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Panting EN, Weight JH, Sartori JA, Coall DA, Smith JT. The role of placental kisspeptin in trophoblast invasion and migration: an assessment in Kiss1r knockout mice, BeWo cell lines and human term placenta. Reprod Fertil Dev 2024; 36:RD23230. [PMID: 38976640 DOI: 10.1071/rd23230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 06/17/2024] [Indexed: 07/10/2024] Open
Abstract
Context There is mounting evidence implicating kisspeptin signalling in placental development and function. Aims This study aimed to elucidate kisspeptin's role in trophoblast invasion and migration using three experimental models. Methods First, we examined the mouse fetus and placenta in a kisspeptin receptor (Kiss1r) knockout (KO) model. Fetal/placental weights and gene expression (quantitative polymerase chain reaction) were assessed. Second, we determined kisspeptin effects on a human trophoblast (BeWo) cell line in vitro . Third, we examined KISS1 and KISS1R gene expression in human placenta from term and pre-term pregnancies. Key results No difference was found in fetal or placental weight between Kiss1r KO and wildtype mice. However, expression of the trophoblast invasion marker, Mmp2 mRNA, was greater in the placental labyrinth zone of Kiss1r KO mice. BeWo cell models of villus cytotrophoblast and syncytiotrophoblast cells exhibited kisspeptin protein expression, with greater expression in syncytiotrophoblast, consistent with KISS1 mRNA. Kisspeptin treatment inhibited the migratory potential of cytotrophoblast-like cells. Finally, while no difference was seen in KISS1 and KISS1R mRNA between term and pre-term placentas, we saw a difference in the relative expression of each gene pre-term. We also observed a positive correlation between KISS1 expression and maternal body mass index. Conclusions Our results indicate that kisspeptin may inhibit trophoblast invasion. Implications Further investigation is required to clarify specific regulatory mechanisms.
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Affiliation(s)
- E N Panting
- School of Human Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - J H Weight
- School of Human Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - J A Sartori
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
| | - D A Coall
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
| | - J T Smith
- School of Human Sciences, The University of Western Australia, Perth, WA 6009, Australia
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2
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Omidvar-Mehrabadi A, Ebrahimi F, Shahbazi M, Mohammadnia-Afrouzi M. Cytokine and chemokine profiles in women with endometriosis, polycystic ovary syndrome, and unexplained infertility. Cytokine 2024; 178:156588. [PMID: 38555853 DOI: 10.1016/j.cyto.2024.156588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/19/2024] [Accepted: 03/22/2024] [Indexed: 04/02/2024]
Abstract
Numerous factors (including immunological, congenital, hormonal, and morphological disorders) can lead to infertility. In this regard, 3 specific diseases associated with infertility are discussed in this review study (i.e., polycystic ovary syndrome [PCOS], endometriosis [EMS], and unexplained infertility [UI]). PCOS is a common endocrine disorder characterized by chronic low-grade inflammation, and EMS is a benign disease characterized by the presence of ectopic endometrial tissue. UI refers to couples who are unable to conceive for no known reason. Conception and pregnancy are significantly affected by the immune system; in this regard, chemokines and cytokines play important roles in the regulation of immune responses. Patients with PCOS, EMS, and UI have altered cytokine and chemokine profiles, suggesting that dysregulation of these molecules may contribute to infertility in these conditions. Accordingly, the issue of infertility is addressed in this review study, a condition that affects approximately 16% of couples worldwide.
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Affiliation(s)
| | - Fateme Ebrahimi
- Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mehdi Shahbazi
- Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran.
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3
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Pirković A, Jovanović Krivokuća M, Vilotić A, Nacka-Aleksić M, Bojić-Trbojević Ž, Dekanski D. Oleuropein Stimulates Migration of Human Trophoblast Cells and Expression of Invasion-Associated Markers. Int J Mol Sci 2023; 25:500. [PMID: 38203672 PMCID: PMC10779171 DOI: 10.3390/ijms25010500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/22/2023] [Accepted: 12/26/2023] [Indexed: 01/12/2024] Open
Abstract
Successful pregnancy establishment requires highly synchronized cross talk between the invasive trophoblast cells and the receptive maternal endometrium. Any disturbances in this tightly regulated process may lead to pregnancy complications. Local factors such as nutrients, hormones, cytokines and reactive oxygen species modulate the invasion of extravillous trophoblasts through critical signaling cascades. Epidemiological studies strongly indicate that a Mediterranean diet can significantly impact molecular pathways during placentation. Therefore, the aim of the current study was to examine whether oleuropein (OLE), one of the main compounds of the Mediterranean diet, may influence trophoblast cell adhesion and migration, as well as the expression of invasion-associated molecular markers and inflammatory pathways fostering these processes. HTR-8/SVneo cells were incubated with OLE at selected concentrations of 10 and 100 µM for 24 h. Results showed that OLE did not affect trophoblast cell viability, proliferation and adhesion after 24 h in in vitro treatment. The mRNA expression of integrin subunits α1, α5 and β1, as well as matrix-degrading enzymes MMP-2 and -9, was significantly increased after treatment with 10 µM OLE. Furthermore, OLE at a concentration of 10 µM significantly increased the protein expression of integrin subunits α1 and β1. Also, OLE inhibited the activation of JNK and reduced the protein expression of COX-2. Finally, a lower concentration of OLE 10 µM significantly stimulated migration of HTR-8/SVneo cells. In conclusion, the obtained results demonstrate the effects of OLE on the function of trophoblast cells by promoting cell migration and stimulating the expression of invasion markers. As suggested from results, these effects may be mediated via inhibition of the JNK signaling pathway.
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Affiliation(s)
| | | | | | | | | | - Dragana Dekanski
- Institute for the Application of Nuclear Energy, Department for Biology of Reproduction, University of Belgrade, Banatska 31b, 11080 Belgrade, Serbia; (A.P.); (M.J.K.); (A.V.); (M.N.-A.); (Ž.B.-T.)
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4
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Alencar AKN, Swan KF, Pridjian G, Lindsey SH, Bayer CL. Connecting G protein-coupled estrogen receptor biomolecular mechanisms with the pathophysiology of preeclampsia: a review. Reprod Biol Endocrinol 2023; 21:60. [PMID: 37393260 DOI: 10.1186/s12958-023-01112-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 06/20/2023] [Indexed: 07/03/2023] Open
Abstract
BACKGROUND Throughout the course of pregnancy, small maternal spiral arteries that are in contact with fetal tissue undergo structural remodeling, lose smooth muscle cells, and become less responsive to vasoconstrictors. Additionally, placental extravillous trophoblasts invade the maternal decidua to establish an interaction between the fetal placental villi with the maternal blood supply. When successful, this process enables the transport of oxygen, nutrients, and signaling molecules but an insufficiency leads to placental ischemia. In response, the placenta releases vasoactive factors that enter the maternal circulation and promote maternal cardiorenal dysfunction, a hallmark of preeclampsia (PE), the leading cause of maternal and fetal death. An underexplored mechanism in the development of PE is the impact of membrane-initiated estrogen signaling via the G protein-coupled estrogen receptor (GPER). Recent evidence indicates that GPER activation is associated with normal trophoblast invasion, placental angiogenesis/hypoxia, and regulation of uteroplacental vasodilation, and these mechanisms could explain part of the estrogen-induced control of uterine remodeling and placental development in pregnancy. CONCLUSION Although the relevance of GPER in PE remains speculative, this review provides a summary of our current understanding on how GPER stimulation regulates some of the features of normal pregnancy and a potential link between its signaling network and uteroplacental dysfunction in PE. Synthesis of this information will facilitate the development of innovative treatment options.
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Affiliation(s)
| | - Kenneth F Swan
- Department of Obstetrics & Gynecology, Tulane University, New Orleans, LA, 70112, USA
| | - Gabriella Pridjian
- Department of Obstetrics & Gynecology, Tulane University, New Orleans, LA, 70112, USA
| | - Sarah H Lindsey
- Department of Pharmacology, Tulane University, New Orleans, LA, 70112, USA
| | - Carolyn L Bayer
- Department of Biomedical Engineering, Tulane University, 500 Lindy Boggs Center, New Orleans, LA, 70118, USA.
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5
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Yu HY, Gumusoglu SB, Cantonwine DE, Carusi DA, Gurnani P, Schickling B, Doss RC, Santillan MK, Rosenblatt KP, McElrath TF. Circulating microparticle proteins predict pregnancies complicated by placenta accreta spectrum. Sci Rep 2023; 12:21922. [PMID: 36604494 PMCID: PMC9814521 DOI: 10.1038/s41598-022-24869-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 11/22/2022] [Indexed: 01/06/2023] Open
Abstract
Placenta accreta spectrum (PAS) is characterized by abnormal attachment of the placenta to the uterus, and attempts at placental delivery can lead to catastrophic maternal hemorrhage and death. Multidisciplinary delivery planning can significantly improve outcomes; however, current diagnostics are lacking as approximately half of pregnancies with PAS are undiagnosed prior to delivery. This is a nested case-control study of 35 cases and 70 controls with the primary objective of identifying circulating microparticle (CMP) protein panels that identify pregnancies complicated by PAS. Size exclusion chromatography and liquid chromatography with tandem mass spectrometry were used for CMP protein isolation and identification, respectively. A two-step iterative workflow was used to establish putative panels. Using plasma sampled at a median of 26 weeks' gestation, five CMP proteins distinguished PAS from controls with a mean area under the curve (AUC) of 0.83. For a separate sample taken at a median of 35 weeks' gestation, the mean AUC was 0.78. In the second trimester, canonical pathway analyses demonstrate over-representation of processes related to iron homeostasis and erythropoietin signaling. In the third trimester, these analyses revealed abnormal immune function. CMP proteins classify PAS well prior to delivery and have potential to significantly reduce maternal morbidity and mortality.
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Affiliation(s)
- Hope Y Yu
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | | | - David E Cantonwine
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Daniela A Carusi
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | | | | | | | - Mark K Santillan
- University of Iowa Carver College of Medicine, Iowa City, IO, USA
| | - Kevin P Rosenblatt
- NX Prenatal Inc., Louisville, KY, USA
- Division of Oncology, Department of Internal Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Thomas F McElrath
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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6
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Gomes VCL, Woods AK, Crissman KR, Landry CA, Beckers KF, Gilbert BM, Ferro LR, Liu CC, Oberhaus EL, Sones JL. Kisspeptin Is Upregulated at the Maternal-Fetal Interface of the Preeclamptic-like BPH/5 Mouse and Normalized after Synchronization of Sex Steroid Hormones. REPRODUCTIVE MEDICINE 2022; 3:263-279. [PMID: 37538930 PMCID: PMC10399610 DOI: 10.3390/reprodmed3040021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/05/2023] Open
Abstract
Insufficient invasion of conceptus-derived trophoblast cells in the maternal decidua is a key event in the development of early-onset preeclampsia (PE), a subtype of PE associated with high maternal and fetal morbidity and mortality. Kisspeptins, a family of peptides previously shown to inhibit trophoblast cell invasion, have been implicated in the pathogenesis of early-onset PE. However, a role of kisspeptin signaling during the genesis of this syndrome has not been elucidated. Herein, we used the preeclamptic-like BPH/5 mouse model to investigate kisspeptin expression and potential upstream regulatory mechanisms in a PE-like syndrome. Expression of the kisspeptin encoding gene, Kiss1, and the 10-amino-acid kisspeptide (Kp-10), are upregulated in the non-pregnant uterus of BPH/5 females during diestrus and in the maternal-fetal interface during embryonic implantation and decidualization. Correspondingly, the dysregulation of molecular pathways downstream to kisspeptins also occurs in this mouse model. BPH/5 females have abnormal sex steroid hormone profiles during early gestation. In this study, the normalization of circulating concentrations of 17β-estradiol (E2) and progesterone (P4) in pregnant BPH/5 females not only mitigated Kiss1 upregulation, but also rescued the expression of multiple molecules downstream to kisspeptin and ameliorated adverse fetoplacental outcomes. Those findings suggest that uterine Kiss1 upregulation occurs pre-pregnancy and persists during early gestation in a PE-like mouse model. Moreover, this study highlights the role of sex steroid hormones in uteroplacental Kiss1 dysregulation and the improvement of placentation by normalization of E2, P4 and Kiss1.
