Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Pregnancy and Childbirth
Published in: BMC Pregnancy and Childbirth 1/2020

01-12-2020 | Research article

Involvement of CXCL12/CXCR4 in the motility of human first-trimester endometrial epithelial cells through an autocrine mechanism by activating PI3K/AKT signaling

Authors: Jiayi Zheng, Danni Qu, Chen Wang, Ling Ding, Wenhui Zhou

Published in: BMC Pregnancy and Childbirth | Issue 1/2020

Login to get access

Abstract

Background

CXCL12(chemokine ligand 12, CXCL12) and its receptors CXCR4 are widely expressed in maternal-fetal interface and plays an adjust role in materno-fetal dialogue and immune tolerance during early pregnancy. This study aimed to evaluate the role and mechanism of self-derived CXCL12 in modulating the functions of human first-trimester endometrial epithelial cells (EECs) and to identify the potential protein kinase signaling pathways involved in the CXCL12/CXCR4’s effect on EECs.

Methods

The expression of CXCL12 and CXCR4 in EECs was measured by using immunohistochemistry, immunofluorescence, real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The effects of EEC-conditioned medium (EEC-CM) and recombinant human CXCL12 (rhCXCL12) on EEC migration and invasion in vitro were evaluated with migration and invasion assays. In-cell western blot analysis was used to examine the phosphorylation of protein kinase B (AKT), extracellular regulated protein kinases (ERKs) and phosphatidylinositol 3-kinase (PI3K) after CXCL12 treatment.

Results

CXCL12 and CXCR4 were both expressed in human first-trimester EECs at the mRNA and protein level. Both EEC-CM and rhCXCL12 significantly increased the migration and invasion of EECs (P < 0.05), which could be blocked by neutralizing antibodies against CXCR4 (P < 0.05) or CXCL12 (P < 0.05), respectively. CXCL12 activated both PI3K/AKT and ERK1/2 signaling and CXCR4 neutralizing antibody effectively reduced CXCL12-induced phosphorylation of AKT and ERK1/2. LY294002, a PI3K-AKT inhibitor, was able to reverse the promotive effect of EEC-CM or rhCXCL12 on EEC migration and invasion.

Conclusions

Human first-trimester EECs promoted their own migration and invasion through the autocrine mechanism with CXCL12/CXCR4 axis involvement by activating PI3K/AKT signaling. This study contributes to a better understanding of the epithelium function mediated by chemokine and chemokine receptor during normal pregnancy.
Literature
1.
Paria BC, Lim H, Das SK, Reese J, Dey SK. Molecular signaling in uterine receptivity for implantation. Semin Cell Dev Biol. 2000;11(2):67–76.CrossRef
2.
Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18(12):1754–67.CrossRef
3.
Wang X, Wu SP, DeMayo FJ. Hormone dependent uterine epithelial-stromal communication for pregnancy support. Placenta. 2017;60(Suppl 1):S20–6.CrossRef
4.
Ding JL, Diao LH, Yin TL, Huang CY, Yin B, Chen C, Zhang Y, Li J, Cheng YX, Zeng Y, Yang J. Aberrant expressions of endometrial Id3 and CTLA-4 are associated with unexplained repeated implantation failure and recurrent miscarriage. Am J Reprod Immunol. 2017;78(2):e12632. https://​doi.​org/​10.​1111/​aji.​12632 Epub 2017 Feb 21.CrossRef
5.
Ruiz-Alonso M, Blesa D, Díaz-Gimeno P, Gómez E, Fernández-Sánchez M, Carranza F, Carrera J, Vilella F, Pellicer A, Simón C. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril. 2013;100(3):818–24.CrossRef
6.
Huang J, Qin H, Yang Y, Chen X, Zhang J, Laird S, Wang CC, Chan TF, Li TC. A comparison of transcriptomic profiles in endometrium during window of implantation between women with unexplained recurrent implantation failure and recurrent miscarriage. Reproduction. 2017;153(6):749–58.CrossRef
7.
Strowitzki T, Germeyer A, Popovici R, von Wolff M. The human endometrium as a fertility-determining factor. Hum Reprod Update. 2006;12(5):617–30.CrossRef
8.
Toth B, Würfel W, Germeyer A, Hirv K, Makrigiannakis A, Strowitzki T. Disorders of implantation--are there diagnostic and therapeutic options? J Reprod Immunol. 2011;90(1):117–23.CrossRef
9.
Yoshinaga K. Research on blastocyst implantation essential factors (BIEFs). Am J Reprod Immunol. 2010;63(6):413–24.CrossRef
10.
Kumar A, Kumar S, Dinda AK, Luthra K. Differential expression of CXCR4 receptor in early and term human placenta. Placenta. 2004;25(4):347–51.CrossRef
11.
Schanz A, Red-Horse K, Hess AP, Baston-Büst DM, Heiss C, Krüssel JS. Oxygen regulates human cytotrophoblast migration by controlling chemokine and receptor expression. Placenta. 2014;35(12):1089–94.CrossRef
12.
Jaleel MA, Tsai AC, Sarkar S, Freedman PV, Rubin LP. Stromal cell-derived factor-1 (SDF-1) signalling regulates human placental trophoblast cell survival. Mol Hum Reprod. 2004;10(12):901–9.CrossRef
13.
Wu X, Jin LP, Yuan MM, Zhu Y, Wang MY, Li DJ. Human first-trimester trophoblast cells recruit CD56brightCD16- NK cells into decidua by way of expressing and secreting of CXCL12/stromal cell-derived factor 1. J Immunol. 2005;175(1):61–8.CrossRef
14.
Barrientos G, Tirado-González I, Freitag N, Kobelt P, Moschansky P, Klapp BF, Thijssen VL, Blois SM. CXCR4(+) dendritic cells promote angiogenesis during embryo implantation in mice. Angiogenesis. 2013;16(2):417–27.CrossRef
15.
Virgintino D, Errede M, Rizzi M, Girolamo F, Strippoli M, Wälchli T, Robertson D, Frei K, Roncali L. The CXCL12/CXCR4/CXCR7 ligand-receptor system regulates neuro-glio-vascular interactions and vessel growth during human brain development. J Inherit Metab Dis. 2013;36(3):455–66.CrossRef
16.
Zhu Y, Murakami F. Chemokine CXCL12 and its receptors in the developing central nervous system: emerging themes and future perspectives. Dev Neurobiol. 2012;72(10):1349–62.CrossRef
17.
Hwang HS, Kwon HS, Sohn IS, Park YW, Kim YH. Increased CXCL12 expression in the placentae of women with pre-eclampsia. Eur J Obstet Gynecol Reprod Biol. 2012;160(2):137–41.CrossRef
18.
Lu J, Zhou WH, Ren L, Zhang YZ. CXCR4, CXCR7, and CXCL12 are associated with trophoblastic cells apoptosis and linked to pathophysiology of severe preeclampsia. Exp Mol Pathol. 2016;100(1):184–91.CrossRef
19.
Jones CJ, Choudhury RH, Aplin JD. Tracking nutrient transfer at the human maternofetal interface from 4 weeks to term. Placenta. 2015;36(4):372–80.CrossRef
20.
Hirota Y, Osuga Y, Hasegawa A, Kodama A, Tajima T, Hamasaki K, Koga K, Yoshino O, Hirata T, Harada M, Takemura Y, Yano T, Tsutsumi O, Taketani Y. Interleukin (IL)-1beta stimulates migration and survival of first-trimester villous cytotrophoblast cells through endometrial epithelial cell-derived IL-8. Endocrinology. 2009;150:350–6.CrossRef
21.
Salamonsen LA, Evans J, Nguyen HP, Edgell TA. The microenvironment of human implantation: determinant of reproductive success. Am J Reprod Immunol. 2016;75(3):218–25.CrossRef
22.
Aplin JD, Ruane PT. J. Embryo-epithelium interactions during implantation at a glance. Cell Sci. 2017;130(1):15–22.CrossRef
23.
Hempstock J, Cindrova-Davies T, Jauniaux E, Burton GJ. Endometrial glands as a source of nutrients, growth factors and cytokines during the first trimester of human pregnancy: a morphological and immunohistochemical study. Reprod Biol Endocrinol. 2004;2:58.CrossRef
24.
Burton GJ, Jauniaux E, Charnock-Jones DS. Human early placental development: potential roles of the endometrial glands. Placenta. 2007;(Suppl A):S64–9.CrossRef
25.
Zhou WH, Du MR, Dong L, Yu J, Li DJ. Chemokine CXCL12 promotes the cross-talk between trophoblasts and decidual stromal cells in human first-trimester pregnancy. Hum Reprod. 2008;23(12):2669–79.CrossRef
26.
Ren L, Liu YQ, Zhou WH, Zhang YZ. Trophoblasts-derived chemokine CXCL12 promotes CXCR4 expression and invasion of human first-trimester decidual stromal cells. Hum Reprod. 2012;27(2):366–74.CrossRef
27.
Zhou WH, Ren L, Liu Y, Zhang YZ. Expression of chemokine receptor CXCR7 in human first-trimester trophoblasts and decidual stromal cells. Chinese J Clinicians. 2013;7:1436–40.
28.
Zhou WH, Wu X, Hu WD, Du MR. Co-expression of CXCR4 and CXCR7 in human endometrial stromal cells is modulated by steroid hormones. Int J Clin Exp Pathol. 2015;8:2449–60.PubMedPubMedCentral
29.
Hu W, Zhen X, Xiong B, Wang B, Zhang W, Zhou W. CXCR6 is expressed in human prostate cancer in vivo and is involved in the in vitro invasion of PC3 and LNCap cells. Cancer Sci. 2008;99(7):1362–9.CrossRef
30.
Hu W, Liu Y, Zhou W, Si L, Ren L. CXCL16 and CXCR6 are coexpressed in human lung cancer in vivo and mediate the invasion of lung cancer cell lines in vitro. PLoS One. 2014;9(6):e99056.CrossRef
31.
Liu YQ, Ren L, Zhou WH, Zhang YZ. Isolation, culture and identification of decidual stromal cells and EECidual epithelial cells of human first-trimester pregnancy. Medical J Wuhan University. 2012;33:195–8.
32.
Zhou WH, Du MR, Dong L, Zhu XY, Yang JY, He YY, Li DJ. Cyclosporin A increases expression of matrix metalloproteinase 9 and 2 and invasiveness in vitro of the first-trimester human trophoblast cells via the mitogen-activated protein kinase pathway. Human Reproduction. 2007;22(10):2743–50.CrossRef
33.
Egorina EM, Sovershaev MA, Osterud B. In-cell Western assay: a new approach to visualize tissue factor in human monocytes. J Thromb Haemost. 2006;4:614–20.CrossRef
34.
Du MR, Zhou WH, Piao HL, Li MQ, Tang CL, Li DJ. Cyclosporin A promotes crosstalk between human cytotrophoblast and deidual stromal cell through up-regulating CXCL12/CXCR4 interaction. Hum Reprod. 2012;27(7):1955–65.CrossRef
35.
Piao HL, Wang SC, Tao Y, Fu Q, Du MR, Li DJ. CXCL12/CXCR4 signal involved in the regulation of trophoblasts on peripheral NK cells leading to Th2 bias at the maternal-fetal interface. Eur Rev Med Pharmacol Sci. 2015;19(12):2153–61.PubMed
36.
Moser G, Weiss G, Gauster M, Sundl M, Huppertz B. Evidence from the very beginning: endoglandular trophoblasts penetrate and replace uterine glands in situ and in vitro. Hum Reprod. 2015;30(12):2747–57.CrossRef
37.
Spencer TE. Biological roles of uterine glands in pregnancy. Semin Reprod Med. 2014;32(5):346–57.CrossRef
38.
Grewal S, Carver JG, Ridley AJ, Mardon HJ. Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration. Proc Natl Acad Sci U S A. 2008;105:16189–94.CrossRef
Metadata
Title
Involvement of CXCL12/CXCR4 in the motility of human first-trimester endometrial epithelial cells through an autocrine mechanism by activating PI3K/AKT signaling
Authors
Jiayi Zheng
Danni Qu
Chen Wang
Ling Ding
Wenhui Zhou
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Pregnancy and Childbirth / Issue 1/2020
Electronic ISSN: 1471-2393
DOI
https://doi.org/10.1186/s12884-020-2788-3

Other articles of this Issue 1/2020

BMC Pregnancy and Childbirth 1/2020 Go to the issue

Research article

Maternal near miss and mortality attributable to hypertensive disorders in a tertiary hospital, Tanzania; a cross-sectional study

Research article

Antenatal depression and anxiety and early pregnancy BMI among White British and South Asian women: retrospective analysis of data from the Born in Bradford cohort

Research article

Attitudes and beliefs in Swedish midwives and obstetricians towards obesity and gestational weight management

Research article

Postpartum haemorrhage (PPH) rates in randomized trials of PPH prophylactic interventions and the effect of underlying participant PPH risk: a meta-analysis

Research article

Coverage of the WHO’s four essential elements of newborn care and their association with neonatal survival in southern Nepal

Research article

Comparison of the labor curves with and without combined spinal-epidural analgesia in nulliparous women- a retrospective study