normal placental vascular development. Collectively, our study found an important role for maternal CXCR4 expression in immune cell function, placental development, and pregnancy maintenance.
Topics: Animals; Female; Mice; Pregnancy; Decidua; Placenta; Placentation; Signal Transduction; Trophoblasts
PubMed: 37815869
DOI: 10.1172/jci.insight.172216 -
BMC Genomics Oct 2023Extravillous trophoblast cell (EVT) differentiation and its communication with maternal decidua especially the leading immune cell type natural killer (NK) cell are...
BACKGROUND
Extravillous trophoblast cell (EVT) differentiation and its communication with maternal decidua especially the leading immune cell type natural killer (NK) cell are critical events for placentation. However, appropriate in vitro modelling system and regulatory programs of these two events are still lacking. Recent trophoblast organoid (TO) has advanced the molecular and mechanistic research in placentation. Here, we firstly generated the self-renewing TO from human placental villous and differentiated it into EVTs (EVT-TO) for investigating the differentiation events. We then co-cultured EVT-TO with freshly isolated decidual NKs for further study of cell communication. TO modelling of EVT differentiation as well as EVT interaction with dNK might cast new aspect for placentation research.
RESULTS
Single-cell RNA sequencing (scRNA-seq) was applied for comprehensive characterization and molecular exploration of TOs modelling of EVT differentiation and interaction with dNKs. Multiple distinct trophoblast states and dNK subpopulations were identified, representing CTB, STB, EVT, dNK1/2/3 and dNKp. Lineage trajectory and Seurat mapping analysis identified the close resemblance of TO and EVT-TO with the human placenta characteristic. Transcription factors regulatory network analysis revealed the cell-type specific essential TFs for controlling EVT differentiation. CellphoneDB analysis predicted the ligand-receptor complexes in dNK-EVT-TO co-cultures, which relate to cytokines, immunomodulation and angiogenesis. EVT was known to affect the immune properties of dNK. Our study found out that on the other way around, dNKs could exert effects on EVT causing expression changes which are functionally important.
CONCLUSION
Our study documented a single-cell atlas for TO and its applications on EVT differentiation and communications with dNKs, and thus provide methodology and novel research cues for future study of human placentation.
Topics: Pregnancy; Female; Humans; Trophoblasts; Placenta; Decidua; Cell Differentiation; Organoids; Killer Cells, Natural; Cell Movement
PubMed: 37853336
DOI: 10.1186/s12864-023-09690-x -
Frontiers in Immunology 2023Numerous lines of evidence confirm that decidual stromal cells (DSCs) play a key role in maternal-fetal immune tolerance. Under the influence of progesterone and other...
BACKGROUND
Numerous lines of evidence confirm that decidual stromal cells (DSCs) play a key role in maternal-fetal immune tolerance. Under the influence of progesterone and other hormones, the DSCs go through a process of differentiation (decidualization) during normal pregnancy. In mice, DSCs inhibit the expression of chemokines that attract abortigenic Th1 and Tc cells to the decidua. We have studied this phenomenon in humans.
METHODS
We established human DSC lines and decidualized these cells with progesterone and cAMP. We determined the expression of the chemokines , and , whose receptor CXCR3 is expressed by Th1 and Tc cells, in undifferentiated DSCs and decidualized DSCs by qRT-PCR. Activated CD3+CXCR3+ cells, including CD4+ Th1 cells and CD8+ Tc cells, were induced . The migration capacity of these activated lymphocytes was investigated in Transwell chambers with conditioned media from undifferentiated and decidualized DSCs.
RESULTS
We demonstrated that was not expressed by DSCs, whereas the expression of and was inhibited in decidualized cells. Conditioned media from decidualized cells significantly inhibited the migration of Th1 and Tc cells. We found that decidualized cells secrete factors of MW less than 6000-8000 Da, which actively inhibit the chemotaxis of these lymphocytes.
DISCUSSION
These results confirm in humans that decidualization of DSCs inhibits the expression by these cells of chemokines that attract Th1 and Tc cells and induces the secretion by DSCs of factors that inhibit the chemotaxis of these lymphocytes, thus preventing the arrival of abortigenic T cells in the decidua.