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Affiliation(s)
- Viviane C. L. Gomes
- Department of Veterinary Clinical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA
| | - Ashley K. Woods
- Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA
| | - Kassandra R. Crissman
- Department of Veterinary Clinical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA
| | - Camille A. Landry
- Department of Veterinary Clinical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA
| | - Kalie F. Beckers
- Department of Veterinary Clinical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA
| | - Bryce M. Gilbert
- School of Animal Sciences, Louisiana Agricultural Experiment Station, LSU AgCenter, Baton Rouge, LA 70803, USA
| | - Lucas R. Ferro
- Department of Veterinary Clinical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA
| | - Chin-Chi Liu
- Department of Veterinary Clinical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA
| | - Erin L. Oberhaus
- School of Animal Sciences, Louisiana Agricultural Experiment Station, LSU AgCenter, Baton Rouge, LA 70803, USA
| | - Jenny L. Sones
- Department of Veterinary Clinical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803, USA
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7
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Hayder H, Shan Y, Chen Y, O’Brien JA, Peng C. Role of microRNAs in trophoblast invasion and spiral artery remodeling: Implications for preeclampsia. Front Cell Dev Biol 2022; 10:995462. [PMID: 36263015 PMCID: PMC9575991 DOI: 10.3389/fcell.2022.995462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 08/25/2022] [Indexed: 11/18/2022] Open
Abstract
It is now well-established that microRNAs (miRNAs) are important regulators of gene expression. The role of miRNAs in placental development and trophoblast function is constantly expanding. Trophoblast invasion and their ability to remodel uterine spiral arteries are essential for proper placental development and successful pregnancy outcome. Many miRNAs are reported to be dysregulated in pregnancy complications, especially preeclampsia and they exert various regulatory effects on trophoblasts. In this review, we provide a brief overview of miRNA biogenesis and their mechanism of action, as well as of trophoblasts differentiation, invasion and spiral artery remodeling. We then discuss the role of miRNAs in trophoblasts invasion and spiral artery remodeling, focusing on miRNAs that have been thoroughly investigated, especially using multiple model systems. We also discuss the potential role of miRNAs in the pathogenesis of preeclampsia.
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Affiliation(s)
- Heyam Hayder
- Department of Biology, York University, Toronto, ON, Canada
| | - Yanan Shan
- Department of Biology, York University, Toronto, ON, Canada
| | - Yan Chen
- Department of Biology, York University, Toronto, ON, Canada
| | | | - Chun Peng
- Department of Biology, York University, Toronto, ON, Canada
- Centre for Research on Biomolecular Interactions, York University, Toronto, ON, Canada
- *Correspondence: Chun Peng,
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8
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Tsoutsouki J, Patel B, Comninos AN, Dhillo WS, Abbara A. Kisspeptin in the Prediction of Pregnancy Complications. Front Endocrinol (Lausanne) 2022; 13:942664. [PMID: 35928889 PMCID: PMC9344876 DOI: 10.3389/fendo.2022.942664] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/16/2022] [Indexed: 11/13/2022] Open
Abstract
Kisspeptin and its receptor are central to reproductive health acting as key regulators of the reproductive endocrine axis in humans. Kisspeptin is most widely recognised as a regulator of gonadotrophin releasing hormone (GnRH) neuronal function. However, recent evidence has demonstrated that kisspeptin and its receptor also play a fundamental role during pregnancy in the regulation of placentation. Kisspeptin is abundantly expressed in syncytiotrophoblasts, and its receptor in both cyto- and syncytio-trophoblasts. Circulating levels of kisspeptin rise dramatically during healthy pregnancy, which have been proposed as having potential as a biomarker of placental function. Indeed, alterations in kisspeptin levels are associated with an increased risk of adverse maternal and foetal complications. This review summarises data evaluating kisspeptin's role as a putative biomarker of pregnancy complications including miscarriage, ectopic pregnancy (EP), preterm birth (PTB), foetal growth restriction (FGR), hypertensive disorders of pregnancy (HDP), pre-eclampsia (PE), gestational diabetes mellitus (GDM), and gestational trophoblastic disease (GTD).
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Affiliation(s)
| | | | | | | | - Ali Abbara
- *Correspondence: Waljit S. Dhillo, ; Ali Abbara,
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9
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Transforming growth factor-β signaling governs the differentiation program of extravillous trophoblasts in the developing human placenta. Proc Natl Acad Sci U S A 2022; 119:e2120667119. [PMID: 35867736 PMCID: PMC9282384 DOI: 10.1073/pnas.2120667119] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Abnormal placentation has been noticed in a variety of pregnancy complications such as miscarriage, early-onset preeclampsia, and fetal growth restriction. Defects in the developmental program of extravillous trophoblasts (EVTs), migrating from placental anchoring villi into the maternal decidua and its vessels, is thought to be an underlying cause. Yet, key regulatory mechanisms controlling commitment and differentiation of the invasive trophoblast lineage remain largely elusive. Herein, comparative gene expression analyses of HLA-G-purified EVTs, isolated from donor-matched placenta, decidua, and trophoblast organoids (TB-ORGs), revealed biological processes and signaling pathways governing EVT development. In particular, bioinformatics analyses and manipulations in different versatile trophoblast cell models unraveled transforming growth factor-β (TGF-β) signaling as a crucial pathway driving differentiation of placental EVTs into decidual EVTs, the latter showing enrichment of a secretory gene signature. Removal of Wingless signaling and subsequent activation of the TGF-β pathway were required for the formation of human leukocyte antigen-G+ (HLA-G+) EVTs in TB-ORGs that resemble in situ EVTs at the level of global gene expression. Accordingly, TGF-β-treated EVTs secreted enzymes, such as DAO and PAPPA2, which were predominantly expressed by decidual EVTs. Their genes were controlled by EVT-specific induction and genomic binding of the TGF-β downstream effector SMAD3. In summary, TGF-β signaling plays a key role in human placental development governing the differentiation program of EVTs.
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10
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Bayramoğlu Tepe N, Bayramoglu D, Taşkum İ. Elevated serum YKL-40 levels as a diagnostic and prognostic marker in the placenta accreta spectrum. Turk J Obstet Gynecol 2022; 19:98-103. [PMID: 35770494 PMCID: PMC9249364 DOI: 10.4274/tjod.galenos.2022.94884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Objective: Placenta accreta spectrum (PAS) is an important problem with increasing cesarean section (CS) rates recently. There is still no serum marker for the diagnosis. We determined whether serum YKL-40 levels can be used in the diagnosis and prognosis of PAS. Materials and Methods: The study was conducted with 50 patients with a PAS diagnosis, 27 individuals without PAS, and 33 normal pregnant women. The operations (CS + placental bed suture, CS + excision of the lower segment, CS-hysterectomy) and for individuals who had the excision of the lower segment /CS-hysterectomy, the histopathological diagnoses (accreta, increta, percreta) were recorded. Serum YKL-40 levels were analyzed. Results: The individuals with PAS possessed significantly greater serum YKL-40 grades (p=0.001). The surgical interventions included 4 CS + excision of the lower segment, 9 CS + placental bed sutures, and 37 CS-hysterectomy. The histopathological outcomes of the individuals who had the excision of the lower segment, CS-hysterectomy and diagnosed 6, 9, and 26 patients with accreta, increta, and percreta, respectively. The accreta, increta, and percreta groups showed statistically significant different serum YKL-40 grades (p=0.001). The receiver operating characteristic analysis was performed to discriminate the cut-off serum YKL-40 level as 32.81 ng/mL with a sensitivity of 66% and specificity of 70.37%. The positive and negative predictive values of YKL-40 in the indicator of PAS were 80.5% and 52.8%, respectively. Conclusion: Elevated serum YKL-40 grades were correlated with the diagnosis and severity of PAS. If our findings are corroborated and elaborated by larger patient series, the YKL-40 levels should be used along with ultrasonography to construct a model identical to that used in aneuploidy screening.
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11
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Zhang Q, Xiao Z, Lee CL, Duan YG, Fan X, Yeung WSB, Chiu PCN, Zhang JV. The Regulatory Roles of Chemerin-Chemokine-Like Receptor 1 Axis in Placental Development and Vascular Remodeling During Early Pregnancy. Front Cell Dev Biol 2022; 10:883636. [PMID: 35656551 PMCID: PMC9152263 DOI: 10.3389/fcell.2022.883636] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
Chemerin is an adipokine that regulates metabolism in pregnancy. An elevation of serum chemerin level is associated with pregnancy complications. Consistently, we demonstrated that the chemerin expression was increased in placenta of preeclamptic patients at deliveries. The G protein-coupled receptor chemokine-like receptor 1 (CMKLR1) mediates the actions of chemerin. The functions of the chemerin-CMKLR1 axis in maintaining pregnancy are still unknown. In this study, we demonstrated that CMKLR1 was expressed in the decidual natural killer (dNK) cells and chorionic villi of human. Chemerin suppressed the proliferation of the dNK cells in vitro. Specific antagonist of CMKLR1, α-Neta abolished the suppressive effect of spent medium from chemerin-treated dNK cells culture on extravillous trophoblast invasion. Activation of the chemerin-CMKLR1 axis promoted fusion and differentiation of human cytotrophoblast to syncytiotrophoblast in vitro. We generated Cmklr1 knockout mice and showed that the Cmklr1 deficiency negatively affected pregnancy outcome in terms of number of implantation sites, litter size and fetal weight at birth. Histologically, the Cmklr1 deficiency impaired formation of the syncytiotrophoblast layer II, induced enlargement of the maternal lacunae in the labyrinth, increased the diameter of the spiral arteries and increased trophoblast invasion in the decidua. The Cmklr1 deficient placenta also displayed an increased number of dNK cells and serum IL-15 level. In summary, the chemerin-CMKLR1 axis regulated placental development and spiral artery remodeling in early pregnancy.
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Affiliation(s)
- Qingqing Zhang
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Obstetrics and Gynecology, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Zhonglin Xiao
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Cheuk-Lun Lee
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Obstetrics and Gynecology, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yong-Gang Duan
- Department of Obstetrics and Gynecology, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Xiujun Fan
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - William S. B. Yeung
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Obstetrics and Gynecology, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Philip C. N. Chiu
- Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Obstetrics and Gynecology, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- *Correspondence: Philip C. N. Chiu, ; Jian V. Zhang,
| | - Jian V. Zhang
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Shenzhen Key Laboratory of Metabolic Health, Shenzhen, China
- *Correspondence: Philip C. N. Chiu, ; Jian V. Zhang,
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12
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Zhang N, Schumacher A, Fink B, Bauer M, Zenclussen AC, Meyer N. Insights into Early-Pregnancy Mechanisms: Mast Cells and Chymase CMA1 Shape the Phenotype and Modulate the Functionality of Human Trophoblast Cells, Vascular Smooth-Muscle Cells and Endothelial Cells. Cells 2022; 11:cells11071158. [PMID: 35406722 PMCID: PMC8997408 DOI: 10.3390/cells11071158] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/25/2022] [Accepted: 03/26/2022] [Indexed: 01/27/2023] Open
Abstract
Spiral-artery (SA) remodeling is a fundamental process during pregnancy that involves the action of cells of the initial vessel, such as vascular smooth-muscle cells (VSMCs) and endothelial cells, but also maternal immune cells and fetal extravillous trophoblast cells (EVTs). Mast cells (MCs), and specifically chymase-expressing cells, have been identified as key to a sufficient SA-remodeling process in vivo. However, the mechanisms are still unclear. The purpose of this study is to evaluate the effects of the MC line HMC-1 and recombinant human chymase (rhuCMA1) on human primary uterine vascular smooth-muscle cells (HUtSMCs), a human trophoblast cell line (HTR8/SV-neo), and human umbilical-vein endothelial cells (HUVEC) in vitro. Both HMC-1 and rhuCMA1 stimulated migration, proliferation, and changed protein expression in HUtSMCs. HMC-1 increased proliferation, migration, and changed gene expression of HTR8/SVneo cells, while rhuCMA treatment led to increased migration and decreased expression of tissue inhibitors of matrix metalloproteinases. Additionally, rhuCMA1 enhanced endothelial-cell-tube formation. Collectively, we identified possible mechanisms by which MCs/rhuCMA1 promote SA remodeling. Our findings are relevant to the understanding of this crucial step in pregnancy and thus of the dysregulated pathways that can lead to pregnancy complications such as fetal growth restriction and preeclampsia.
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Affiliation(s)
- Ningjuan Zhang
- Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, 04318 Leipzig, Germany; (N.Z.); (A.S.); (B.F.); (M.B.); (A.C.Z.)
- Perinatal Immunology, Saxonian Incubator for Clinical Translation (SIKT), Medical Faculty, University Leipzig, 04103 Leipzig, Germany
| | - Anne Schumacher
- Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, 04318 Leipzig, Germany; (N.Z.); (A.S.); (B.F.); (M.B.); (A.C.Z.)
- Perinatal Immunology, Saxonian Incubator for Clinical Translation (SIKT), Medical Faculty, University Leipzig, 04103 Leipzig, Germany
| | - Beate Fink
- Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, 04318 Leipzig, Germany; (N.Z.); (A.S.); (B.F.); (M.B.); (A.C.Z.)
| | - Mario Bauer
- Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, 04318 Leipzig, Germany; (N.Z.); (A.S.); (B.F.); (M.B.); (A.C.Z.)
| | - Ana Claudia Zenclussen
- Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, 04318 Leipzig, Germany; (N.Z.); (A.S.); (B.F.); (M.B.); (A.C.Z.)
- Perinatal Immunology, Saxonian Incubator for Clinical Translation (SIKT), Medical Faculty, University Leipzig, 04103 Leipzig, Germany
| | - Nicole Meyer
- Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, 04318 Leipzig, Germany; (N.Z.); (A.S.); (B.F.); (M.B.); (A.C.Z.)
- Perinatal Immunology, Saxonian Incubator for Clinical Translation (SIKT), Medical Faculty, University Leipzig, 04103 Leipzig, Germany
- Correspondence: ; Tel.: +49-341-235-1542
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Yi Y, Zhu H, Klausen C, Chang HM, Inkster AM, Terry J, Leung PCK. Dysregulated BMP2 in the Placenta May Contribute to Early-Onset Preeclampsia by Regulating Human Trophoblast Expression of Extracellular Matrix and Adhesion Molecules. Front Cell Dev Biol 2022; 9:768669. [PMID: 34970543 PMCID: PMC8712873 DOI: 10.3389/fcell.2021.768669] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/24/2021] [Indexed: 01/05/2023] Open
Abstract
Many pregnancy disorders, including early-onset preeclampsia (EOPE), are associated with defects in placental trophoblast cell invasion and differentiation during early placental development. Bone morphogenetic protein 2 (BMP2) belongs to the TGF-β superfamily and controls various physiological and developmental processes. However, the expression of BMP2 in the placenta and underlying molecular mechanisms of how BMP2 regulates trophoblast function remain unclear. In this study, we analyzed several publicly available microarray and RNA-seq datasets and revealed differences in expression of TGF-β superfamily members between gestational age-matched non-preeclamptic control and EOPE placentas. Importantly, BMP2 levels were significantly reduced in EOPE placentas compared with controls, and RNAscope in situ hybridization further demonstrated BMP2 expression was disrupted in EOPE placental villi. To explore the molecular mechanisms of BMP2-regulated early trophoblast differentiation, we examined BMP2 expression in first-trimester human placenta and found it to be localized to all subtypes of trophoblasts and the decidua. RNA-seq analysis on control and BMP2-treated primary human trophoblast cells identified 431 differentially expressed genes, including several canonical TGF-β/BMP signaling targets (BAMBI, ID1, INHBA, IGFBP3). Gene ontology annotations revealed that differentially expressed genes were involved in cell adhesion and extracellular matrix organization. Furthermore, we identified adhesion molecule with IgG-like domain 2 (AMIGO2) as a novel target for BMP2 that contributed to BMP2-induced trophoblast invasion and endothelial-like tube formation. Overall, our findings provide insight into the molecular processes controlled by BMP2 during early placental development that may contribute to the pathogenesis of EOPE.
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Affiliation(s)
- Yuyin Yi
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Hua Zhu
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Christian Klausen
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Hsun-Ming Chang
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Amy M Inkster
- Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Jefferson Terry
- Department of Pathology and Laboratory Medicine, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Peter C K Leung
- Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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14
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Yoshida T, Takada K, Komine-Aizawa S, Kamei Y, Ishihara O, Hayakawa S. Lactobacillus crispatus promotes invasion of the HTR-8/SVneo trophoblast cell line. Placenta 2021; 111:76-81. [PMID: 34175522 DOI: 10.1016/j.placenta.2021.06.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 05/15/2021] [Accepted: 06/13/2021] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Recent studies have shown that the endometrium possesses unique microbiomes, including Lactobacillus. However, the roles of these microbes are currently unknown, especially in placentation and the early stage of pregnancy. METHODS The immortalized human first-trimester trophoblast cell line HTR-8/SVneo was cultured in the presence or absence of Lactobacillus crispatus. Invasive and migrative activities were directly evaluated using an optical microscope and a time-lapse imaging system. Protein levels of the invasion-related protein matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9 were evaluated using ELISA. RESULTS Matrigel invasion of HTR-8/SVneo cells was significantly increased by L. crispatus, though migration was not affected. The culture supernatant of L. crispatus also promoted invasion. Additionally, levels of the active forms of MMP-1 and MMP-2 in the cell culture medium were upregulated by L. crispatus treatment, but that of MMP-9 was not changed. DISCUSSION L. crispatus promotes trophoblast invasion with an increase in MMP-1 and MMP-2 activation. Our results might explain why Lactobacillus dominance in the endometrium seems beneficial for implantation. Nevertheless, further research is required to determine whether the promotion of trophoblast invasion by L. cripatus is favorable for successful placentation at the early stage of pregnancy.
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Affiliation(s)
- Tomoaki Yoshida
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan; Department of Obstetrics and Gynecology, Saitama Medical University Hospital, Saitama, Japan
| | - Kazuhide Takada
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan.
| | - Shihoko Komine-Aizawa
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan
| | - Yoshimasa Kamei
- Department of Obstetrics and Gynecology, Saitama Medical University Hospital, Saitama, Japan
| | - Osamu Ishihara
- Department of Obstetrics and Gynecology, Saitama Medical University Hospital, Saitama, Japan
| | - Satoshi Hayakawa
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan
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15
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Bazhenov DO, Khokhlova EV, Viazmina LP, Furaeva KN, Mikhailova VA, Kostin NA, Selkov SA, Sokolov DI. Characteristics of Natural Killer Cell Interaction with Trophoblast Cells During Pregnancy. Curr Mol Med 2021; 20:202-219. [PMID: 31393246 DOI: 10.2174/1566524019666190808103227] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 07/19/2019] [Accepted: 07/30/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Maternal natural killer cells (NK cells) are a prevailing leukocyte population in the uteroplacental bed. Current descriptions of the effect of cytokines from the placental microenvironment on the expression of receptors by trophoblast and NK cells are inadequate and contradictory. There is insufficient information about the ability of NK cells to migrate through trophoblast cells. OBJECTIVE To assess the impact of conditioned media obtained during culturing of placentas from the first and the third trimesters of healthy pregnancies on the phenotype of trophoblast and NK cells and impact on adhesion and transmigration of NK cells through trophoblast cell layer. RESULTS We established that conditioned media obtained from both first and third trimester placentas increased the intensity of CD106, CD49e, CD49a, CD31, CD51/61, and integrin β6 expression by trophoblast cells. Conditioned media obtained from first trimester placentas increased the intensity of CD11a, CD29, CD49d, CD58, CD29 expression by NK cells. The presence of conditioned media from third trimester placentas resulted in more intense CD29, CD49d, CD11a, CD29, CD49d, and CD58 expression by NK cells. Migration of NK cells through trophoblast cells in the presence of conditioned media from first trimester placentas was increased compared with the migration level in the presence of conditioned media from third trimester placentas. This may be associated with increased expression of CD18 by NK cells. CONCLUSION First trimester placental secretory products increase adhesion receptor expression by both trophoblast and NK cells. Under these conditions, trophoblast is capable of ensuring NK cell adhesion and transmigration.
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Affiliation(s)
- Dmitry Olegovich Bazhenov
- Federal State Budgetary Scientific Institution Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott, Mendeleevskya line, 199034, Saint-Petersburg, Russian Federation.,Federal State Budgetary Scientific Institution Research Institute of Experimental Medicine, Russian Federation
| | - Evgeniya Valerevna Khokhlova
- Federal State Budgetary Scientific Institution Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott, Mendeleevskya line, 199034, Saint-Petersburg, Russian Federation
| | - Larisa Pavlovna Viazmina
- Federal State Budgetary Scientific Institution Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott, Mendeleevskya line, 199034, Saint-Petersburg, Russian Federation
| | - Kseniya Nikolaevna Furaeva
- Federal State Budgetary Scientific Institution Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott, Mendeleevskya line, 199034, Saint-Petersburg, Russian Federation
| | - Valentina Anatolievna Mikhailova
- Federal State Budgetary Scientific Institution Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott, Mendeleevskya line, 199034, Saint-Petersburg, Russian Federation
| | - Nikolay Anatolievich Kostin
- Resource Centre for the Molecular and Cell Technologies Development, Saint Petersburg State University, Saint- Petersburg, Russian Federation
| | - Sergey Alekseevich Selkov
- Federal State Budgetary Scientific Institution Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott, Mendeleevskya line, 199034, Saint-Petersburg, Russian Federation
| | - Dmitry Igorevich Sokolov
- Federal State Budgetary Scientific Institution Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott, Mendeleevskya line, 199034, Saint-Petersburg, Russian Federation.,Federal State Budgetary Scientific Institution Research Institute of Experimental Medicine, Russian Federation
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16
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Gomes VCL, Sones JL. From inhibition of trophoblast cell invasion to proapoptosis: what are the potential roles of kisspeptins in preeclampsia? Am J Physiol Regul Integr Comp Physiol 2021; 321:R41-R48. [PMID: 34009045 DOI: 10.1152/ajpregu.00258.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Preeclampsia (PE) is a life-threatening human gestational syndrome with incompletely understood etiopathogenesis. The disorder has a spectrum of clinical features, likely due to a complex interaction between maternal predisposing factors and abnormalities at the maternal-fetal interface. Poor trophoblast cell invasion, inadequate uterine vascular remodeling, and placental hypoperfusion are considered as key placental events leading to PE. Kisspeptins, a family of small peptides derived from the KISS1 gene, have been implicated in the development of this syndrome. Most studies of kisspeptin expression in PE have reported an upregulation of kisspeptins and/or their cognate receptor in preeclamptic placentas. Conversely, maternal peripheral blood concentration of kisspeptins is reportedly lower in PE than in uncomplicated pregnancies. This apparent paradox remains to be further elucidated. Although kisspeptins were initially known for inhibiting cellular migration and invasion, other biological activities attributed to these peptides include neuroendocrine regulation of reproduction, metabolism regulation, inhibition of angiogenesis, and induction of apoptosis. This review summarizes the current knowledge on expression and biological activity of kisspeptins at the maternal-fetal interface in the context of PE.
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Affiliation(s)
- Viviane C L Gomes
- Department of Veterinary Clinical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana
| | - Jenny L Sones
- Department of Veterinary Clinical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana
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17
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Lala PK, Nandi P, Hadi A, Halari C. A crossroad between placental and tumor biology: What have we learnt? Placenta 2021; 116:12-30. [PMID: 33958236 DOI: 10.1016/j.placenta.2021.03.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 02/27/2021] [Accepted: 03/02/2021] [Indexed: 01/06/2023]
Abstract
Placenta in certain species including the human has evolved as a highly invasive tumor-like organ invading the uterus aned its vasculature to derive oxygen and nutrients for the fetus and exchange waste products. While several excellent reviews have been written comparing hemochorial placentation with tumors, no comprehensive review is available dealing with mechanistic insights into what makes them different, and what tumor biologists can learn from placental biologists, and vice versa. In this review, we analyze the structure-function relationship of the human placenta, emphasizing the functional need of the spatio-temporally orchestrated trophoblast invasiveness for fetal development and growth, and pathological consequences of aberrant invasiveness for fetal and maternal health. We then analyze similarities and differences between the placenta and invasive tumors in terms of hallmarks of cancer, some key molecules regulating their invasive functions, and how placental cancers (choriocarcinomas) or other cancers become refractory or even addicted to these invasion-restraining molecules. We cite in vitro models of human trophoblast and choriocarcinoma cell lines utilized to study mechanisms in normal placental development as well as those responsible for tumor progression. We discuss the pathobiology of hyper-invasive placentas and show thattrophoblastic neoplasias are a unique and heterogeneous class of tumors. We delve into the questions as to why metastasis from other organs rarely occurs at the placental site and whether pregnancy makes the mother more or less vulnerable to cancer-related morbidity/mortality. We attempt to compare trophoblast stem cells and cancer stem cells. Finally, we leave the readers with some thoughts as foods of future investigations.
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Affiliation(s)
- Peeyush K Lala
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Westernat Ontario, London, Ontario, N6A5C1, Canada; Associate Scientist, Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada N6C2V5.
| | - Pinki Nandi
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Westernat Ontario, London, Ontario, N6A5C1, Canada.
| | - Ali Hadi
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Westernat Ontario, London, Ontario, N6A5C1, Canada.
| | - Chidambra Halari
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Westernat Ontario, London, Ontario, N6A5C1, Canada.
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18
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Schmidt JK, Keding LT, Block LN, Wiepz GJ, Koenig MR, Meyer MG, Dusek BM, Kroner KM, Bertogliat MJ, Kallio AR, Mean KD, Golos TG. Placenta-derived macaque trophoblast stem cells: differentiation to syncytiotrophoblasts and extravillous trophoblasts reveals phenotypic reprogramming. Sci Rep 2020; 10:19159. [PMID: 33154556 PMCID: PMC7644694 DOI: 10.1038/s41598-020-76313-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 10/19/2020] [Indexed: 02/07/2023] Open
Abstract
Nonhuman primates are excellent models for studying human placentation as experimental manipulations in vitro can be translated to in vivo pregnancy. Our objective was to develop macaque trophoblast stem cells (TSCs) as an in vitro platform for future assessment of primate trophoblast development and function. Macaque TSC lines were generated by isolating first and second trimester placental villous cytotrophoblasts followed by culture in TSC medium to maintain cellular proliferation. TSCs grew as mononuclear colonies, whereas upon induction of syncytiotrophoblast (ST) differentiation multinuclear structures appeared, indicative of syncytium formation. Chorionic gonadotropin secretion was > 4000-fold higher in ST culture media compared to TSC media. The secretion of chorionic gonadotropin by TSC-derived ST reflects a reprogramming of macaque TSCs to an earlier pregnancy phenotype. Characteristic trophoblast hallmarks were defined in TSCs and ST including expression of C19MC miRNAs and the macaque placental nonclassical MHC class I molecule, Mamu-AG. Extravillous trophoblasts (EVTs) were derived that express macaque EVT markers Mamu-AG and CD56, and also secrete high levels of MMP2. Our analyses of macaque TSCs suggests that these cells represent a proliferative, self-renewing population capable of differentiating to STs and EVTs in vitro thereby establishing an experimental model of primate placentation.
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Affiliation(s)
- Jenna Kropp Schmidt
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA.
| | - Logan T Keding
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Lindsey N Block
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Gregory J Wiepz
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Michelle R Koenig
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Michael G Meyer
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Brittany M Dusek
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Kamryn M Kroner
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Mario J Bertogliat
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Avery R Kallio
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Katherine D Mean
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Thaddeus G Golos
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, USA
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, USA
- Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI, USA
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Comparative Study of PPAR γ Targets in Human Extravillous and Villous Cytotrophoblasts. PPAR Res 2020; 2020:9210748. [PMID: 32308672 PMCID: PMC7152979 DOI: 10.1155/2020/9210748] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/26/2020] [Accepted: 02/11/2020] [Indexed: 12/15/2022] Open
Abstract
Trophoblasts, as the cells that make up the main part of the placenta, undergo cell differentiation processes such as invasion, migration, and fusion. Abnormalities in these processes can lead to a series of gestational diseases whose underlying mechanisms are still unclear. One protein that has proven to be essential in placentation is the peroxisome proliferator-activated receptor γ (PPARγ), which is expressed in the nuclei of extravillous cytotrophoblasts (EVCTs) in the first trimester and villous cytotrophoblasts (VCTs) throughout pregnancy. Here, we aimed to explore the genome-wide effects of PPARγ on EVCTs and VCTs via treatment with the PPARγ-agonist rosiglitazone. EVCTs and VCTs were purified from human chorionic villi, cultured in vitro, and treated with rosiglitazone. The transcriptomes of both types of cells were then quantified using microarray profiling. Differentially expressed genes (DEGs) were filtered and submitted for gene ontology (GO) annotation and pathway analysis with ClueGO. The online tool STRING was used to predict PPARγ and DEG protein interactions, while iRegulon was used to predict the binding sites for PPARγ and DEG promoters. GO and pathway terms were compared between EVCTs and VCTs with clusterProfiler. Visualizations were prepared in Cytoscape. From our microarray data, 139 DEGs were detected in rosiglitazone-treated EVCTs (RT-EVCTs) and 197 DEGs in rosiglitazone-treated VCTs (RT-VCTs). Downstream annotation analysis revealed the similarities and differences between RT-EVCTs and RT-VCTs with respect to the biological processes, molecular functions, cellular components, and KEGG pathways affected by the treatment, as well as predicted binding sites for both protein-protein interactions and transcription factor-target gene interactions. These results provide a broad perspective of PPARγ-activated processes in trophoblasts; further analysis of the transcriptomic signatures of RT-EVCTs and RT-VCTs should open new avenues for future research and contribute to the discovery of possible drug-targeted genes or pathways in the human placenta.
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20
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Park HR, Elkin ER, Castillo-Castrejon M, Loch-Caruso R. Brominated diphenyl ether-47 differentially regulates cellular migration and invasion in a human first trimester trophoblast cell line. Reprod Toxicol 2020; 93:191-198. [PMID: 32142752 DOI: 10.1016/j.reprotox.2020.02.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 02/06/2020] [Accepted: 02/27/2020] [Indexed: 02/06/2023]
Abstract
Polybrominated diphenyl ethers (PBDEs) are flame retardant compounds detected in human placenta and linked to adverse pregnancy outcomes. Impaired trophoblast migration and invasion during early pregnancy have been implicated as potential mechanisms of pregnancy disorders. The present study investigated the effect of BDE-47, a prevalent PBDE congener, on cell migration, invasion, and matrix metalloproteinase (MMP) expression in a human first trimester extravillous trophoblast cell line, HTR-8/SVneo. BDE-47 stimulated cell migration in HTR-SV/neo cells while decreasing invasion of cells into Matrigel. In addition, BDE-47 led to differential expression of MMP-1, -2, -3, and -9 at protein and mRNA levels. In summary, BDE-47 differentially regulated cellular migration and invasion with divergent changes in MMP expression in trophoblasts. Because proper regulation of trophoblast migration and invasion is critical for placental development and function, further research is warranted to determine if exposure to PBDEs disrupts trophoblast functions with increased risk for adverse pregnancy outcomes.
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Affiliation(s)
- Hae-Ryung Park
- Department of Environmental Health Sciences, University of Michigan, 1415 Washington Heights, Ann Arbor, MI, 48109-2029 USA.
| | - Elana R Elkin
- Department of Environmental Health Sciences, University of Michigan, 1415 Washington Heights, Ann Arbor, MI, 48109-2029 USA
| | - Marisol Castillo-Castrejon
- Department of Environmental Health Sciences, University of Michigan, 1415 Washington Heights, Ann Arbor, MI, 48109-2029 USA
| | - Rita Loch-Caruso
- Department of Environmental Health Sciences, University of Michigan, 1415 Washington Heights, Ann Arbor, MI, 48109-2029 USA
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21
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The role of Galectin-1 in HIV associated preeclampsia. Eur J Obstet Gynecol Reprod Biol 2020; 246:138-144. [PMID: 32018196 DOI: 10.1016/j.ejogrb.2020.01.024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/16/2020] [Accepted: 01/20/2020] [Indexed: 11/24/2022]
Abstract
OBJECTIVE In this study, the role of Gal1, a regulatory protein involved in receptor binding and gene transcription within trophoblast cells, in the pathophysiology of HIV associated preeclampsia was determined by immunolocalizing its expression in the placenta of a South African cohort. STUDY DESIGN this is an analytical study carried out at the Optics and Imaging Center, Neslon R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa. A hundred and twenty HIV negative or positive, Black African primigrad or multigravid women with pre-eclamptic and normotensive pregnancies were involved in the study. Post-delivery, full thickness of centrally located placental tissue obtained was fixed for immunohistochemistry. The expression of Gal1 was immunolocalized using immunohistochemical assay kit and further quantified with using AxioVision Image analysis software package. Student t-test was used to compare the levels of the analytes while One-way ANOVA was used for comparison across the groups. RESULTS Gal1 immunoreactivity was observed within the Hofbauer cells, cytotrophoblast, syncytial knots and in the endothelial cells lining blood vessels in both exchange and conducting villi of both normotensive and preeclamptic pregnancies regardless of HIV status. There was a down regulation in Gal1 immunoreactivity in both the exchange and conducting villi of preeclamptic compared to normotensive pregnancies. However, there was no significant effect of HIV infection on Gal1 immunostaining in both villi types. CONCLUSION The down regulation of Gal1 in preeclampsia may be due to the inhibition of the MAPK pathway. Since Gal1 influences differentiation and migration, the defective trophoblast invasion in preeclampsia may emanate from its decreased immunoexpression. This highlights the role of Gal1 in angiogenesis and placentation.
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22
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Mesalam A, Lee KL, Khan I, Chowdhury MMR, Zhang S, Song SH, Joo MD, Lee JH, Jin JI, Kong IK. A combination of bovine serum albumin with insulin-transferrin-sodium selenite and/or epidermal growth factor as alternatives to fetal bovine serum in culture medium improves bovine embryo quality and trophoblast invasion by induction of matrix metalloproteinases. Reprod Fertil Dev 2019; 31:333-346. [PMID: 30086822 DOI: 10.1071/rd18162] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 07/07/2018] [Indexed: 12/17/2022] Open
Abstract
This study investigated the use of bovine serum albumin (BSA) plus insulin-transferrin-sodium selenite (ITS) and/or epidermal growth factor (EGF) as alternatives to fetal bovine serum (FBS) in embryo culture medium. The developmental ability and quality of bovine embryos were determined by assessing their cell number, lipid content, gene expression and cryotolerance, as well as the invasion ability of trophoblasts. The percentage of embryos that underwent cleavage and formed a blastocyst was higher (P<0.01) in medium containing ITS plus EGF and BSA than in medium containing FBS. Culture with ITS plus EGF and BSA also increased the hatching ability of blastocysts and the total cell number per blastocyst. Furthermore, the beneficial effects of BAS plus ITS and EGF on embryos were associated with a significantly reduced intracellular lipid content, which increased their cryotolerance. An invasion assay confirmed that culture with ITS plus EGF and BSA significantly improved the invasion ability of trophoblasts. Real-time quantitative polymerase chain reaction analysis showed that the mRNA levels of matrix metalloproteinase-2 (MMP2) and MMP9, acyl-CoA synthetase long-chain family member 3, acyl-coenzyme A dehydrogenase long-chain and hydroxymethylglutaryl-CoA reductase significantly increased upon culture with ITS plus EGF and BSA. Moreover, protein expression levels of matrix metalloproteinase-2 and -9 increased (P<0.01) in medium supplemented with ITS plus EGF and BSA compared with medium supplemented with FBS. Taken together, these data suggest that supplementation of medium with ITS plus EGF and BSA improves invitro bovine embryo production, cryotolerance and invasion ability of trophoblasts.
