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    Modulatory effects of trophoblast-secreted CXCL12 on the migration and invasion of human first-trimester decidual epithelial cells are mediated by CXCR4 rather than CXCR7. Zheng Jiayi,Wang Haiping,Zhou Wenhui Reproductive biology and endocrinology : RB&E BACKGROUND:Maternal-fetal crosstalk during embryo implantation is complex and regulated by local signaling molecules. Chemokines and their receptors are critical signaling components required for implantation and the process of pregnancy. This study aimed to explore whether human first-trimester trophoblast cells (TCs) were capable of modulating the migration and invasion of human first-trimester decidual epithelial cells (DECs) via CXCL12/CXCR4/CXCR7 signaling. METHOD:The expression of CXCR4 and CXCR7 in DECs was examined by immunohistochemistry, immunocytochemistry, immunofluorescence, flow cytometry, real-time polymerase chain reactions and western blotting. The effects of recombinant human CXCL12 (rhCXCL12) and TC-conditioned medium (TC-CM) on DEC viability in vitro were explored using a viability assay. The modulatory effects of rhCXCL12 and TC/DEC co-cultures on DEC migration and invasion were examined with migration/invasion assays. RESULT:CXCR4 and CXCR7 were co-expressed in human first-trimester DECs. Human rhCXCL12 and TC-CM had no effects on DEC viability in vitro (P > 0.05). Both exogenous CXCL12 and co-culture with TCs significantly increased the migration and invasion of DECs (P < 0.05). Neutralizing antibodies against CXCR4 (P < 0.05) or CXCL12 (P < 0.05), but not CXCR7 (P > 0.05), significantly blocked the enhanced migration and invasion of DECs induced by exogenous CXCL12 or TC co-culture. CONCLUSIONS:CXCR4 and CXCR7 were co-expressed in human first-trimester DECs. TC-derived CXCL12 promoted the migration and invasion of DECs via CXCR4, but not CXCR7, in a paracrine manner during early pregnancy. 10.1186/s12958-018-0333-2
    Chemokines as the modulators of endometrial epithelial cells remodelling. Złotkowska A,Andronowska A Scientific reports Previous studies highlighted chemokines as potential factors regulating changes in the endometrium during early pregnancy. The current study aimed to screen the effects of a broad range of chemokines and indicate those that are involved in porcine luminal epithelial (LE) cell remodelling. Messenger RNA expression of chemokines (CCL2, CCL4, CCL5, CCL8, CXCL2, CXCL8, CXCL10 and CXCL12) and both the mRNA and protein expression of their receptors (CCR1, CCR2, CCR3, CCR5, CXCR2, CXCR3, CXCR4) were detected in LE cells. Exogenous CCL8 enhanced the proliferative and migration potential of LE cells and their motility in the environment with its stable concentration. The adhesive properties of LE cells were negatively affected by CCL8. However, CXCL12 positively affected the proliferation, motility and adhesion of LE cells as well as caused a decrease in MUC1 mRNA expression. To conclude, our studies determined that exogenous chemokines affected critical endometrial epithelial cell functions in the context of embryo implantation. We suggest that of all the examined factors, chemokine CCL8 participates in the establishment of a proper environment for embryo implantation, whereas CXCL12, apart from participation in endometrial receptivity, promotes embryo attachment. 10.1038/s41598-019-49502-5
    The chemokine receptor CXCR4 and its ligand CXCL12 are activated during implantation and placentation in sheep. Ashley Ryan L,Antoniazzi Alfredo Q,Anthony Russell V,Hansen Thomas R Reproductive biology and endocrinology : RB&E BACKGROUND:The progression of implantation and placentation in ruminants is complex and is regulated by interplay between sex steroids and local signaling molecules, many of which have immune function. Chemokines and their receptors are pivotal factors in implantation and vascularization of the placenta. Based on known critical roles for chemokine receptor 4 (CXCR4) during early pregnancy in other species, we hypothesized that CXCR4 and its ligand CXCL12 would increase in the endometrium and conceptus in response to implantation in ewes. The objectives of the current study were to determine if CXCL12 and CXCR4 were upregulated in: endometrium from pregnant compared to non-pregnant ewes and in, conceptuses, cotyledons, caruncles and intercaruncular tissue. METHODS:Tissues were collected from sheep on Days 12, 13, 14, and 15 of either the estrous cycle or pregnancy and from pregnant ewes on Days 35 and 50. Blood samples from jugular and uterine vein were also collected on all days. Conceptuses were collected from mature ewes on Days 13, 15, 16, 17, 21 and 30 of gestation. Real time PCR was used to determine relative mRNA concentrations for CXCL12 and CXCR4 and Western blot analysis was employed to confirm protein concentration. RESULTS:Differences described are P < 0.05. In the endometrium, CXCR4 mRNA and protein was greater on Day 15 of pregnancy compared to the estrous cycle. CXCL12 and CXCR4 mRNA in conceptuses was greater on Days 21 and 30 compared to earlier days. CXCL12 mRNA was greater in cotyledons on Day 35 compared to Day 50. On Day 35 of gestation, CXCR4 was greater compared to Day 50 in caruncle and intercaruncular tissue. White blood cells obtained from jugular and uterine vein collection had the greatest mRNA concentration of CXCL12 on Day 35 of pregnancy. CONCLUSIONS:A comprehensive analysis of CXCL12 and CXCR4 expression in fetal and maternal tissues during early pregnancy is reported with noteworthy differences occurring during implantation and placentation in sheep. We interpreted these data to mean that the CXCL12/CXCR4 pathway is activated during implantation and placentation in sheep and is likely playing a role in the communication between trophoblast cells and the maternal endometrium. 10.1186/1477-7827-9-148
    Chorionic gonadotrophin regulates CXCR4 expression in human endometrium via E-series prostanoid receptor 2 signalling to PI3K-ERK1/2: implications for fetal-maternal crosstalk for embryo implantation. Sales Kurt J,Grant Vivien,Catalano Rob D,Jabbour Henry N Molecular human reproduction Murine knock-out models and blastocyst co-culture studies have identified prostaglandin-endoperoxide synthase (PTGS) 2, prostaglandin (PG) E receptor 2 (PTGER2) and the chemokine receptor CXCR4 as important regulators of early pregnancy events. In vitro studies and studies in non-human primates have shown that these proteins are regulated in the endometrium by the early embryonic signal, chorionic gonadotrophin (CG). Here we show that expressions of PTGER2 and CXCR4 are elevated during the mid-secretory phase of the menstrual cycle and decidua of early pregnancy in humans. Using first trimester decidua explants, we show that CG induces expression of PTGS2 and biosynthesis of PGE₂, and expression of PTGER2. Subsequently, PGE₂via PTGER2 induces expression of CXCR4. Using an in vitro model system of Ishikawa endometrial epithelial cells stably expressing PTGER2 and human first trimester decidua explants, we demonstrate that CXCR4 expression is regulated by PTGER2 via the epidermal growth factor receptor (EGFR)-phosphatidylinositol-3-kinase (PI3K)-extracellular signal-regulated kinase (ERK1/2) pathway.Taken together, our data suggest that early embryonic signals may regulate fetal-maternal crosstalk in the human endometrium by inducing CXCR4 expression via the PGE₂-PTGER2-mediated induction of the EGFR, PI3K and ERK1/2 pathways. 10.1093/molehr/gaq069
    The expression and biological function of chemokine CXCL12 and receptor CXCR4/CXCR7 in placenta accreta spectrum disorders. Long Yu,Jiang Yonghua,Zeng Jingjing,Dang Yiwu,Chen Yue,Lin Jueying,Wei Hongwei,Xia Hongwei,Long Junqing,Luo Cuizhen,Chen Zhiwei,Huang Yaling,Li MuJun Journal of cellular and molecular medicine OBJECTIVES:Investigation of mechanism related to excessive invasion of trophoblast cells in placenta accreta spectrum disorders (PAS) provides more strategies and ideas for clinical diagnosis and treatment. MATERIALS AND METHODS:Blood and placental samples were collected from included patients. The distribution and expression of CXCL12, CXCR4 and CXCR7 proteins in the paraffin of placental tissue in the included cases were analysed, and we analyse the downstream pathways or key proteins involved in cell invasion. RESULTS:Firstly, our results determined that CXCL12 and CXCR4/CXCR7 were increased in extravillous trophoblastic cell (CXCL12: P < .001; CXCR4: P < .001; CXCR7: P < .001), and the expression levels were closely related to the invasion depth of trophoblastic cells. Secondly, CXCL12 has the potential to become a biochemical indicator of PAS since the high expression of placental trophoblast CXCL12 may be an important source of blood CXCL12. Using lentivirus-mediated RNA interference and overexpression assay, it was found that both chemokine CXCL12 and receptor CXCR4/CXCR7 are associated with regulation of trophoblast cell proliferation, migration and invasion. Further results proved that through the activating the phosphorylation and increasing the expression of MLC and AKT proteins in the Rho/rock, PI3K/AKT signalling pathway, CXCL12, CXCR4 and CXCR7 could up-regulate the expression of RhoA, Rac1 and Cdc42 proteins to promote the migration and invasion of extravillous trophoblastic cell and ultimately formate the placenta accrete compare to the normal placenta. CONCLUSIONS:Our research proved that trophoblasts may contribute to a PAS-associated increase in CXCL12 levels in maternal blood. CXCL12 is not only associated with biological roles of PAS, but may also be potential for prediction of PAS. 10.1111/jcmm.14990