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Transcriptomic analysis of the interaction of choriocarcinoma spheroids with receptive vs. non-receptive endometrial epithelium cell lines: an in vitro model for human implantation

  • Paula Vergaro
  • Gustavo Tiscornia
  • Amelia Rodríguez
  • Josep Santaló
  • Rita VassenaEmail author
Reproductive Physiology and Disease
  • 46 Downloads

Abstract

Purpose

Several in vitro systems have been reported to model human implantation; however, the molecular dynamics of the trophoblast vs. the epithelial substrate during attachment have not been described. We have established an in vitro model which allowed us to dissect the transcriptional responses of the trophoblast and the receptive vs. non-receptive epithelium after co-culture.

Methods

We established an in vitro system based on co-culture of (a) immortalized cells representing receptive (Ishikawa) or non-receptive (HEC-1-A) endometrial epithelium with (b) spheroids of a trophoblastic cell line (JEG-3) modified to express green fluorescent protein (GFP). After 48 h of co-culture, GFP+ (trophoblast cells) and GFP− cell fractions (receptive or non-receptive epithelial cells) were isolated by fluorescence-activated flow cytometry (FACS) and subjected to RNA-seq profiling and gene set enrichment analysis (GSEA).

Results

Compared to HEC-1-A, the trophoblast challenge to Ishikawa cells differentially regulated the expression of 495 genes, which mainly involved cell adhesion and extracellular matrix (ECM) molecules. GSEA revealed enrichment of pathways related to cell division, cell cycle regulation, and metabolism in the Ishikawa substrate. Comparing the gene expression profile of trophoblast spheroids revealed that 1877 and 323 genes were upregulated or downregulated when co-cultured on Ishikawa substrates (compared to HEC-1-A), respectively. Pathways favorable to development, including tissue remodeling, organogenesis, and angiogenesis, were enhanced in the trophoblast compartment after co-culture of spheroids with receptive epithelium. By contrast, the co-culture with less receptive epithelium enriched pathways mainly related to trophoblast cell proliferation and cell cycle regulation.

Conclusions

Endometrial receptivity requires a transcriptional signature that determines the trophoblast response and drives attachment.

Keywords

Implantation Attachment Endometrial receptivity Transcriptomics 

Notes

Acknowledgements

The authors wish to thank all members of the Basic Laboratory from Clínica EUGIN, especially Montserrat Barragán and Anna Ferrer, for critical discussion; José Buratini from Sao Paulo State University (Brasil) for critical revision of the manuscript; Camille Stephan Otto from the Biostatistics/Bioinformatics facility of the Institute for Research in Biomedicine (Barcelona) for bioinformatics analysis; Charles Pineau, Natalie Melaine, and Emmanuelle Com from Proteomics Core Facility Biogenouest (Rennes) for assistance with data analysis; and Prof. Daniel Grinberg from Universitat de Barcelona for technical support.

Author’s contribution

Paula Vergaro: experimental execution, study design, data analysis, and manuscript preparation. Gustavo Tiscornia: study design and supervision, data analysis, manuscript edition, and expert knowledge. Amelia Rodríguez: study supervision. Josep Santaló: study supervision, expert knowledge, and manuscript edition. Rita Vassena: study design and supervision, expert knowledge, and manuscript edition.