Topics: Female; Pregnancy; Humans; Animals; Mice; Chemotaxis; Culture Media, Conditioned; Progesterone; Fetus; CD8-Positive T-Lymphocytes
PubMed: 37680635
DOI: 10.3389/fimmu.2023.1223539 -
BioRxiv : the Preprint Server For... Dec 2023The uterus has critical biomechanical functions in pregnancy and undergoes dramatic material growth and remodeling from implantation to parturition. The intrinsic...
The uterus has critical biomechanical functions in pregnancy and undergoes dramatic material growth and remodeling from implantation to parturition. The intrinsic material properties of the human uterus and how they evolve in pregnancy are poorly understood. To address this knowledge gap and assess the heterogeneity of these tissues, the time-dependent material properties of all human uterine layers were measured with nanoindentation. The endometrium-decidua layer was found to be the least stiff, most viscous, and least permeable layer of the human uterus in nonpregnant and third-trimester pregnant tissues. In pregnancy, endometrium-decidua becomes stiffer and less viscous with no material property changes observed in the myometrium or perimetrium. Additionally, uterine material properties did not significantly differ between third-trimester pregnant tissues with and without placenta accreta. The foundational data generated by this study will facilitate the development of physiologically accurate models of the human uterus to investigate gynecologic and obstetric disorders.
PubMed: 37609213
DOI: 10.1101/2023.08.07.551726 -
Frontiers in Nutrition 2023Imprinted genes are important for the offspring development. To assess the relationship between obesity-related methylation and and gene expression and offspring...
BACKGROUND AND OBJECTIVE
Imprinted genes are important for the offspring development. To assess the relationship between obesity-related methylation and and gene expression and offspring growth and body composition.
METHODS
Thirty-nine overweight/obese and 25 normal weight pregnant women were selected from the "Araraquara Cohort Study" according to their pre-pregnancy BMI. Fetal growth and body composition and newborn growth were assessed, respectively, by ultrasound and anthropometry. The methylation of in maternal blood, cord blood, maternal decidua and placental villi tissues was evaluated by methylation-sensitive restriction endonuclease qPCR, and and expression by relative real-time PCR quantification. Multiple linear regression models explored the associations of DNA methylation and gene expression with maternal, fetal, and newborn parameters.
RESULTS
was less methylated in maternal blood of the overweight/obese group. There were associations of methylation in cord blood with centiles of fetal biparietal diameter (BPD) and abdominal subcutaneous fat thickness and newborn head circumference (HC); methylation in maternal decidua with fetal occipitofrontal diameter (OFD), HC, and length; methylation in placental villi with fetal OFD, HC and abdominal subcutaneous fat thickness and with newborn HC. expression in maternal decidua was associated with fetal BPD and femur length centiles and in placental villi with fetal OFD and subcutaneous arm fat. expression in maternal decidua was associated with fetal BPD and in placental villi with fetal OFD.
CONCLUSION
To our knowledge, this is the first study to demonstrate associations of imprinted genes variations at the maternal-fetal interface of the placenta and in cord blood with fetal body composition, supporting the involvement of epigenetic mechanisms in offspring growth and body composition.
PubMed: 37810933
DOI: 10.3389/fnut.2023.1170411 -
ELife Jul 2023Decidualization, denoting the transformation of endometrial stromal cells into specialized decidual cells, is a prerequisite for normal embryo implantation and a...
Gαq-PKD/PKCμ signal regulating the nuclear export of HDAC5 to induce the IκB expression and limit the NF-κB-mediated inflammatory response essential for early pregnancy.
Decidualization, denoting the transformation of endometrial stromal cells into specialized decidual cells, is a prerequisite for normal embryo implantation and a successful pregnancy in human. Here, we demonstrated that knockout of Gαq lead to an aberrantly enhanced inflammatory state during decidualization. Furthermore, we showed that deficiency of Gαq resulted in over-activation of nuclear factor (NF)-κB signaling, due to the decreased expression of , which encode the IκB protein and is the negative regulator for NF-κB. Mechanistically, Gαq deficiency decreased the Protein kinase D (PKD, also called PKCμ) phosphorylation levels, leading to attenuated HDAC5 phosphorylation and thus its nuclear export. Aberrantly high level of nuclear HDAC5 retarded histone acetylation to inhibit the induced transcription during decidualization. Consistently, pharmacological activation of the PKD/PKCμ or inhibition of the HDAC5 restored the inflammatory state and proper decidual response. Finally, we disclosed that over-active inflammatory state in Gαq-deficient decidua deferred the blastocyst hatching and adhesion in vitro, and the decidual expression of Gαq was significantly lower in women with recurrent pregnancy loss compared with normal pregnancy. In brief, we showed here that Gαq as a key regulator of the inflammatory cytokine's expression and decidual homeostasis in response to differentiation cues, which is required for successful implantation and early pregnancy.
Topics: Pregnancy; Female; Humans; NF-kappa B; Decidua; Active Transport, Cell Nucleus; Protein Kinase C; GTP-Binding Proteins; Stromal Cells; Histone Deacetylases
PubMed: 37498654
DOI: 10.7554/eLife.83083 -
Medicine Aug 2023Preeclampsia is a pregnancy complication Aim of this study was to investigate expression of Beclin1 and tumor necrosis factor (TNF)-α in normotensive and preeclamptic...
BACKGROUND
Preeclampsia is a pregnancy complication Aim of this study was to investigate expression of Beclin1 and tumor necrosis factor (TNF)-α in normotensive and preeclamptic placentas of pregnant women patients.
METHODS
Twenty normotensive and 20 preeclamptic patients placentas were dissected for paraffin- wax processing. Placental samples were embedded in parafin blocks. Sections were stained with Hematoxylin-Eosin staining and TNF-α and Beclin1 immunostaining.
RESULTS
In control group, root and floating villi were normal in histological perspectives, syncytial node number was low, vessels were normal with connective tissue. No hemorrhage was observed in the intervillous area. In preeclampsia group, decidual cell degeneration and fibrinoid accumulation increased. Vascular dilatation and congestion with mononuclear cell infiltration were observed. Beclin1 reaction was generally negative in control group. In preeclampsia group, Beclin1 reaction was increased in decidual cells, syncytial nodes and bridges and in chorionic villi and in some Hoffbauer cells. In control group, TNF-α expression was mainly negative but only in some decidual cells. In preeclampsia, TNF-α reaction was observed in degenerated decidua cells, in leukocytes and in villi.
CONCLUSION
In preeclampsia placentas, degenerated decidua cells and inflammation increased. It was thought that Beclin1 and TNF-α signals could be used as a marker in affecting the fetal structure of blood flow in preeclamptic placentas.
Topics: Female; Humans; Pregnancy; Beclin-1; Chorionic Villi; Placenta; Pre-Eclampsia; Tumor Necrosis Factor-alpha
PubMed: 37603530
DOI: 10.1097/MD.0000000000034757 -
Frontiers in Cellular and Infection... 2023Preterm birth is a leading cause of neonatal mortality, which is often complicated by intrauterine infection and inflammation. We have established a nonhuman primate...
BACKGROUND
Preterm birth is a leading cause of neonatal mortality, which is often complicated by intrauterine infection and inflammation. We have established a nonhuman primate model of Group B (GBS, ) infection-associated preterm birth. Immune checkpoints are modulators of the immune response by activating or suppressing leukocyte function and are understudied in preterm birth. The objective of this study was to spatially profile changes in immune protein expression at the maternal-fetal interface during a GBS infection with a focus on immune checkpoints.
METHODS
Twelve nonhuman primates (pigtail macaques, ) received a choriodecidual inoculation of either: 1) 1-5 X 10 colony forming units (CFU) of hyperhemolytic/hypervirulent GBS (GBSΔ, N=4); 2) an isogenic/nonpigmented strain (GBS ΔΔ, N=4); or, 3) saline (N=4). A Cesarean section was performed at preterm labor or 3 days after GBS infection or 7 days after saline inoculation. Nanostring GeoMx® Digital Spatial Profiling technology was used to segment protein expression within the amnion, chorion, and maternal decidua at the inoculation site using an immuno-oncology panel targeting 56 immunoproteins enriched in stimulatory and inhibitory immune checkpoint proteins or their protein ligands. Statistical analysis included R studio, Kruskal-Wallis, Pearson and Spearman tests.