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Affiliation(s)
- Ayman Mesalam
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - Kyeong-Lim Lee
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - Imran Khan
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - M M R Chowdhury
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - Shimin Zhang
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - Seok-Hwan Song
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - Myeong-Don Joo
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - Jae-Hoon Lee
- Department of Veterinary Science, College of Veterinary Science, Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - Jong-In Jin
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
| | - Il-Keun Kong
- Department of Animal Science, Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
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Ma L, Zhang Z, Dong K, Ma Y. TWIST1 Alleviates Hypoxia-induced Damage of Trophoblast Cells by inhibiting mitochondrial apoptosis pathway. Exp Cell Res 2019; 385:111687. [DOI: 10.1016/j.yexcr.2019.111687] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 10/21/2019] [Accepted: 10/23/2019] [Indexed: 11/28/2022]
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Yu Y, Fang L, Wang S, Li Y, Guo Y, Sun YP. Amphiregulin promotes trophoblast invasion and increases MMP9/TIMP1 ratio through ERK1/2 and Akt signal pathways. Life Sci 2019; 236:116899. [DOI: 10.1016/j.lfs.2019.116899] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 09/20/2019] [Accepted: 09/20/2019] [Indexed: 12/26/2022]
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Estradiol promotes trophoblast viability and invasion by activating SGK1. Biomed Pharmacother 2019; 117:109092. [DOI: 10.1016/j.biopha.2019.109092] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 05/24/2019] [Accepted: 06/04/2019] [Indexed: 01/02/2023] Open
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New Insights into the Process of Placentation and the Role of Oxidative Uterine Microenvironment. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9174521. [PMID: 31341539 PMCID: PMC6615000 DOI: 10.1155/2019/9174521] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/28/2019] [Indexed: 12/18/2022]
Abstract
For a successful pregnancy to occur, a predecidualized receptive endometrium must be invaded by placental differentiated cells (extravillous trophoblast cells (EVTs)) and, at the same time, continue decidualization. EVT invasion is aimed at anchoring the placenta to the maternal uterus and ensuring local blood supply increase necessary to provide normal placental and foetal development. The first is achieved by migrating through the maternal endometrium and deeper into the myometrium, while the second by transforming uterine spiral arteries into large vessels. This process is a tightly regulated battle comprising interests of both the mother and the foetus. Invading EVTs are required to perform a scope of functions: move, adhere, proliferate, differentiate, interact, and digest the extracellular matrix (ECM); tolerate hypoxia; transform the maternal spiral arteries; and die by apoptosis. All these functions are modulated by their surrounding microenvironment: oxygen, soluble factors (e.g., cytokines, growth factors, and hormones), ECM proteins, and reactive oxygen species. A deeper comprehension of oxidative uterine microenvironment contribution to trophoblast function will be addressed in this review.
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Pollheimer J, Vondra S, Baltayeva J, Beristain AG, Knöfler M. Regulation of Placental Extravillous Trophoblasts by the Maternal Uterine Environment. Front Immunol 2018; 9:2597. [PMID: 30483261 PMCID: PMC6243063 DOI: 10.3389/fimmu.2018.02597] [Citation(s) in RCA: 254] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/22/2018] [Indexed: 12/22/2022] Open
Abstract
During placentation invasive extravillous trophoblasts (EVTs) migrate into the maternal uterus and modify its vessels. In particular, remodeling of the spiral arteries by EVTs is critical for adapting blood flow and nutrient transport to the developing fetus. Failures in this process have been noticed in different pregnancy complications such as preeclampsia, intrauterine growth restriction, stillbirth, or recurrent abortion. Upon invasion into the decidua, the endometrium of pregnancy, EVTs encounter different maternal cell types such as decidual macrophages, uterine NK (uNK) cells and stromal cells expressing a plethora of growth factors and cytokines. Here, we will summarize development of the EVT lineage, a process occurring independently of the uterine environment, and formation of its different subtypes. Further, we will discuss interactions of EVTs with arteries, veins and lymphatics and illustrate how the decidua and its different immune cells regulate EVT differentiation, invasion and survival. The present literature suggests that the decidual environment and its soluble factors critically modulate EVT function and reproductive success.
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Affiliation(s)
- Jürgen Pollheimer
- Department of Obstetrics and Gynaecology, Medical University of Vienna, Vienna, Austria
| | - Sigrid Vondra
- Department of Obstetrics and Gynaecology, Medical University of Vienna, Vienna, Austria
| | - Jennet Baltayeva
- British Columbia's Children's Hospital Research Institute, Vancouver, BC, Canada.,Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
| | - Alexander Guillermo Beristain
- British Columbia's Children's Hospital Research Institute, Vancouver, BC, Canada.,Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada
| | - Martin Knöfler
- Department of Obstetrics and Gynaecology, Medical University of Vienna, Vienna, Austria
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Liu L, Sun L, Zheng J, Wang Y. Silencing BRIT1 Facilitates the Abilities of Invasiveness and Migration in Trophoblast Cells. Med Sci Monit 2018; 24:7451-7458. [PMID: 30337515 PMCID: PMC6284355 DOI: 10.12659/msm.910229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background The improper invasion of trophoblast cells (TC) can cause various diseases. BRCT-repeat inhibitor of hTERT expression (BRIT1) is involved in the invasion of tumors. Here, we analyzed the effects of BRIT1 on the invasion of TC. Material/Methods The expression of BRIT1 in JEG-3, B6Tert, and HTR8/SVneo cells was evaluated by transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting. The viability, invasion, and migration of HTR8/SVneo cells were measured using cell counting kit-8 (CCK-8) and Transwell assays. The activities of pro-matrix metalloproteinase-2 (pro-MMP-2) and pro-MMP-9 were tested by gelatin zymography assay. The levels of invasion- and Wnt/β-catenin pathway-related factors were assessed by RT-qPCR and Western blotting. Results Levels of BRIT1 in HTR8/SVneo cells were higher than that of JEG-3 and B6Tert cells. The transfection efficiency of BRIT1 siRNA-2 was better than BRIT1 siRNA-1 in HTR8/SVneo cells. BRIT1 siRNA-2 did not change cell viability, whereas it promoted cell invasion and migration. BRIT1 siRNA-2 enhanced the activities of pro-MMP-2 and pro-MMP-9, as well MMP-2 and MMP-9 levels, and reduced tissue inhibitor of metalloproteinases-1 (TIMP-1) and TIMP-2 expression. Moreover, BRIT1 siRNA-2 significantly increased the levels of Wnt2, Wnt3, and β-catenin. Conclusions BRIT1 silencing accelerated the invasion and migration of TC and activated the Wnt/β-catenin pathway. Our results may provide new insights for finding new molecular targets to cure disease caused by insufficient invasion of TC.
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Affiliation(s)
- Luping Liu
- Department of Obstetrics and Gynecology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China (mainland)
| | - Li Sun
- Department of Obstetrics and Gynecology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China (mainland)
| | - Jing Zheng
- Department of Obstetrics and Gynecology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China (mainland)
| | - Yanchun Wang
- Department of Obstetrics and Gynecology, Yantai Hospital of Traditional Chinese Medicine, Yantai, Shandong, China (mainland)
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Wie JH, Ko HS, Choi SK, Park IY, Kim A, Kim HS, Shin JC. Effects of Oncostatin M on Invasion of Primary Trophoblasts under Normoxia and Hypoxia Conditions. Yonsei Med J 2018; 59:879-886. [PMID: 30091322 PMCID: PMC6082983 DOI: 10.3349/ymj.2018.59.7.879] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 06/29/2018] [Accepted: 07/03/2018] [Indexed: 11/27/2022] Open
Abstract
PURPOSE To investigate the effect of oncostatin M (OSM) on protein expression levels and enzymatic activities of matrix metalloprotainase (MMP)-2 and MMP-9 in primary trophoblasts and the invasiveness thereof under normoxia and hypoxia conditions. MATERIALS AND METHODS Protein expression levels and enzymatic activities of MMP-2 and MMP-9 in primary trophoblasts under normoxia and hypoxia conditions were examined by Western blot and zymography, respectively. Effects of exogenous OSM on the in vitro invasion activity of trophoblasts according to oxygen concentration were also determined. Signal transducer and activator of transcription 3 (STAT3) siRNA was used to determine whether STAT3 activation in primary trophoblasts was involved in the effect of OSM. RESULTS OSM enhanced protein expression levels and enzymatic activities of MMP-2 and MMP-9 in term trophoblasts under hypoxia condition, compared to normoxia control (p<0.05). OSM-induced MMP-2 and MMP-9 enzymatic activities were significantly suppressed by STAT3 siRNA silencing under normoxia and hypoxia conditions (p<0.05). Hypoxia alone or OSM alone did not significantly increase the invasiveness of term trophoblasts. However, the invasion activity of term trophoblasts was significantly increased by OSM under hypoxia, compared to that without OSM treatment under normoxia. CONCLUSION OSM might be involved in the invasiveness of extravillous trophoblasts under hypoxia conditions via increasing MMP-2 and MMP-9 enzymatic activities through STAT3 signaling. Increased MMP-9 activity by OSM seems to be more important in primary trophoblasts.
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Affiliation(s)
- Jeong Ha Wie
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyun Sun Ko
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sae Kyung Choi
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - In Yang Park
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ahyoung Kim
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ho Shik Kim
- Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong Chul Shin
- Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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Graubner FR, Gram A, Kautz E, Bauersachs S, Aslan S, Agaoglu AR, Boos A, Kowalewski MP. Uterine responses to early pre-attachment embryos in the domestic dog and comparisons with other domestic animal species. Biol Reprod 2018. [PMID: 28651344 PMCID: PMC5803782 DOI: 10.1093/biolre/iox063] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
In the dog, there is no luteolysis in the absence of pregnancy. Thus, this species lacks any anti-luteolytic endocrine signal as found in other species that modulate uterine function during the critical period of pregnancy establishment. Nevertheless, in the dog an embryo-maternal communication must occur in order to prevent rejection of embryos. Based on this hypothesis, we performed microarray analysis of canine uterine samples collected during pre-attachment phase (days 10-12) and in corresponding non-pregnant controls, in order to elucidate the embryo attachment signal. An additional goal was to identify differences in uterine responses to pre-attachment embryos between dogs and other mammalian species exhibiting different reproductive patterns with regard to luteolysis, implantation, and preparation for placentation. Therefore, the canine microarray data were compared with gene sets from pigs, cattle, horses, and humans. We found 412 genes differentially regulated between the two experimental groups. The functional terms most strongly enriched in response to pre-attachment embryos related to extracellular matrix function and remodeling, and to immune and inflammatory responses. Several candidate genes were validated by semi-quantitative PCR. When compared with other species, best matches were found with human and equine counterparts. Especially for the pig, the majority of overlapping genes showed opposite expression patterns. Interestingly, 1926 genes did not pair with any of the other gene sets. Using a microarray approach, we report the uterine changes in the dog driven by the presence of embryos and compare these results with datasets from other mammalian species, finding common-, contrary-, and exclusively canine-regulated genes.
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Affiliation(s)
- Felix R Graubner
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Aykut Gram
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Ewa Kautz
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Stefan Bauersachs
- Institute of Agricultural Sciences, Animal Physiology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Selim Aslan
- Department of Obstetrics and Gynecology, Faculty of Veterinary Medicine, Near East University, Nicosia, North Cyprus
| | - Ali R Agaoglu
- Department of Obstetrics and Gynecology, Faculty of Veterinary Medicine, Mehmet Akif Ersoy University, Burdur, Turkey
| | - Alois Boos
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Mariusz P Kowalewski
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
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Danisik H, Bogdanova N, Markoff A. Micromolar Zinc in Annexin A5 Anticoagulation as a Potential Remedy for RPRGL3-Associated Recurrent Pregnancy Loss. Reprod Sci 2018; 26:348-356. [PMID: 29716435 DOI: 10.1177/1933719118773497] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Deficient expression of the placental anticoagulant annexin A5 (ANXA5) has been associated with thrombophilia-related pregnancy complications and ultimately with recurrent pregnancy loss (RPL). Carrier status of M2/ANXA5 ( RPRGL3), common ANXA5 promoter variant, has been identified as genetic cause of reduced ANXA5 levels and proposed as biomarker for successful anticoagulant treatment of RPL women. A murine model of AnxA5 loss of function displayed characteristic placental pathology and fetal loss that was alleviated through anticoagulant intervention. This study identified an alternative means of supplementing anticoagulation, through elevated ANXA5 expression. Physiological micromolar Zn2+ stimulated ANXA5 transcription, raising ANXA5 protein expression and surface abundance on BeWo and human umbilical vein endothelial cells (HUVEC), thus resulting in prolonged coagulation times. Zn2-fed AnxA5 functionally deficient pregnant mice showed a trend to increase litter size when primiparous that grew comparable to wild-type progeny in subsequent pregnancies. Elevated AnxA5 signal upon Zn2+ treatment was confirmed in murine placentae. Micromolar Zn2+ stimulated ANXA5 expression in cell culture directly and alleviated RPL in AnxA5 genetically deficient mice, without notable toxicity effects.
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Affiliation(s)
- Hayrünnisa Danisik
- 1 Institute of Human Genetics, University Clinic Muenster, Muenster, Germany
| | - Nadia Bogdanova
- 1 Institute of Human Genetics, University Clinic Muenster, Muenster, Germany
| | - Arseni Markoff
- 1 Institute of Human Genetics, University Clinic Muenster, Muenster, Germany
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Deng Q, Liu X, Yang Z, Xie L. Expression of N-Acetylglucosaminyltransferase III Promotes Trophoblast Invasion and Migration in Early Human Placenta. Reprod Sci 2018; 26:1373-1381. [PMID: 29642803 DOI: 10.1177/1933719118765967] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Trophoblast migration and invasion at the maternal-fetal interface are crucial events for normal placentation and successful pregnancy. This progress is well controlled by many placenta-specific factors. Inadequate trophoblast invasion results in poor placenta plantation or even complications such as preeclampsia. It has been shown that N-acetylglucosaminyltransferase III (GnT-III) participates in tumor invasion and metastasis as a suppressor; however, the expression of GnT-III and its role in normal pregnancy is unclear. Our objective was to characterize GnT-III expression and function during placental development and identify the underlying mechanisms. METHODS The expression of GnT-III in human placental tissue from the first trimester was determined by immunohistochemistry. The HTR8/SVneo cell line was used to investigate the effects of GnT-III on proliferation, apoptosis, migration/invasion, matrix metalloproteinase (MMP) 2/9 activity, and the expression of the tissue inhibitor of metalloproteinase (TIMP) 1/2 using cell 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays, flow cytometric analysis, transwell migration/invasion assays, gelatin zymography, and Western blot, respectively. Moreover, a placental villous explant model was employed to determine its functions in placentation. RESULTS In the first-trimester placental tissue, GnT-III was localized within the cytotrophoblast, the syncytiotrophoblast and the trophoblast columns of human placental villi, decidual cells, and some extravillous cells in the maternal decidua. GnT-III silencing significantly inhibited HTR8/SVneo cell invasion and migration as well as extravillous explant outgrowth. The application of GnT-III siRNA significantly attenuated MMP2/9 activity and increased TIMP1/2 expression. DISCUSSION AND CONCLUSION GnT-III is expressed in trophoblasts during normal human pregnancy and is involved in regulating trophoblast function.
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Affiliation(s)
- Qinyin Deng
- Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Xiru Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhongmei Yang
- Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Lan Xie
- Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
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Li N, Li S, Wang Y, Wang J, Wang K, Liu X, Li Y, Liu J. Decreased expression of WNT2 in villi of unexplained recurrent spontaneous abortion patients may cause trophoblast cell dysfunction via downregulated Wnt/β-catenin signaling pathway. Cell Biol Int 2018. [PMID: 28627774 DOI: 10.1002/cbin.10807] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
WNT2 has been reported to be important for placental development, especially for the proper vascularization of the placenta. However, its precise role in first-trimester trophoblast cells is still unknown. WNT2 expression in the villous tissues of unexplained recurrent spontaneous abortion (URSA) patients was compared with that of healthy women by Western blot. The function of WNT2 in HTR-8/SVneo trophoblast cells was evaluated by altering the cellular WNT2 level through overexpression and shRNA knockdown. The molecular mechanism of the effect of WNT2 on trophoblast cells was investigated. The association of WNT2 with the Wnt/β-catenin signaling pathway was studied through Western blot and immunofluorescence. Results showed that WNT2 protein expression was significantly decreased in villi of the URSA group compared with the control group. In vitro studies showed that WNT2 could promote human trophoblast cell proliferation and migration through activating the Wnt/β-catenin signaling pathway. Moreover, upon the knockdown of WNT2, trophoblast cell proliferation and migration were significantly suppressed. In conclusion, our study indicated that WNT2 plays an important role in trophoblast function. WNT2 insufficiency might cause impaired trophoblast cell proliferation and migration via downregulation of Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Ning Li
- Central Laboratory, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Shuhong Li
- Department of Obstetrics and Gynecology, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Yanwei Wang
- Central Laboratory, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Jiahui Wang
- Central Laboratory, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Kai Wang
- School of Agriculture, Ludong University, Yantai, Shandong, China
| | - Xin Liu
- Central Laboratory, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Yan Li
- College of Life Science, Yantai University, Yantai, Shandong, China
| | - Juan Liu
- Central Laboratory, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
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Ding L, Li S, Zhang Y, Gai J, Kou J. MXRA5 is decreased in preeclampsia and affects trophoblast cell invasion through the MAPK pathway. Mol Cell Endocrinol 2018; 461:248-255. [PMID: 28919298 DOI: 10.1016/j.mce.2017.09.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 09/13/2017] [Accepted: 09/13/2017] [Indexed: 01/07/2023]
Abstract
Preeclampsia causes gestational failure in a significant number of women annually. Insufficient trophoblast cell invasion plays an essential role in preeclampsia pathogenesis. Matrix-remodeling associated 5 (MXRA5) is a proteoglycan involved in adhesion and matrix remodeling. This study sought to explore the role of MXRA5 in trophoblast cell invasion. Preeclamptic villi were obtained for the delineation of MXRA5 expression. Specific MXRA5 siRNA and pcDNA3.1/MXRA5 were used to manipulate MXRA5 expression in HTR-8/SVneo. Cell viability was determined by MTT and apoptosis by flow cytometry. Cell invasion was evaluated using Matrigel invasion assay. MXRA5 expression was lower in preeclamptic villi and cytotrophoblasts. Silencing MXRA5 expression in HTR-8/SVneo decreased cell viability and invasion, which were augmented by MXRA5 overexpression. Furthermore, MXRA5 modulated N-cadherin, E-cadherin, MMP-2, and MMP-9 expression through p38 MAPK and ERK1/2 signaling transduction. In addition, the expression of MXRA5 was influenced by exogenous TNF-α but not by IFN-γ. Overexpression of MXRA5 attenuated HTR-8/SVneo apoptosis induced by TNF-α. MXRA5 is downregulated in preeclamptic cytotrophoblasts and can regulate trophoblast cell invasion via the MAPK pathway.
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Affiliation(s)
- Lan Ding
- The First Department of Obstetrics, Cangzhou Central Hospital, Cangzhou 061001, China
| | - Shaocong Li
- Department of Gynecology and Obstetrics, Liaocheng People's Hospital, Liaocheng 252000, China
| | - Yanshang Zhang
- Department of Obstetrics, Hebei General Hospital, Shijiazhuang 050051, China
| | - Junfeng Gai
- Department of Gynaecology, Binzhou City Center Hospital, Binzhou 251700, China
| | - Jianfang Kou
- Department of Gynaecology, The Affiliated Zhengzhou Hospital of Jinan University, Zhengzhou Second Hospital, Zhengzhou 450006, China.
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Chen Y, Zhang H, Han F, Yue L, Qiao C, Zhang Y, Dou P, Liu W, Li Y. The depletion of MARVELD1 leads to murine placenta accreta via integrin β4-dependent trophoblast cell invasion. J Cell Physiol 2017; 233:2257-2269. [PMID: 28708243 DOI: 10.1002/jcp.26098] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 07/12/2017] [Indexed: 12/12/2022]
Abstract
The placenta is a remarkable organ, it serves as the interface between the mother and the fetus. Proper invasion of trophoblast cells is required for a successful pregnancy. Previous studies have found that the adhesion molecule integrin β4 plays important roles during trophoblast cell invasion. Here, we found that the overall birth rate of the MARVELD1 knockout mouse is much lower than that of the wild-type mouse (p < 0.001). In E18.5 MARVELD1 knockout mice, we observed an over-invasion of trophoblast cells, and indeed, the pregnant mice had a partial placenta accreta phenotype. The HTR8/SVneo cell line was used as an in vitro model to elucidate the underlying mechanisms of MARVELD1-mediated trophoblast invasion. We detected a diminished expression of integrin β4 upon the downregulation of MARVELD1 and enhanced migrate and invasive abilities of trophoblast cells both in vivo and in vitro. The integrin β4 rescue assay also supported the results. In conclusion, this study found that MARVELD1 mediated the invasion of trophoblast cells via regulating the expression of integrin β4 during placenta development.
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Affiliation(s)
- Yue Chen
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Hui Zhang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Fang Han
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Lei Yue
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Chunxiao Qiao
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yao Zhang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Peng Dou
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Weizhe Liu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yu Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
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Gözükara İ, Özgür T, Dolapçıoğlu K, Güngören A, Karapınar OS. YKL-40 expression in abnormal invasive placenta cases. J Perinat Med 2017; 45:571-575. [PMID: 27977409 DOI: 10.1515/jpm-2016-0208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 10/27/2016] [Indexed: 11/15/2022]
Abstract
OBJECTIVE YKL-40 is a secreted glycoprotein and has been implicated in the proliferation and differentiation of malignant cells, extracellular tissue remodelling, neovascularisation, inhibition of cancer cell apoptosis and stimulation of tumour-associated fibroblasts. The purpose of this study was to evaluate YKL-40 tissue expression in extravillous trophoblast invasion and its possible implication in placenta creta. METHODS A total of 35 placenta creta cases and six control cases were included in the study, of which eight cases were placenta accreta, 12 were increta and 15 were percreta. Histological YKL-40 staining was scored in tissue as weak (1), medium (2) and strong (3). RESULTS YKL-40 immunoreactivity intensity in the percreta group was significantly higher compared to the increta and accreta groups (2.47±0.74, 1.33±0.49 and 1.37±0.52, respectively; P=0.000). YKL-40 immunoreactivity intensity was positively correlated with creta (r=0.6; P=0.000), depth of invasion (r=0.49; P=0.003) and depth of invasion to full thickness ratio (r=0.58; P=0.000). CONCLUSION This study demonstrated that YKL-40 is strongly expressed in placenta percreta and is correlated with extravillous trophoblast invasion. These findings may be informative for understanding the pathophysiology of placenta creta.