Funding

This work was supported by intramural funding of Clínica EUGIN and by the Secretary for Universities and Research of the Ministry of Economy and Knowledge of the Government of Catalonia (GENCAT 2015 DI 050).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10815_2019_1442_MOESM1_ESM.pdf (5 kb)
Supplementary Fig. 1 Principal component analysis representing all samples from experimental triplicates according to principal component 1 (PC1) and principal component 2 (PC2): HEC-1-A control (H-c), HEC-1-A substrates co-cultured with JEG-3 spheroids (H-co-S), Ishikawa control (I-c), Ishikawa substrates co-cultured with JEG-3 spheroids (I-co-S), JEG-3 spheroids control (S-c), JEG-3 spheroids co-cultured with HEC-1-A substrates (S-co-H) and JEG-3 spheroids co-cultured with Ishikawa substrates (S-co-I). (PDF 5 kb)
10815_2019_1442_MOESM2_ESM.xlsx (6.4 mb)
Supplementary file S1 List of differentially expressed genes between HEC-1-A control (H-c) vs. Ishikawa control (I-c). Statistical significance was set at absolute log2FC cutoff of 1 and adjusted p-value <0.05. Negative fold changes mean that expression in H-c is lower than that in I-c; positive fold changes mean expression in H-c is higher than that in I-c. (XLSX 6561 kb)
10815_2019_1442_MOESM3_ESM.xlsx (5.6 mb)
Supplementary file S2 List of differentially expressed genes between Ishikawa substrates co-cultured with JEG-3 spheroids (I-co-S) vs. Ishikawa control (I-c). Statistical significance was set at absolute log2FC cutoff of 1 and adjusted p-value <0.05. Negative fold changes mean that expression in I-co-S is lower than that in I-c; positive fold changes mean expression in I-co-S is higher than that in I-c. (XLSX 5739 kb)
10815_2019_1442_MOESM4_ESM.xlsx (2.6 mb)
Supplementary file S3 List of differentially expressed genes between HEC-1-A substrates co-cultured with JEG-3 spheroids (H-co-S) vs. HEC-1-A control (H-c). Statistical significance was set at absolute log2FC cutoff of 1 and adjusted p-value <0.05. Negative fold changes mean that expression in H-co-S is lower than that in H-c; positive fold changes mean expression in H-co-S is higher than that in H-c. (XLSX 2680 kb)
10815_2019_1442_MOESM5_ESM.xlsx (5.7 mb)
Supplementary file S4 List of differential expression patterns between HEC-1-A substrates co-cultured with JEG-3 spheroids (H-co-S) vs. HEC-1-A control (H-c) compared to Ishikawa substrates co-cultured with JEG-3 spheroids (I-co-S) vs. Ishikawa control (I-c). Statistical significance was set at absolute log2FC cutoff of 1 and adjusted p-value <0.05. Negative fold changes mean that difference in gene expression is enriched in H-co-S vs. H-c; positive fold changes mean that difference in gene expression is enriched in I-co-S vs. I-c. (XLSX 5788 kb)
10815_2019_1442_MOESM6_ESM.xlsx (6.1 mb)
Supplementary file S5 List of differentially expressed genes between JEG-3 spheroids co-cultured with Ishikawa substrates (S-co-I) vs. JEG-3 spheroids control (S-c), Statistical significance was set at absolute log2FC cutoff of 1 and adjusted p-value <0.05. Negative fold changes mean that expression in S-co-I is lower than that in S-c; positive fold changes mean expression in S-co-I is higher than that in S-c. (XLSX 6195 kb)
10815_2019_1442_MOESM7_ESM.xlsx (5.7 mb)
Supplementary file S6 List of differentially expressed genes between JEG-3 spheroids co-cultured with HEC-1-A substrates (S-co-H) vs. JEG-3 spheroids control (S-c), Statistical significance was set at absolute log2FC cutoff of 1 and adjusted p-value <0.05. Negative fold changes mean that expression in S-co-H is lower than that in S-c; positive fold changes mean expression in S-co-H is higher than that in S-c. (XLSX 5796 kb)
10815_2019_1442_MOESM8_ESM.xlsx (5.8 mb)
Supplementary file S7 List of differentially expressed genes between JEG-3 spheroids co-cultured with HEC-1-A substrates (S-co-H) vs. JEG-3 spheroids co-cultured with Ishikawa substrates (S-co-I). Statistical significance was set at absolute log2FC cutoff of 1 and adjusted p-value <0.05. Negative fold changes mean that expression in S-co-H is lower than that in S-co-I; positive fold changes mean expression in S-co-H is higher than that in S-co-I. (XLSX 5954 kb)
10815_2019_1442_MOESM9_ESM.xlsx (11 kb)
Supplementary file S8 List of the 208 common genes between JEG-3 spheroids co-cultured with Ishikawa substrates and Ishikawa substrates co-cultured with JEG-3 spheroids (“S-co-H vs. S-co-I” and “I-co-S vs. I-c” comparisons). (XLSX 10 kb)

References

  1. 1.
    Sharkey AM, Macklon NS. The science of implantation emerges blinking into the light. Reprod BioMed Online. 2013;27(5):453–60.  https://doi.org/10.1016/j.rbmo.2013.08.005.Google Scholar
  2. 2.
    Hannan NJ, Jones RL, White CA, Salamonsen LA. The chemokines, CX3CL1, CCL14, and CCL4, promote human trophoblast migration at the feto-maternal interface. Biol Reprod. 2006;74(5):896–904.  https://doi.org/10.1095/biolreprod.105.045518.Google Scholar
  3. 3.
    Hannan NJ, Paiva P, Meehan KL, Rombauts LJ, Gardner DK, Salamonsen LA. Analysis of fertility-related soluble mediators in human uterine fluid identifies VEGF as a key regulator of embryo implantation. Endocrinology. 2011;152(12):4948–56.  https://doi.org/10.1210/en.2011-1248.Google Scholar
  4. 4.
    Greening DW, Nguyen HP, Elgass K, Simpson RJ, Salamonsen LA. Human endometrial exosomes contain hormone-specific cargo modulating trophoblast adhesive capacity: insights into endometrial-embryo interactions. Biol Reprod. 2016;94(2):38.  https://doi.org/10.1095/biolreprod.115.134890.Google Scholar
  5. 5.
    Wang H, Dey SK. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet. 2006;7(3):185–99.  https://doi.org/10.1038/nrg1808.Google Scholar
  6. 6.
    Teklenburg G, Salker M, Molokhia M, Lavery S, Trew G, Aojanepong T, et al. Natural selection of human embryos: decidualizing endometrial stromal cells serve as sensors of embryo quality upon implantation. PLoS One. 2010;5(4):e10258.  https://doi.org/10.1371/journal.pone.0010258.Google Scholar
  7. 7.
    Weimar CH, Kavelaars A, Brosens JJ, Gellersen B, de Vreeden-Elbertse JM, Heijnen CJ, et al. Endometrial stromal cells of women with recurrent miscarriage fail to discriminate between high- and low-quality human embryos. PLoS One. 2012;7(7):e41424.  https://doi.org/10.1371/journal.pone.0041424.Google Scholar
  8. 8.
    Salker MS, Nautiyal J, Steel JH, Webster Z, Sucurovic S, Nicou M, et al. Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy loss. PLoS One. 2012;7(12):e52252.  https://doi.org/10.1371/journal.pone.0052252.Google Scholar
  9. 9.
    Brighton PJ, Maruyama Y, Fishwick K, Vrljicak P, Tewary S, Fujihara R, Muter J, Lucas ES, Yamada T, Woods L, Lucciola R, Hou Lee Y, Takeda S, Ott S, Hemberger M, Quenby S, Brosens JJ Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium. eLife. 2017;6. doi: https://doi.org/10.7554/eLife.31274.
  10. 10.
    Ruane PT, Berneau SC, Koeck R, Watts J, Kimber SJ, Brison DR, et al. Apposition to endometrial epithelial cells activates mouse blastocysts for implantation. Mol Hum Reprod. 2017;23(9):617–27.  https://doi.org/10.1093/molehr/gax043.Google Scholar
  11. 11.
    Polanski LT, Baumgarten MN, Quenby S, Brosens J, Campbell BK, Raine-Fenning NJ. What exactly do we mean by ‘recurrent implantation failure’? A systematic review and opinion. Reprod BioMed Online. 2014;28(4):409–23.  https://doi.org/10.1016/j.rbmo.2013.12.006.Google Scholar
  12. 12.
    Miller PB, Parnell BA, Bushnell G, Tallman N, Forstein DA, Higdon HL 3rd, et al. Endometrial receptivity defects during IVF cycles with and without letrozole. Hum Reprod. 2012;27(3):881–8.  https://doi.org/10.1093/humrep/der452.Google Scholar
  13. 13.
    Namiki T, Ito J, Kashiwazaki N. Molecular mechanisms of embryonic implantation in mammals: lessons from the gene manipulation of mice. RMB. 2018;17(4):331–42.  https://doi.org/10.1002/rmb2.12103.Google Scholar
  14. 14.
    Melford SE, Taylor AH, Konje JC. Of mice and (wo)men: factors influencing successful implantation including endocannabinoids. Hum Reprod Update. 2014;20(3):415–28.  https://doi.org/10.1093/humupd/dmt060.Google Scholar
  15. 15.
    Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18(12):1754–67.  https://doi.org/10.1038/nm.3012.Google Scholar
  16. 16.
    Aplin JD, Ruane PT. Embryo-epithelium interactions during implantation at a glance. J Cell Sci. 2017;130(1):15–22.  https://doi.org/10.1242/jcs.175943.Google Scholar
  17. 17.
    Dominguez F, Avila S, Cervero A, Martin J, Pellicer A, Castrillo JL, et al. A combined approach for gene discovery identifies insulin-like growth factor-binding protein-related protein 1 as a new gene implicated in human endometrial receptivity. J Clin Endocrinol Metab. 2003;88(4):1849–57.  https://doi.org/10.1210/jc.2002-020724.Google Scholar
  18. 18.
    Heneweer C, Schmidt M, Denker HW, Thie M. Molecular mechanisms in uterine epithelium during trophoblast binding: the role of small GTPase RhoA in human uterine Ishikawa cells. J Exp Clin Assist Reprod. 2005;2(1):4.  https://doi.org/10.1186/1743-1050-2-4.Google Scholar
  19. 19.
    Uchida H, Maruyama T, Ohta K, Ono M, Arase T, Kagami M, et al. Histone deacetylase inhibitor-induced glycodelin enhances the initial step of implantation. Hum Reprod. 2007;22(10):2615–22.  https://doi.org/10.1093/humrep/dem263.Google Scholar
  20. 20.
    Singh H, Nardo L, Kimber SJ, Aplin JD. Early stages of implantation as revealed by an in vitro model. Reproduction. 2010;139(5):905–14.  https://doi.org/10.1530/REP-09-0271.Google Scholar
  21. 21.
    Tamm-Rosenstein K, Simm J, Suhorutshenko M, Salumets A, Metsis M. Changes in the transcriptome of the human endometrial Ishikawa cancer cell line induced by estrogen, progesterone, tamoxifen, and mifepristone (RU486) as detected by RNA-sequencing. PLoS One. 2013;8(7):e68907.  https://doi.org/10.1371/journal.pone.0068907.Google Scholar
  22. 22.
    Kang YJ, Forbes K, Carver J, Aplin JD. The role of the osteopontin-integrin alphavbeta3 interaction at implantation: functional analysis using three different in vitro models. Hum Reprod. 2014;29(4):739–49.  https://doi.org/10.1093/humrep/det433.Google Scholar
  23. 23.
    Berger C, Boggavarapu NR, Menezes J, Lalitkumar PG, Gemzell-Danielsson K. Effects of ulipristal acetate on human embryo attachment and endometrial cell gene expression in an in vitro co-culture system. Hum Reprod. 2015;30(4):800–11.  https://doi.org/10.1093/humrep/dev030.Google Scholar
  24. 24.
    Boggavarapu NR, Berger C, von Grothusen C, Menezes J, Gemzell-Danielsson K, Lalitkumar PG. Effects of low doses of mifepristone on human embryo implantation process in a three-dimensional human endometrial in vitro co-culture system. Contraception. 2016;94(2):143–51.  https://doi.org/10.1016/j.contraception.2016.03.009.Google Scholar
  25. 25.
    Carver J, Martin K, Spyropoulou I, Barlow D, Sargent I, Mardon H. An in-vitro model for stromal invasion during implantation of the human blastocyst. Hum Reprod. 2003;18(2):283–90.Google Scholar
  26. 26.
    Tiscornia G, Singer O, Verma IM. Production and purification of lentiviral vectors. Nat Protoc. 2006;1(1):241–5.  https://doi.org/10.1038/nprot.2006.37.Google Scholar
  27. 27.
    Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21.  https://doi.org/10.1093/bioinformatics/bts635.Google Scholar
  28. 28.
    Liao Y, Smyth GK, Shi W. The subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res. 2013;41(10):e108.  https://doi.org/10.1093/nar/gkt214.Google Scholar
  29. 29.
    Smedley D, Haider S, Durinck S, Pandini L, Provero P, Allen J, et al. The BioMart community portal: an innovative alternative to large, centralized data repositories. Nucleic Acids Res. 2015;43(W1):W589–98.  https://doi.org/10.1093/nar/gkv350.Google Scholar
  30. 30.
    Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550.  https://doi.org/10.1186/s13059-014-0550-8.Google Scholar
  31. 31.
    Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50.  https://doi.org/10.1073/pnas.0506580102.Google Scholar
  32. 32.
    Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Gen. 2000;25(1):25–9.  https://doi.org/10.1038/75556. Google Scholar
  33. 33.
    Morgan M FSaGR. Morgan M, Falcon S and Gentleman R (2017). GSEABase: Gene set enrichment data structures and methods. R package version 1.40.1. 2017.Google Scholar
  34. 34.
    Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1(6):417–25.  https://doi.org/10.1016/j.cels.2015.12.004.Google Scholar
  35. 35.
    Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP. Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011;27(12):1739–40.  https://doi.org/10.1093/bioinformatics/btr260.Google Scholar
  36. 36.
    Xie F, Sun G, Stiller JW, Zhang B. Genome-wide functional analysis of the cotton transcriptome by creating an integrated EST database. PLoS One. 2011;6(11):e26980.  https://doi.org/10.1371/journal.pone.0026980.Google Scholar
  37. 37.
    Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3(7):RESEARCH0034.Google Scholar
  38. 38.
    Borthwick JM, Charnock-Jones DS, Tom BD, Hull ML, Teirney R, Phillips SC, et al. Determination of the transcript profile of human endometrium. Mol Hum Reprod. 2003;9(1):19–33.Google Scholar
  39. 39.
    White FJ, Burghardt RC, Hu J, Joyce MM, Spencer TE, Johnson GA. Secreted phosphoprotein 1 (osteopontin) is expressed by stromal macrophages in cyclic and pregnant endometrium of mice, but is induced by estrogen in luminal epithelium during conceptus attachment for implantation. Reproduction. 2006;132(6):919–29.  https://doi.org/10.1530/REP-06-0068.Google Scholar
  40. 40.
    Quenby S, Anim-Somuah M, Kalumbi C, Farquharson R, Aplin JD. Different types of recurrent miscarriage are associated with varying patterns of adhesion molecule expression in endometrium. Reprod BioMed Online. 2007;14(2):224–34.Google Scholar
  41. 41.
    Kodithuwakku SP, Ng PY, Liu Y, Ng EH, Yeung WS, Ho PC, et al. Hormonal regulation of endometrial olfactomedin expression and its suppressive effect on spheroid attachment onto endometrial epithelial cells. Hum Reprod. 2011;26(1):167–75.  https://doi.org/10.1093/humrep/deq298.Google Scholar
  42. 42.
    Tepekoy F, Akkoyunlu G, Demir R. The role of Wnt signaling members in the uterus and embryo during pre-implantation and implantation. J Assist Reprod Genet. 2015;32(3):337–46.  https://doi.org/10.1007/s10815-014-0409-7.Google Scholar
  43. 43.
    Zhang Q, Yan J. Update of Wnt signaling in implantation and decidualization. RMB. 2016;15(2):95–105.  https://doi.org/10.1007/s12522-015-0226-4.Google Scholar
  44. 44.
    Farah O, Biechele S, Rossant J, Dufort D. Porcupine-dependent Wnt activity within the uterine epithelium is essential for fertility. Biol Reprod. 2017;97(5):688–97.  https://doi.org/10.1093/biolre/iox119.Google Scholar
  45. 45.
    Haouzi D, Dechaud H, Assou S, Monzo C, de Vos J, Hamamah S. Transcriptome analysis reveals dialogues between human trophectoderm and endometrial cells during the implantation period. Hum Reprod. 2011;26(6):1440–9.  https://doi.org/10.1093/humrep/der075.Google Scholar
  46. 46.
    Singh H, Aplin JD. Endometrial apical glycoproteomic analysis reveals roles for cadherin 6, desmoglein-2 and plexin b2 in epithelial integrity. Mol Hum Reprod. 2015;21(1):81–94.  https://doi.org/10.1093/molehr/gau087.Google Scholar
  47. 47.
    Altmae S, Reimand J, Hovatta O, Zhang P, Kere J, Laisk T, et al. Research resource: interactome of human embryo implantation: identification of gene expression pathways, regulation, and integrated regulatory networks. Mol Endocrinol. 2012;26(1):203–17.  https://doi.org/10.1210/me.2011-1196.Google Scholar
  48. 48.
    Aberkane A, Essahib W, Spits C, De Paepe C, Sermon K, Adriaenssens T, et al. Expression of adhesion and extracellular matrix genes in human blastocysts upon attachment in a 2D co-culture system. Mol Hum Reprod. 2018;24(7):375–87.  https://doi.org/10.1093/molehr/gay024.Google Scholar
  49. 49.
    Arase T, Uchida H, Kajitani T, Ono M, Tamaki K, Oda H, et al. The UDP-glucose receptor P2RY14 triggers innate mucosal immunity in the female reproductive tract by inducing IL-8. J Immunol. 2009;182(11):7074–84.  https://doi.org/10.4049/jimmunol.0900001.Google Scholar
  50. 50.
    Altmae S, Koel M, Vosa U, Adler P, Suhorutsenko M, Laisk-Podar T, et al. Meta-signature of human endometrial receptivity: a meta-analysis and validation study of transcriptomic biomarkers. Sci Rep. 2017;7(1):10077.  https://doi.org/10.1038/s41598-017-10098-3.Google Scholar
  51. 51.
    Chan C, Virtanen C, Winegarden NA, Colgan TJ, Brown TJ, Greenblatt EM. Discovery of biomarkers of endometrial receptivity through a minimally invasive approach: a validation study with implications for assisted reproduction. Fertil Steril. 2013;100(3):810–7.  https://doi.org/10.1016/j.fertnstert.2013.04.047.Google Scholar
  52. 52.
    Humphreys GI, Ziegler YS, Nardulli AM. 17beta-estradiol modulates gene expression in the female mouse cerebral cortex. PLoS One. 2014;9(11):e111975.  https://doi.org/10.1371/journal.pone.0111975.Google Scholar
  53. 53.
    Cui D, Sui L, Han X, Zhang M, Guo Z, Chen W, et al. Aquaporin-3 mediates ovarian steroid hormone-induced motility of endometrial epithelial cells. Hum Reprod. 2018;33(11):2060–73.  https://doi.org/10.1093/humrep/dey290.Google Scholar
  54. 54.
    Sun XL, Zhang J, Fan Y, Ding JH, Sha JH, Hu G. Aquaporin-4 deficiency induces subfertility in female mice. Fertil Steril. 2009;92(5):1736–43.  https://doi.org/10.1016/j.fertnstert.2008.07.1785.Google Scholar
  55. 55.
    Korgun ET, Cayli S, Asar M, Demir R. Distribution of laminin, vimentin and desmin in the rat uterus during initial stages of implantation. J Mol Histol. 2007;38(4):253–60.  https://doi.org/10.1007/s10735-007-9095-4.Google Scholar
  56. 56.
    Li M, Yee D, Magnuson TR, Smithies O, Caron KM. Reduced maternal expression of adrenomedullin disrupts fertility, placentation, and fetal growth in mice. J Clin Invest. 2006;116(10):2653–62.  https://doi.org/10.1172/JCI28462.Google Scholar
  57. 57.
    Li M, Wu Y, Caron KM. Haploinsufficiency for adrenomedullin reduces pinopodes and diminishes uterine receptivity in mice. Biol Reprod. 2008;79(6):1169–75.  https://doi.org/10.1095/biolreprod.108.069336.Google Scholar
  58. 58.
    Matson BC, Pierce SL, Espenschied ST, Holle E, Sweatt IH, Davis ES, et al. Adrenomedullin improves fertility and promotes pinopodes and cell junctions in the peri-implantation endometrium. Biol Reprod. 2017;97(3):466–77.  https://doi.org/10.1093/biolre/iox101.Google Scholar
  59. 59.
    Liao SB, Li HW, Ho JC, Yeung WS, Ng EH, Cheung AN, et al. Possible role of adrenomedullin in the pathogenesis of tubal ectopic pregnancy. J Clin Endocrinol Metab. 2012;97(6):2105–12.  https://doi.org/10.1210/jc.2011-3290.Google Scholar
  60. 60.
    Havemann D, Balakrishnan M, Borahay M, et al. Intermedin/adrenomedullin 2 is associated with implantation and placentation via trophoblast invasion in human pregnancy. J Clin Endocrinol Metab. 2013;98(2):695–703. Published online 2013 Jan 21.  https://doi.org/10.1210/jc.2012-2172.Google Scholar
  61. 61.
    Chobotova K, Spyropoulou I, Carver J, Manek S, Heath JK, Gullick WJ, et al. Heparin-binding epidermal growth factor and its receptor ErbB4 mediate implantation of the human blastocyst. Mech Dev. 2002;119(2):137–44.Google Scholar
  62. 62.
    Sugihara K, Sugiyama D, Byrne J, Wolf DP, Lowitz KP, Kobayashi Y, et al. Trophoblast cell activation by trophinin ligation is implicated in human embryo implantation. Proc Natl Acad Sci U S A. 2007;104(10):3799–804.  https://doi.org/10.1073/pnas.0611516104.Google Scholar
  63. 63.
    Harbuz R, Zouari R, Pierre V, Ben Khelifa M, Kharouf M, Coutton C, et al. A recurrent deletion of DPY19L2 causes infertility in man by blocking sperm head elongation and acrosome formation. Am J Hum Genet. 2011;88(3):351–61.  https://doi.org/10.1016/j.ajhg.2011.02.007.Google Scholar
  64. 64.
    Modarres P, Tanhaei S, Tavalaee M, Ghaedi K, Deemeh MR, Nasr-Esfahani MH. Assessment of DPY19L2 deletion in familial and non-familial individuals with globozoospermia and DPY19L2 genotyping. Int J Fertil Steril. 2016;10(2):196–207.Google Scholar
  65. 65.
    Tamm K, Room M, Salumets A, Metsis M. Genes targeted by the estrogen and progesterone receptors in the human endometrial cell lines HEC1A and RL95-2. Reprod Biol Endocrinol. 2009;7:150.  https://doi.org/10.1186/1477-7827-7-150.Google Scholar
  66. 66.
    Harrison SE, Sozen B, Christodoulou N, Kyprianou C, Zernicka-Goetz M. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro. Science. 2017;356(6334):eaal1810.  https://doi.org/10.1126/science.aal1810.Google Scholar
  67. 67.
    Shahbazi MN, Scialdone A, Skorupska N, Weberling A, Recher G, Zhu M, et al. Pluripotent state transitions coordinate morphogenesis in mouse and human embryos. Nature. 2017;552(7684):239–43.  https://doi.org/10.1038/nature24675.Google Scholar
  68. 68.
    Sozen B, Amadei G, Cox A, Wang R, Na E, Czukiewska S, et al. Self-assembly of embryonic and two extra-embryonic stem cell types into gastrulating embryo-like structures. Nat Cell Biol. 2018;20(8):979–89.  https://doi.org/10.1038/s41556-018-0147-7.Google Scholar
  69. 69.
    Koot YE, van Hooff SR, Boomsma CM, van Leenen D, Groot Koerkamp MJ, Goddijn M, et al. An endometrial gene expression signature accurately predicts recurrent implantation failure after IVF. Sci Rep. 2016;6:19411.  https://doi.org/10.1038/srep19411.Google Scholar
  70. 70.
    Diaz-Gimeno P, Ruiz-Alonso M, Sebastian-Leon P, Pellicer A, Valbuena D, Simon C. Window of implantation transcriptomic stratification reveals different endometrial subsignatures associated with live birth and biochemical pregnancy. Fertil Steril. 2017;108(4):703–10 e3.  https://doi.org/10.1016/j.fertnstert.2017.07.007.Google Scholar
  71. 71.
    Huang J, Qin H, Yang Y, Chen X, Zhang J, Laird S, et al. A comparison of transcriptomic profiles in endometrium during window of implantation between women with unexplained recurrent implantation failure and recurrent miscarriage. