Talk:Ectopic Implantation Research

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Cite this page: Hill, M.A. (2024, May 30) Embryology Ectopic Implantation Research. Retrieved from

Gavin Sacks - uNK cells

University of New South Wales, Sydney, NSW, Australia

St George Hospital, Kogarah, Sydney, NSW, Australia

Royal Hospital for Women, Randwick, NSW, Australia

IVFAustralia, Sydney, NSW, Australia

Correspondence: Gavin Sacks, University of New South Wales, 1601 Westfield Tower 2, 101 Grafton St, Bondi Junction, Sydney, NSW, 2022, Australia. Email:

PubMed - Sacks G


Expression of ENPP3 in human cyclic endometrium: a novel molecule involved in embryo implantation

Reprod Fertil Dev. 2018 Apr 4. doi: 10.1071/RD17257. [Epub ahead of print]

Chen Q, Xin A, Qu R, Zhang W, Li L, Chen J, Lu X, Gu Y, Li J, Sun X.


Ectonucleotide pyrophosphatase-phosphodiesterase 3 (ENPP3), a protein detected in the human uterus, has been found to play an important role in the development and invasion of tumours. It was recently discovered that ENPP3 was upregulated during the window of implantation in the human endometrium but its functional relevance remains elusive. The objective was to determine ENPP3 expression in human endometrium and its roles in endometrial receptivity and embryo implantation. ENPP3 expression was analysed using immunohistochemistry and western blot assay. The effects of ENPP3 on embryo implantation were evaluated using a BeWo cell (a human choriocarcinoma cell line) spheroid attachment assay and BeWo cells were dual cultured with Ishikawa cells transfected with lentiviral vectors (LV5-NC or LV5-ENPP3) to mimic embryo implantation in a Transwell model. The effects of endometrial ENPP3 on factors related to endometrial receptivity were also determined. The results showed that ENPP3 was expressed in human endometrial epithelial cells and its expression levels changed during the menstrual cycle, peaking in the mid-secretory phase, corresponding to the time of embryo implantation. The overexpression of endometrial ENPP3 not only increased the embryo implantation rate but also had positive effects on the expression of factors related to endometrial receptivity in human endometrial cells. The results indicate that ENPP3 levels undergo cyclic changes in the endometrium and affect embryo adhesion and invasion via altering the expression of implantation factors in the human endometrium. Therefore, ENPP3 may play an important role in embryo implantation and may be a unique biomarker of endometrial receptivity. PMID: 29614240 DOI: 10.1071/RD17257

Gene - ectonucleotide pyrophosphatase/phosphodiesterase 3

The protein encoded by this gene belongs to a series of ectoenzymes that are involved in hydrolysis of extracellular nucleotides. These ectoenzymes possess ATPase and ATP pyrophosphatase activities and are type II transmembrane proteins. Expression of the related rat mRNA has been found in a subset of immature glial cells and in the alimentary tract. The corresponding rat protein has been detected in the pancreas, small intestine, colon, and liver. The human mRNA is expressed in glioma cells, prostate, and uterus. Expression of the human protein has been detected in uterus, basophils, and mast cells. Two transcript variants, one protein coding and the other non-protein coding, have been found for this gene.

Antibodies - ectonucleotide pyrophosphatase/phosphodiesterase 3


Immunity. 2017 Dec 19;47(6):1100-1113.e6. doi: 10.1016/j.immuni.2017.11.018. Natural Killer Cells Promote Fetal Development through the Secretion of Growth-Promoting Factors. Fu B1, Zhou Y1, Ni X1, Tong X2, Xu X1, Dong Z3, Sun R1, Tian Z4, Wei H5.