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Ahn JH, Park HR, Park CW, Park DW, Kwak-Kim J. Expression of TWIST in the first-trimester trophoblast and decidual tissue of women with recurrent pregnancy losses. Am J Reprod Immunol 2017; 78. [DOI: 10.1111/aji.12670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 02/22/2017] [Indexed: 11/29/2022] Open
Affiliation(s)
- Jin Hee Ahn
- Laboratory of Reproductive Medicine; Cheil General Hospital & Women's Healthcare Center; College of Medicine; Dankook University; Seoul Korea
| | - Hye Ran Park
- Laboratory of Reproductive Medicine; Cheil General Hospital & Women's Healthcare Center; College of Medicine; Dankook University; Seoul Korea
| | - Chan-Woo Park
- Department of Obstetrics and Gynecology; Cheil General Hospital & Women's Healthcare Center; College of Medicine; Dankook University; Seoul Korea
| | - Dong-Wook Park
- Laboratory of Reproductive Medicine; Cheil General Hospital & Women's Healthcare Center; College of Medicine; Dankook University; Seoul Korea
| | - Joanne Kwak-Kim
- Reproductive Medicine; Department of Obstetrics and Gynecology; Chicago Medical School at Rosalind Franklin University of Medicine and Science; Vernon Hills IL USA
- Department of Microbiology and Immunology; Chicago Medical School at Rosalind Franklin University of Medicine and Science; North Chicago IL USA
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Sehgal S, Bhatnagar S, Pallavi SK. Provocative ideas on human placental biology: A prerequisite for prevention and treatment of neonatal health challenges. Am J Reprod Immunol 2017; 77. [PMID: 28276106 DOI: 10.1111/aji.12656] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 01/28/2017] [Indexed: 01/09/2023] Open
Abstract
A 2-day invite-only meeting on generating "Provocative Ideas on human placental research" was organized on 1-2 December 2015 at the Translational Health Science and Technology Institute, Faridabad. This meeting was sponsored by Department of Biotechnology, Ministry of Science and Technology, Govt. of India. The objectives of this meeting were the critical evaluation of placental physiology and its development. Special emphasis was placed on understanding the consequences and implications of placental development in sustenance of pregnancy and in pregnancy-associated complications such as preeclampsia, intrauterine growth restriction, and preterm birth. This meeting brought together experienced as well as novice clinicians and biologists who have a keen interest in the field of placental biology, including development of new technologies and methods for evaluating the role of placenta in predicting pregnancy outcomes. The meeting primarily focused on (i) high-throughput "-omics" approaches, (ii) maternal nutrition and placental function, (iii) placental infection and inflammation, (iv) real-time evaluation of placental development: tools for placental research, and (v) epidemiologic relevance of placental-based research. Unanimous consensus emerged among the participants to carry out additional work focused on these areas. In this article, we summarize the talks and review the published literature on the above-mentioned niches. As a direct outcome of this meeting, a request for applications has been announced by the Department of Biotechnology, Government of India, for pursuing research in this vital but understudied domain.
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Affiliation(s)
- Shilpi Sehgal
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
| | - Shinjini Bhatnagar
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
| | - S K Pallavi
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
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Single-cell transcriptomics of the human placenta: inferring the cell communication network of the maternal-fetal interface. Genome Res 2017; 27:349-361. [PMID: 28174237 PMCID: PMC5340963 DOI: 10.1101/gr.207597.116] [Citation(s) in RCA: 217] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Accepted: 01/12/2017] [Indexed: 02/02/2023]
Abstract
Organismal function is, to a great extent, determined by interactions among their fundamental building blocks, the cells. In this work, we studied the cell-cell interactome of fetal placental trophoblast cells and maternal endometrial stromal cells, using single-cell transcriptomics. The placental interface mediates the interaction between two semiallogenic individuals, the mother and the fetus, and is thus the epitome of cell interactions. To study these, we inferred the cell-cell interactome by assessing the gene expression of receptor-ligand pairs across cell types. We find a highly cell-type-specific expression of G-protein-coupled receptors, implying that ligand-receptor profiles could be a reliable tool for cell type identification. Furthermore, we find that uterine decidual cells represent a cell-cell interaction hub with a large number of potential incoming and outgoing signals. Decidual cells differentiate from their precursors, the endometrial stromal fibroblasts, during uterine preparation for pregnancy. We show that decidualization (even in vitro) enhances the ability to communicate with the fetus, as most of the receptors and ligands up-regulated during decidualization have their counterpart expressed in trophoblast cells. Among the signals transmitted, growth factors and immune signals dominate, and suggest a delicate balance of enhancing and suppressive signals. Finally, this study provides a rich resource of gene expression profiles of term intravillous and extravillous trophoblasts, including the transcriptome of the multinucleated syncytiotrophoblast.
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Cortina ME, Litwin S, Rial Hawila MR, Miranda S. Multiparity upregulates placental plasminogen and urokinase-type plasminogen activator. Am J Reprod Immunol 2017; 77. [DOI: 10.1111/aji.12633] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 01/02/2017] [Indexed: 12/13/2022] Open
Affiliation(s)
- María E. Cortina
- Instituto de Investigaciones Cardiológicas (ININCA); Universidad de Buenos Aires; CONICET; Buenos Aires Argentina
| | - Silvana Litwin
- Instituto de Investigaciones Cardiológicas (ININCA); Universidad de Buenos Aires; CONICET; Buenos Aires Argentina
| | - María R. Rial Hawila
- Instituto de Investigaciones Cardiológicas (ININCA); Universidad de Buenos Aires; CONICET; Buenos Aires Argentina
| | - Silvia Miranda
- Instituto de Investigaciones Cardiológicas (ININCA); Universidad de Buenos Aires; CONICET; Buenos Aires Argentina
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Tanaka K, Sakai K, Matsushima M, Matsuzawa Y, Izawa T, Nagashima T, Furukawa S, Kobayashi Y, Iwashita M. Branched-chain amino acids regulate insulin-like growth factor-binding protein 1 (IGFBP1) production by decidua and influence trophoblast migration through IGFBP1. Mol Hum Reprod 2016; 22:890-9. [PMID: 27193429 DOI: 10.1093/molehr/gaw032] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Accepted: 05/13/2016] [Indexed: 11/13/2022] Open
Abstract
STUDY QUESTION Do branched-chain amino acids (BCAAs) influence the migration of human extravillous trophoblast (EVT) cells through changes in insulin-like growth factor-binding protein 1 (IGFBP1) production in decidual cells? STUDY FINDING Decidua-derived IGFBP1 had a stimulating effect on migration of EVT. WHAT IS KNOWN ALREADY IGFBP1 is abundantly secreted from human decidual cells and influences trophoblast migration in human placenta of early pregnancy. In hepatic cells, the expression of IGFBP1 is influenced by nutritional status and BCAAs regulate IGFBP1 production. STUDY DESIGN, SAMPLES/MATERIALS, METHODS This is a laboratory-based study using human decidual cells and trophoblast cells isolated from placental tissue of early pregnancy (n = 50) and grown as primary cultures. Production of IGFBP1 from decidual cells was examined by enzyme-linked immunosorbent assay and immunoblotting after incubation with or without BCAAs. EVT migration was evaluated using the media conditioned by decidual cells. The effect of conditioned media on phosphorylation of focal adhesion kinase (FAK) in EVT was also analyzed by immunoblotting. The same experiments were repeated in the presence of RGD peptide, which inhibits IGFBP1 binding to α5β1 integrin. An EVT migration assay and the immunoblotting of phosphorylated FAK were also conducted with exogenous IGFBP1. The effect of the conditioned media on cytotrophoblast cell number was also assessed using WST-1 in a cell proliferation assay. MAIN RESULTS AND THE ROLE OF CHANCE Deprivation of BCAAs on decidual cells significantly suppressed IGFBP1 secretion (P < 0.05, versus BCAA+). Exogenous IGFBP1-stimulated EVT migration (P < 0.05) and phosphorylation of FAK (P < 0.05), and the RGD peptide inhibited these effects. EVT migration and phosphorylation of FAK were stimulated by the conditioned media, presumably by IGFBP1 in the media. RGD treatment abrogated the stimulating effects of conditioned media. The conditioned media deprived of BCAAs had suppressive effects on EVT migration (P < 0.05, versus BCAA+) and phosphorylation of FAK (P < 0.05, versus BCAA+). The conditioned media did not affect number of cytotrophoblast cells. LIMITATIONS, REASONS FOR CAUTION The conclusions are based on in vitro experiments with human decidual cells and trophoblast cells isolated from placental tissue of early pregnancy, and we were unable to ascertain whether these mechanisms actually operate in vivo. We investigated the effect of decidua-derived IGFBP1 on EVT migration, however, we cannot completely rule out the possibility that endogenous IGF could also influence cell migration. WIDER IMPLICATIONS OF FINDINGS Interruption of the BCAA supply to uterine decidual cells in early pregnancy may suppress EVT migration through reduced IGFBP1 secretion, which may be one of the pathophysiological conditions responsible for pre-eclampsia. LARGE SCALE DATA None. STUDY FUNDING/ AND COMPETING INTERESTS All funds were obtained through Kyorin University School of Medicine. The authors have no conflict of interest to declare.
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Affiliation(s)
- Kei Tanaka
- Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
| | - Keiji Sakai
- Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
| | - Miho Matsushima
- Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
| | - Yukiko Matsuzawa
- Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
| | - Tomoko Izawa
- Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
| | - Takashi Nagashima
- Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
| | - Seishi Furukawa
- Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
| | - Yoichi Kobayashi
- Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
| | - Mitsutoshi Iwashita
- Department of Obstetrics and Gynecology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
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42
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G protein-coupled receptor 30 regulates trophoblast invasion and its deficiency is associated with preeclampsia. J Hypertens 2016; 34:710-8. [DOI: 10.1097/hjh.0000000000000844] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Silva JF, Serakides R. Intrauterine trophoblast migration: A comparative view of humans and rodents. Cell Adh Migr 2016; 10:88-110. [PMID: 26743330 DOI: 10.1080/19336918.2015.1120397] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Trophoblast migration and invasion through the decidua and maternal uterine spiral arteries are crucial events in placentation. During this process, invasive trophoblast replace vascular endothelial cells as the uterine arteries are remodeled to form more permissive vessels that facilitate adequate blood flow to the growing fetus. Placentation failures resulting from either extensive or shallow trophoblastic invasion can cause pregnancy complications such as preeclampsia, intrauterine growth restriction, placenta creta, gestational trophoblastic disease and even maternal or fetal death. Consequently, the use of experimental animal models such as rats and mice has led to great progress in recent years with regards to the identification of mechanisms and factors that control trophoblast migration kinetics. This review aims to perform a comparative analysis of placentation and the mechanisms and factors that coordinate intrauterine trophoblast migration in humans, rats and mice under physiological and pathological conditions.
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Affiliation(s)
- Juneo F Silva
- a Laboratório de Endocrinologia e Metabolismo, Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais , Belo Horizonte , Minas Gerais , Brazil
| | - Rogéria Serakides
- b Laboratório de Patologia, Departamento de Clínica e Cirurgia Veterinárias, Escola de Veterinária, Universidade Federal de Minas Gerais , Belo Horizonte , Minas Gerais , Brazil
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Majali-Martinez A, Hiden U, Ghaffari-Tabrizi-Wizsy N, Lang U, Desoye G, Dieber-Rotheneder M. Placental membrane-type metalloproteinases (MT-MMPs): Key players in pregnancy. Cell Adh Migr 2016; 10:136-46. [PMID: 26745344 DOI: 10.1080/19336918.2015.1110671] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Membrane-type matrix metalloproteinases (MT-MMPs) are a sub-family of zinc-dependent endopeptidases involved in the degradation of the extracellular matrix. Although MT-MMPs have been mainly characterized in tumor biology, they also play a relevant role during pregnancy. Placental MT-MMPs are required for cytotrophoblast migration and invasion of the uterine wall and in the remodeling of the spiral arteries. They are involved in the fusion of cytotrophoblasts to form the syncytiotrophoblast as well as in angiogenesis. All these processes are crucial for establishing and maintaining a successful pregnancy and, thus, MT-MMP activity has to be tightly regulated in time and space. Indeed, a de-regulation of MT-MMP expression has been linked with pregnancy complications such as preeclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM) and was also found in maternal obesity. Here we review what is currently known about MT-MMPs in the placenta, with a focus on their general features, their localization and their involvement in pregnancy disorders.
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Affiliation(s)
| | - Ursula Hiden
- a Department of Obstetrics and Gynecology , Medical University of Graz , Graz , Austria
| | | | - Uwe Lang
- a Department of Obstetrics and Gynecology , Medical University of Graz , Graz , Austria
| | - Gernot Desoye
- a Department of Obstetrics and Gynecology , Medical University of Graz , Graz , Austria
| | - Martina Dieber-Rotheneder
- a Department of Obstetrics and Gynecology , Medical University of Graz , Graz , Austria.,c Institute of Pathology, Medical University of Graz , Graz , Austria
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Weiss G, Huppertz B, Siwetz M, Lang I, Moser G. Arterial endothelial cytokines guide extravillous trophoblast invasion towards spiral arteries; an in-vitro study with the trophoblast cell line ACH-3P and female non-uterine endothelial cells. Placenta 2015; 38:49-56. [PMID: 26907382 DOI: 10.1016/j.placenta.2015.12.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 12/15/2015] [Accepted: 12/17/2015] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Invasion of extravillous trophoblasts (EVT) is tightly linked to appropriate cell to cell contact as well as paracrine guidance of EVT by maternal uterine cells, conducted by a variety of locally expressed cytokines. Here we investigated the interaction of the first trimester trophoblast cell line ACH-3P with adult iliac arterial (AEC) and venous endothelial cells (VEC). METHODS The impact of ACH-3P conditioned medium (Cdm), obtained at 2.5% and 21% oxygen, on endothelial cell viability (LDH-Assay) and network formation (Matrigel-Assay) was tested. We investigated cytokine expression of AEC- and VEC-Cdm and confirmed results with ELISA analysis, and investigated the influence of Cdm on ACH-3P proliferation and invasion. Additionally, direct co-culture experiments with ACH-3P and AEC on Matrigel were performed. A subset of experiments was verified with primary trophoblasts as well as with first trimester placenta in situ specimens. RESULTS ACH-3P-Cdm significantly enhanced cell viability of AEC and VEC after 72 h. ACH-3P-Cdm at 2.5% oxygen stabilized endothelial network structures in Matrigel up to 24 h, similar to the effect of a direct co-culture of AEC and ACH-3P. AEC and VEC showed a similar pattern of secreted cytokines. However, elevated levels of cytokines secreted by AEC were found for GRO, IL-6, MMP-1 and uPAR. ELISA confirmed elevated concentrations of IL-6 and uPAR in AEC compared to VEC. ACH-3P and primary trophoblasts more likely invaded towards AEC-Cdm than towards VEC-Cdm. Addition of IL-6 to Cdm increased the invasion potential of both cell types. AEC- and VEC-Cdm reduced ACH-3P cell proliferation after 24 h of culture. IL-6 was highly expressed in uterine AEC compared to VEC as visualized by immunohistochemistry. DISCUSSION The presented results clearly demonstrate that cytokines of both cell types, AEC and trophoblasts, differentially contribute to successful guidance and interaction in the process of trophoblast invasion.
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Affiliation(s)
- Gregor Weiss
- From the Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria.
| | - Berthold Huppertz
- From the Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria
| | - Monika Siwetz
- From the Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria
| | - Ingrid Lang
- From the Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria
| | - Gerit Moser
- From the Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria
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Takaya J. Small for Gestational Age and Magnesium: Intrauterine magnesium deficiency may induce metabolic syndrome in later life. AIMS Public Health 2015; 2:793-803. [PMID: 29546136 PMCID: PMC5690443 DOI: 10.3934/publichealth.2015.4.793] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 11/16/2015] [Indexed: 12/22/2022] Open
Abstract
Magnesium deficiency during pregnancy as a result of insufficient or low intake of magnesium is common in developing and developed countries. Previous reports have shown that intracellular magnesium of cord blood platelets is lower among small for gestational age (SGA) groups than that of appropriate for gestational age (AGA) groups, suggesting that intrauterine magnesium deficiency may result in SGA. Additionally, the risk of adult-onset diseases such as insulin resistance syndrome is greater among children whose mothers were malnourished during pregnancy, and who consequently had a low birth weight. In a number of animal models, poor nutrition during pregnancy leads to offspring that exhibit pathophysiological changes similar to human diseases. The offspring of pregnant rats fed a magensium restricted diet have developed hypermethylation in the hepatic 11β-hydroxysteroid dehydrogenase-2 promoter. These findings indicate that maternal magnesium deficiencies during pregnancy influence regulation of non-imprinted genes by altering the epigenetic regulation of gene expression, thereby inducing different metabolic phenotypes. Magnesium deficiency during pregnancy may be responsible for not only maternal and fetal nutritional problems, but also lifelong consequences that affect the offspring throughout their life. Epidemiological, clinical, and basic research on the effects of magnesium deficiency now indicates underlying mechanisms, especially epigenetic processes.
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Affiliation(s)
- Junji Takaya
- Department of Pediatrics, Kawachi General Hospital, Higashi-Osaka, Osaka 578-0954, Japan
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Dong H, Yu C, Mu J, Zhang J, Lin W. Role of EFNB2/EPHB4 signaling in spiral artery development during pregnancy: An appraisal. Mol Reprod Dev 2015; 83:12-8. [PMID: 26501487 DOI: 10.1002/mrd.22593] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2014] [Accepted: 10/22/2015] [Indexed: 12/30/2022]
Abstract
EFNB2 and EPHB4, which belong to a large tyrosine kinase receptor superfamily, are molecular markers of arterial and venous blood vessels, respectively. EFNB2/EPHB4 signaling plays an important role in physiological and pathological angiogenesis, and its role in tumor vessel development has been extensively studied. Pregnancy and tumors share similar features, including continuous cell proliferation and increased demand for a blood supply. Our previous studies showed that Efnb2 and Ephb4 were expressed dynamically in the spiral arteries, uterine natural killer cells, and trophoblasts during mouse gestation Days 6.5-12.5. Moreover, uterine natural killer cells and trophoblasts are required for the modification of spiral arteries. Oxygen tension within the pregnant uterus, which contributes to the vascular development, also affects EFNB2 and EPHB4 expression. Considering the role of EFNB2/EPHB4 signaling in embryonic and tumor vascular development, and its dynamic expression in the decidua and placenta, we hypothesize that EFNB2 and EPHB4 are involved in the regulation of spiral artery remodeling. Investigating this hypothesis will help clarify the mechanisms of pathological pregnancy that may underlie abnormal spiral artery development.
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Affiliation(s)
- Hongmei Dong
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Chaoran Yu
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Jiao Mu
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Ji Zhang
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Wei Lin
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
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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; 30:2747-57. [PMID: 26493408 DOI: 10.1093/humrep/dev266] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 09/30/2015] [Indexed: 12/23/2022] Open
Abstract
STUDY QUESTION How is histiotrophic nutrition of the embryo secured during the first trimester of pregnancy? SUMMARY ANSWER Rather than specifically focusing on invasion into spiral arteries, extravillous trophoblasts also invade into uterine glands (endoglandular trophoblast) from the very beginning and open them toward the intervillous space. WHAT IS KNOWN ALREADY Extravillous trophoblasts can be found in close contact and within the lumen of uterine glands, sometimes replacing glandular epithelial cells. STUDY DESIGN, SIZE, DURATION As well as extensive screening of specimens from first trimester placentation sites in situ we used a previously established three-dimensional co-culture in vitro model system of first trimester villous explants with non-invaded decidua parietalis. PARTICIPANTS/MATERIALS, SETTING, METHODS First trimester placentas were obtained from elective terminations of pregnancies (n = 48) at 5-11 weeks of gestational age. A subset was processed for confrontation co-culture (n = 31). Invaded decidua basalis was obtained from 20 placentas. All tissues were sectioned, subsequently immunostained and immunodoublestained with antibodies against keratin 7 (KRT7), major histocompatibility complex, class I, G (HLA-G), matrix metallopeptidase 9 (MMP9), von Willebrand factor (VWF) and the appropriate Immunoglobulin G (IgG) negative controls. Replacement of endothelial/epithelial cells by extravillous trophoblasts was quantified semi-quantitatively. Additionally, hematoxylin and eosin-stained archival specimens from early implantation sites were assessed. MAIN RESULTS AND THE ROLE OF CHANCE The earliest available specimen was from around Day 10 after conception; already at this stage trophoblasts had penetrated into uterine glands and had started to replace the epithelium of the glands. Endoglandular trophoblasts replaced uterine glands in vitro and in situ and could be found in the lumen of invaded glands. Quantitative analysis revealed significantly more replacement of epithelial cells in glands (63.8 ± 22.1%) compared with endothelial cells in vessels (26.4 ± 8.8%). Accumulated detached glandular epithelial cells could be repeatedly observed in the lumen of invaded glands. Additionally, in areas of trophoblast invasion the glandular epithelium seemed to be completely disintegrated compared with glandular epithelium in the non-invaded parts of the decidua. Whole tissue specimens were used in vitro and in situ instead of cell lines; these systems mostly maintain the context of the in vivo situation. LIMITATIONS, REASONS FOR CAUTION This is a descriptive study supported by in vitro experiments. However, a histological section will always only be a snapshot and quantification from histological sections has its limitations. WIDER IMPLICATIONS OF THE FINDINGS This study further strengthens the hypothesis of histiotrophic nutrition of the embryo prior to the establishment of the maternal blood flow toward the placenta. Invasion of uterine glands by endoglandular trophoblasts may have more impact on the outcome of early pregnancy than assumed up to now.
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Affiliation(s)
- G Moser
- Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria
| | - G Weiss
- Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria
| | - M Gauster
- Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria
| | - M Sundl
- Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria
| | - B Huppertz
- Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Harrachgasse 21/7, 8010 Graz, Austria
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Lash GE. Molecular Cross-Talk at the Feto-Maternal Interface. Cold Spring Harb Perspect Med 2015; 5:cshperspect.a023010. [PMID: 26385089 DOI: 10.1101/cshperspect.a023010] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Molecular cross-talk at the feto-maternal interface occurs between many different cell types, including uterine leukocytes, extravillous trophoblast cells, and uterine spiral arteries, is essential for the establishment and maintenance of pregnancy. This review concentrates on human pregnancy and examines three main areas in which cross-talk occurs; immune tolerance, regulation of extravillous trophoblast invasion, and remodeling of the uterine spiral arteries.
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Affiliation(s)
- Gendie E Lash
- Reproductive and Vascular Biology Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom
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50
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Zhuang B, Luo X, Rao H, Li Q, Shan N, Liu X, Qi H. Oxidative stress-induced C/EBPβ inhibits β-catenin signaling molecule involving in the pathology of preeclampsia. Placenta 2015; 36:839-46. [PMID: 26166436 DOI: 10.1016/j.placenta.2015.06.016] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Revised: 06/16/2015] [Accepted: 06/30/2015] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Oxidative stress-induced trophoblast cell dysfunction is a major pathology in preeclampsia (PE). Recently, CCAAT/enhancer binding protein beta (C/EBPβ) has been investigated as a tumor suppressor that participates in tumor invasion. However, the function of C/EBPβ in trophoblast cells remains unknown. Our study was designed to detect the expression of C/EBPβ in the preeclamptic placenta and to identify the underlying mechanisms of oxidative stress. METHODS Human placental tissues with PE were collected. The expression of C/EBPβ and β-catenin were detected. Human first trimester extravillous trophoblast cell (HTR8/SVneo) line exposed to hypoxia/reoxygenation (H/R) was employed as an oxidative stress model in vitro to investigate the effects of C/EBPβ on invasion and the expression of β-catenin. Moreover, first trimester-derived placental villous explants were used to verify the effects of C/EBPβ and β-catenin in placentation. RESULTS In preeclamptic placentas, C/EBPβ was overexpressed and β-catenin was decreased. In addition, C/EBPβ was found to have increased expression in H/R-treated HTR8/SVneo cells and villous explants. C/EBPβ knockdown and β-catenin activation could significantly promote the invasion of HTR8/SVneo cells, enhance the outgrowth and migration in villous explants and inhibit the excessive generation of intracellular ROS. These findings might be related to the increased activities of MMP-2/9 and the decreased expression of TIMP-1/2. Meanwhile, C/EBPβ knockdown remarkably increased the expression of β-catenin. DISCUSSION We hypothesize that the oxidative stress-induced overexpression of C/EBPβ might influence the activity of MMPs by regulating the Wnt/β-catenin signaling pathway to affect the invasion of trophoblast cells, which then participate in the pathogenesis of preeclampsia.
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Affiliation(s)
- B Zhuang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Yixue Road, Yuzhong District, Chongqing 400016, China
| | - X Luo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Yixue Road, Yuzhong District, Chongqing 400016, China
| | - H Rao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Yixue Road, Yuzhong District, Chongqing 400016, China
| | - Q Li
- Department of Pathology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Yixue Road, Yuzhong District, Chongqing 400016, China
| | - N Shan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Yixue Road, Yuzhong District, Chongqing 400016, China
| | - X Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Yixue Road, Yuzhong District, Chongqing 400016, China
| | - H Qi
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Yixue Road, Yuzhong District, Chongqing 400016, China.
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