RESULTS
Both inhibitory and stimulatory immune checkpoint proteins were significantly upregulated within the chorioamniotic membranes and decidua (VISTA, LAG3, PD-1, CD40, GITR), as well as their ligands (PD-L1, PD-L2, CD40L; all p<0.05). Immunostaining for VISTA revealed positive (VISTA+) cells, predominantly in the chorion and decidua. There were strong correlations between VISTA and amniotic fluid concentrations of IL-1β, IL-6, IL-8, and TNF-α (all p<0.05), as well as maternal placental histopathology scores (p<0.05).
CONCLUSION
Differential regulation of multiple immune checkpoint proteins in the decidua at the site of a GBS infection indicates a major perturbation in immunologic homeostasis that could benefit the host by restricting immune-driven pathologies or the pathogen by limiting immune surveillance. Protein expression of VISTA, an inhibitory immune checkpoint, was upregulated in the chorion and decidua after GBS infection. Investigating the impact of innate immune cell expression of inhibitory immune checkpoints may reveal new insights into placental host-pathogen interactions at the maternal-fetal interface.
Topics: Infant, Newborn; Animals; Humans; Pregnancy; Female; Streptococcus agalactiae; Placenta; Immune Checkpoint Proteins; Up-Regulation; Premature Birth; Cesarean Section; Streptococcal Infections; Primates
PubMed: 38239507
DOI: 10.3389/fcimb.2023.1299644 -
Current Issues in Molecular Biology Nov 2023Galectins are known to play an important role in immunoregulatory processes and autoimmune diseases. Galectin-10 is a cytoplasmic protein of human eosinophils and is...
Galectins are known to play an important role in immunoregulatory processes and autoimmune diseases. Galectin-10 is a cytoplasmic protein of human eosinophils and is involved in various eosinophilic diseases. Since increased galectin expression is already detected in the placentas of mothers with gestational diabetes mellitus (GDM), this study focuses on the specific role of galectin-10 and hints at consequences for the diagnosis and therapeutic options of GDM. It is hypothesized that the difference in galectin-10 expression will raise the pathophysiological understanding of gestational diabetes. The study population consists of 80 women: 40 healthy mothers and 40 women suffering from gestational diabetes mellitus. The expression of galectin-10 was analyzed in the syncytiotrophoblast (SCT) and the decidua of the placenta via immunohistochemistry and immunofluorescence double staining. The immunoreactivity score (IRS) was used for evaluation. The results in this study were significant for an overexpression of galectin-10 in GDM placentas compared with the control group. The syncytiotrophoblast showed overexpression in the nucleus and the cytoplasm, whereas expression of galectin-10 in the decidua was significant in the cytoplasm only. This study identified the expression changes in galectin-10 in placental tissue between healthy and GDM mothers and intensified the understanding of gestational diabetes. Assuming that gestational diabetes mellitus is involved in inflammatory processes, galectin-10 might play a role in the development and maintenance of GDM. Further investigation is required to strengthen these findings.
PubMed: 37998731
DOI: 10.3390/cimb45110554 -
Microorganisms Mar 2024The uterine microbiota has been the subject of increasing study, but its interaction with the local immune system remains unclear. Successful embryo implantation relies...
The uterine microbiota has been the subject of increasing study, but its interaction with the local immune system remains unclear. Successful embryo implantation relies on endometrial receptivity, which is pivotal for immunological tolerance to fetal antigens and precise regulation of inflammatory mediators. Emerging data suggest a dynamic interplay between endometrial microflora and the immune system, making dysbiosis a potential determinant of pregnancy outcomes. Imbalances in the regulation of immune cells in the endometrium and decidua have been associated with infertility, miscarriage, and obstetric complications. A thorough comprehension of the immune system in the female reproductive tract shows potential for improving women's health and pregnancy outcomes. The objective of this study was to evaluate the patterns of endometrial microbiota in patients with recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) and to explore their implications for endometrial immune cells and chronic endometritis (CE). Immune cells in biopsies from 107 RIF and 93 RPL patients were examined using flow cytometry. The endometrial microbial composition was analyzed using real-time polymerase chain reaction (RT-PCR). The research uncovered disrupted endometrial microbiota in most women with RIF and RPL, which was often associated with significant effects on lymphocytes, T cells, and uNK cells.
PubMed: 38543598
DOI: 10.3390/microorganisms12030547