Abstract Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy. However, the role of NK cells in fetal growth is unclear. Here, we have identified a CD49a+Eomes+ subset of NK cells that secreted growth-promoting factors (GPFs), including pleiotrophin and osteoglycin, in both humans and mice. The crosstalk between HLA-G and ILT2 served as a stimulus for GPF-secreting function of this NK cell subset. Decreases in this GPF-secreting NK cell subset impaired fetal development, resulting in fetal growth restriction. The transcription factor Nfil3, but not T-bet, affected the function and the number of this decidual NK cell subset. Adoptive transfer of induced CD49a+Eomes+ NK cells reversed impaired fetal growth and rebuilt an appropriate local microenvironment. These findings reveal properties of NK cells in promoting fetal growth. In addition, this research proposes approaches for therapeutic administration of NK cells in order to reverse restricted nourishments within the uterine microenvironment during early pregnancy. KEYWORDS: aged pregnancy; decidual NK cells; fetal development; fetal growth restriction; growth-promoting factors; maternal-fetal interface; tissue-resident NK PMID: 29262349 DOI: 10.1016/j.immuni.2017.11.018


Microarray analysis of microRNA deregulation and angiogenesis-related proteins in endometriosis

Genet Mol Res. 2016 Jun 3;15(2). doi: 10.4238/gmr.15027826.

Yang RQ1, Teng H1, Xu XH1, Liu SY2, Wang YH1, Guo FJ1, Liu XJ3.

1Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin Province, China. 2Department of Anesthesia, The Second Hospital of Jilin University, Changchun, Jilin Province, China. 3Department of Pathology, The First Hospital of Jilin University, Changchun, Jilin Province, China.


We examined the aberrant microRNA (miRNA) expression profile responsible for the changes in angiogenesis observed in endometriotic lesions. This study revealed characteristic miRNA expression profiles associated with endometriosis in endometrial tissue and endometriotic lesions from the same patient, and their correlation with the most important angiogenic and fibrinolytic factors. miRNA expression was quantified using a microRNA array and reverse-transcription microRNA polymerase chain reaction. Levels of vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor 2 (EGFR2), phosphatase and tensin homolog (PTEN), and C-X-C chemokine receptor type 4 (CXCR4) were quantified using enzyme-linked immunosorbent assay. The endometrial tissue showed significantly lower levels of miR-200b, miR-15a-5p, miR-19b-1-5p, miR-146a-5p, and miR-200c, and higher levels of miR-16-5p, miR-106b-5p, and miR-145-5p. VEGFA was significantly upregulated, whereas EGFR2, PTEN, and CXCR4 were markedly downregulated, in the endometriotic tissues compared to that in the normal endometrial tissues. In conclusion, differences in the miRNA levels could modulate the expression of VEGFA, EGFR2, PTEN, and CXCR4, and may play an important role in the pathogenesis of endometriosis. The higher angiogenic and proteolytic activities observed in the eutopic endometrium might facilitate the implantation of endometrial cells at ectopic sites.

PMID 27323121

The Transcription Factor NFIL3 Is Essential for Normal Placental and Embryonic Development but Not for Uterine Natural Killer (UNK) Cell Differentiation in Mice

Biol Reprod. 2016 Mar 16. pii: biolreprod.116.138495.

Redhead ML, Portilho NA, Felker AM, Mohammad S, Mara DL, Croy BA.


Mice ablated for the gene encoding the transcription factor Nfil3 lack peripheral Natural Killer (NK) cells but retain tissue resident NK cells, particularly in mucosal sites, including virgin uterus. We undertook a time-course histological study of implantation sites from syngeneically (Nfil3-/-) and allogeneically (BALB/c) mated Nfil3-/- females. We also examined implantation sites from Rag2-/-Il2rg-/- females preconditioned by adoptive transfer of Nfil3-/- marrow or uterine cell suspensions to identify the Nfil3-/- pregnancy aberrations that could be attributed to non-lymphoid cells. Uterine (u)NKs reactive and non-reactive with the lectin Dolichos biflorus agglutinin (DBA), differentiate, localize and mature within Nfil3-/- implantation sites although at reduced abundance. DBA non-reactive uNK cells were enriched following Nfil3-/- marrow transplantation. Uterine lumen closure, early embryonic development and differentiation of antimesometrial decidua were delayed in Nfil3-/- implantation sites. Major disturbances to the decidual-trophoblast interface that did not lead to fetal death were attributed to NFIL3 deficiency in trophoblast. At mid gestation, vessels of the placental labyrinth were enlarged, suggestive of reduced branching morphogenesis. A major term complication in most Nfil3-/- x Nfil3-/- pregnancies but not Nfil3-/- x Nfil3+/- pregnancies was dystocia. These studies highlight the differentiation potential and functions of Nfil3-/- uNK cell progenitors and illustrate that much of the implantation site histopathology associated with this strain is due to Nfil3 deletion in non-lymphoid cell lineages. Copyright 2016 by The Society for the Study of Reproduction. KEYWORDS: Decidua; Developmental biology; Immunology; Null mutation / knockout; Pregnancy PMID 26985000


Am J Obstet Gynecol. 2016 Feb;214(2):284.e1-284.e47. doi: 10.1016/j.ajog.2015.08.075. Epub 2015 Sep 5. Inflammatory gene networks in term human decidual cells define a potential signature for cytokine-mediated parturition. Ibrahim SA1, Ackerman WE 4th1, Summerfield TL1, Lockwood CJ1, Schatz F1, Kniss DA2. Author information Abstract BACKGROUND: Inflammation is a proximate mediator of preterm birth and fetal injury. During inflammation several microRNAs (22 nucleotide noncoding ribonucleic acid (RNA) molecules) are up-regulated in response to cytokines such as interleukin-1β. MicroRNAs, in most cases, fine-tune gene expression, including both up-regulation and down-regulation of their target genes. However, the role of pro- and antiinflammatory microRNAs in this process is poorly understood. OBJECTIVE: The principal goal of the work was to examine the inflammatory genomic profile of human decidual cells challenged with a proinflammatory cytokine known to be present in the setting of preterm parturition. We determined the coding (messenger RNA) and noncoding (microRNA) sequences to construct a network of interacting genes during inflammation using an in vitro model of decidual stromal cells. STUDY DESIGN: The effects of interleukin-1β exposure on mature microRNA expression were tested in human decidual cell cultures using the multiplexed NanoString platform, whereas the global inflammatory transcriptional response was measured using oligonucleotide microarrays. Differential expression of select transcripts was confirmed by quantitative real time-polymerase chain reaction. Bioinformatics tools were used to infer transcription factor activation and regulatory interactions. RESULTS: Interleukin-1β elicited up- and down-regulation of 350 and 78 nonredundant transcripts (false discovery rate < 0.1), respectively, including induction of numerous cytokines, chemokines, and other inflammatory mediators. Whereas this transcriptional response included marked changes in several microRNA gene loci, the pool of fully processed, mature microRNA was comparatively stable following a cytokine challenge. Of a total of 6 mature microRNAs identified as being differentially expressed by NanoString profiling, 2 (miR-146a and miR-155) were validated by quantitative real time-polymerase chain reaction. Using complementary bioinformatics approaches, activation of several inflammatory transcription factors could be inferred downstream of interleukin-1β based on the overall transcriptional response. Further analysis revealed that miR-146a and miR-155 both target genes involved in inflammatory signaling, including Toll-like receptor and mitogen-activated protein kinase pathways. CONCLUSION: Stimulation of decidual cells with interleukin-1β alters the expression of microRNAs that function to temper proinflammatory signaling. In this setting, some microRNAs may be involved in tissue-level inflammation during the bulk of gestation and assist in pregnancy maintenance. Copyright © 2016 Elsevier Inc. All rights reserved. KEYWORDS: inflammation; microribonucleic acid; preterm birth; systems biology; transcription factor PMID 26348374

Carcinogenesis. 2016 Mar;37(3):245-61. doi: 10.1093/carcin/bgv249. Epub 2016 Jan 6. MicroRNA profiles in colorectal carcinomas, adenomas and normal colonic mucosa: variations in miRNA expression and disease progression. Slattery ML, Herrick JS, Pellatt DF, Stevens JR1, Mullany LE, Wolff E, Hoffman MD, Samowitz WS2, Wolff RK. Author information Abstract MiRNAs are small, non-protein-coding RNA molecules that regulate gene expression either by post-transcriptionally suppressing mRNA translation or by mRNA degradation. We examine differentially expressed miRNAs in colorectal carcinomas, adenomas and normal colonic mucosa. Data come from population-based studies of colorectal cancer conducted in Utah and the Kaiser Permanente Medical Care Program. A total of 1893 carcinoma/normal-paired samples and 290 adenoma tissue samples were run on the Agilent Human miRNA Microarray V19.0 which contained 2006 miRNAs. We tested for significant differences in miRNA expression between paired carcinoma/adenoma/normal colonic tissue samples. Fewer than 600 miRNAs were expressed in >80% of people for colonic tissue; of these 86.5% were statistically differentially expressed between carcinoma and normal colonic mucosa using a false discovery rate of 0.05. Roughly half of these differentially expressed miRNAs showed a progression in levels of expression from normal to adenoma to carcinoma tissue. Other miRNAs appeared to be altered at the normal to adenoma stage, while others were only altered at the adenoma to carcinoma stage or only at the normal to carcinoma stage. Evaluation of the Agilent platform showed a high degree of repeatability (r = 0.98) and reasonable agreement with the NanoString platform. Our data suggest that miRNAs are highly dysregulated in colorectal tissue among individuals with colorectal cancer; the pattern of disruption varies by miRNA as tissue progresses from normal to adenoma to carcinoma. © The Author 2016. Published by Oxford University Press. PMID 26740022

J Neurosurg. 2016 Feb 26:1-10. [Epub ahead of print] MicroRNA and gene expression changes in unruptured human cerebral aneurysms. Bekelis K1, Kerley-Hamilton JS2, Teegarden A3, Tomlinson CR2, Kuintzle R3, Simmons N1,4, Singer RJ1,4, Roberts DW1,4, Kellis M5,6,7, Hendrix DA3,8,7. Author information Abstract OBJECTIVE The molecular mechanisms behind cerebral aneurysm formation and rupture remain poorly understood. In the past decade, microRNAs (miRNAs) have been shown to be key regulators in a host of biological processes. They are noncoding RNA molecules, approximately 21 nucleotides long, that posttranscriptionally inhibit mRNAs by attenuating protein translation and promoting mRNA degradation. The miRNA and mRNA interactions and expression levels in cerebral aneurysm tissue from human subjects were profiled. METHODS A prospective case-control study was performed on human subjects to characterize the differential expression of mRNA and miRNA in unruptured cerebral aneurysms in comparison with control tissue (healthy superficial temporal arteries [STA]). Ion Torrent was used for deep RNA sequencing. Affymetrix miRNA microarrays were used to analyze miRNA expression, whereas NanoString nCounter technology was used for validation of the identified targets. RESULTS Overall, 7 unruptured cerebral aneurysm and 10 STA specimens were collected. Several differentially expressed genes were identified in aneurysm tissue, with MMP-13 (fold change 7.21) and various collagen genes (COL1A1, COL5A1, COL5A2) being among the most upregulated. In addition, multiple miRNAs were significantly differentially expressed, with miR-21 (fold change 16.97) being the most upregulated, and miR-143-5p (fold change -11.14) being the most downregulated. From these, miR-21, miR-143, and miR-145 had several significantly anticorrelated target genes in the cohort that are associated with smooth muscle cell function, extracellular matrix remodeling, inflammation signaling, and lipid accumulation. All these processes are crucial to the pathophysiology of cerebral aneurysms. CONCLUSIONS This analysis identified differentially expressed genes and miRNAs in unruptured human cerebral aneurysms, suggesting the possibility of a role for miRNAs in aneurysm formation. Further investigation for their importance as therapeutic targets is needed. KEYWORDS: AAA = abdominal aortic aneurysm; ECM = extracellular matrix; FDR = false discovery rate; GO = Gene Ontology; PCR = polymerase chain reaction; PCT = probability of conserved target; STA = superficial temporal artery; VSMC = vascular smooth muscle cell; cerebral aneurysms; deep sequencing; gene expression; miRNA = microRNA; microRNA expression; molecular mechanisms of disease; vascular disorders PMID 26918470

Cancer Res. 2015 Jul 1;75(13):2587-93. doi: 10.1158/0008-5472.CAN-15-0262. Epub 2015 Jun 11. Evaluating Robustness and Sensitivity of the NanoString Technologies nCounter Platform to Enable Multiplexed Gene Expression Analysis of Clinical Samples. Veldman-Jones MH1, Brant R2, Rooney C2, Geh C2, Emery H2, Harbron CG2, Wappett M2, Sharpe A2, Dymond M2, Barrett JC3, Harrington EA2, Marshall G2. Author information Abstract Analysis of clinical trial specimens such as formalin-fixed paraffin-embedded (FFPE) tissue for molecular mechanisms of disease progression or drug response is often challenging and limited to a few markers at a time. This has led to the increasing importance of highly multiplexed assays that enable profiling of many biomarkers within a single assay. Methods for gene expression analysis have undergone major advances in biomedical research, but obtaining a robust dataset from low-quality RNA samples, such as those isolated from FFPE tissue, remains a challenge. Here, we provide a detailed evaluation of the NanoString Technologies nCounter platform, which provides a direct digital readout of up to 800 mRNA targets simultaneously. We tested this system by examining a broad set of human clinical tissues for a range of technical variables, including sensitivity and limit of detection to varying RNA quantity and quality, reagent performance over time, variability between instruments, the impact of the number of fields of view sampled, and differences between probe sequence locations and overlapping genes across CodeSets. This study demonstrates that Nanostring offers several key advantages, including sensitivity, reproducibility, technical robustness, and utility for clinical application. ©2015 American Association for Cancer Research. PMID 26069246

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Open source software for quantification of cell migration, protrusions, and fluorescence intensities

J Cell Biol. 2015 Apr 13;209(1):163-80. doi: 10.1083/jcb.201501081. Epub 2015 Apr 6.

Barry DJ1, Durkin CH1, Abella JV1, Way M2.


Cell migration is frequently accompanied by changes in cell morphology (morphodynamics) on a range of spatial and temporal scales. Despite recent advances in imaging techniques, the application of unbiased computational image analysis methods for morphodynamic quantification is rare. For example, manual analysis using kymographs is still commonplace, often caused by lack of access to user-friendly, automated tools. We now describe software designed for the automated quantification of cell migration and morphodynamics. Implemented as a plug-in for the open-source platform, ImageJ, ADAPT is capable of rapid, automated analysis of migration and membrane protrusions, together with associated fluorescently labeled proteins, across multiple cells. We demonstrate the ability of the software by quantifying variations in cell population migration rates on different extracellular matrices. We also show that ADAPT can detect and morphologically profile filopodia. Finally, we have used ADAPT to compile an unbiased description of a "typical" bleb formed at the plasma membrane and quantify the effect of Arp2/3 complex inhibition on bleb retraction. © 2015 Barry et al.

PMID 25847537



Increasing chlamydia diagnoses but little change in hospitalisations for ectopic pregnancy and infertility among women in New South Wales from 2001 to 2008

Sex Health. 2012 Sep;9(4):355-9. doi: 10.1071/SH11143.

Liu B1, Donovan B, Parker J, Guy R, Hocking J, Kaldor JM, Wand H, Jorm L.


BACKGROUND: As genital chlamydia (Chlamydia trachomatis) notifications have increased in Australia, time trends in hospitalisations for ectopic pregnancy and female infertility between 2001 and 2008 in New South Wales (NSW), Australia, and their relationship to trends in chlamydia notifications in women were assessed. METHODS: Annual rates of chlamydia notification, and hospitalisations for female infertility or ectopic pregnancy in women aged 15-44 years in NSW were calculated using routinely collected data. Chlamydia notifications and hospital separations occurring within each year belonging to the same woman were linked using probabilistic linkage of identifiers so that multiple notifications and admissions for one woman in each calendar year were only counted once. RESULTS: From 2001 to 2008, the annual rate of chlamydia diagnoses in women increased from 157 to 477 per 100000 population (P(trend)<0.001). Over the same period, the annual hospitalisation rate for women with an ectopic pregnancy decreased from 14.3 to 12.6 per 1000 births (P(trend)<0.001). This decrease was mostly in women aged 25-44 years, with no appreciable fall in women aged 15-24 years (P(trend)=0.8). Meanwhile, the hospitalisation rate for women with infertility of female origin did not follow a consistent trend: between 2001 and 2008, it fluctuated between a low of 479 and a high of 554 per 10000 women who were seeking pregnancy. CONCLUSIONS: These trends in ectopic pregnancy and female infertility suggest that the large increase in chlamydia notifications may not reflect hospitalisations for these two proposed chlamydia-related sequelae.

PMID 22877595

Reporting rates of ectopic pregnancy: are we any closer to achieving consensus?

J Obstet Gynaecol. 2012 Jan;32(1):64-7. doi: 10.3109/01443615.2011.618894.

de Rosnay P1, Irvine LM.


Calculating rates of ectopic pregnancy in a reliable and reproducible way can be challenging. To date, there is no consensus as to which denominators to use but the authors suggest using the total number of deliveries as a benchmark. In many developing countries where ectopic pregnancy is a major cause of maternal morbidity and mortality, standardisation of epidemiological data is arguably even more important. Using the number of deliveries is probably the most pragmatic and reliable way of quoting ectopic pregnancy rates in developing countries, as structures are usually already in place to record births/deliveries. This would ensure greater consistency and allow more meaningful comparisons to be made, both within individual units over time as well as globally. Using additional denominators is more labour intensive and lends itself to inaccuracy but may nevertheless be useful depending on the issues being addressed. Ultimately, the correct denominator(s) to use should be determined by the clinical question(s) of interest. The authors acknowledge that the statistical analysis used in this paper is based on one retrospective study alone and that further work is required in this area before definitive conclusions can be made.

PMID 22185541


Trends in the diagnosis and treatment of ectopic pregnancy in the United States

Obstet Gynecol. 2010 Mar;115(3):495-502. doi: 10.1097/AOG.0b013e3181d0c328.

Hoover KW1, Tao G, Kent CK.


OBJECTIVE: To estimate trends in the rates of diagnosis and treatment of ectopic pregnancy in the United States. METHODS: We analyzed data from a large administrative claims database of more than 200 U.S. commercial health plans, and estimated time trends in the rate and incidence of ectopic pregnancy among girls and women aged 15-44 years by 5-year age groups and by region from 2002 to 2007. We also estimated time trends in the proportion of cases that were treated surgically, either by laparoscopy or laparotomy, or medically with methotrexate. RESULTS: We identified 11,989 ectopic pregnancies during the period from 2002 to 2007. The overall rate of ectopic pregnancy among pregnant girls and women aged 15-44 years during the 6-year study period was 0.64%. We did not observe a trend in the rate of ectopic pregnancy by 5-year age group or by geographic region. The ectopic pregnancy rate increased with age; it was 0.3% among girls and women aged 15-19 years and 1.0% among women aged 35-44 years. Methotrexate treatment increased from 11.1% in 2002 to 35.1% in 2007 (P<.001); the methotrexate failure rate was 14.7% over the 6-year study period. Surgical management with laparotomy decreased over the study period from 40.0% to 33.1% (P<.001). CONCLUSION: We did not find an increasing or decreasing trend in the rate of ectopic pregnancy among U.S. commercially insured women from 2002 to 2007. The use of administrative claims data are likely the most feasible method for estimating the rate and monitoring trends of ectopic pregnancy in the United States. Comment in Ectopic pregnancy: still cause for concern. [Obstet Gynecol. 2010]

PMID 20177279


Trends in the incidence of ectopic pregnancy in New South Wales between 1990-1998

Aust N Z J Obstet Gynaecol. 2001 Nov;41(4):436-8.

Boufous S1, Quartararo M, Mohsin M, Parker J.


During the last three decades, ectopic pregnancy rates have increased considerably in different parts of the world including Australia. Recent reports, however, suggest that the incidence is decreasing or at least stabilising. An analysis of the New South Wales Inpatient Statistics Data collected during the period between 1990 and 1998 has shown a decline in the rate of ectopic pregnancy after 1993. Overall the rate decreased from 17.4 per 1,000 births in 1990-1991 to 16.2 per 1,000 births in 1997-1998. The decline was greater for women aged 35-44 years than for younger women. The findings are consistent with recent studies in other countries, which indicate slowing or the end of the previous upward trend in the incidence of ectopic pregnancy

PMID 11787921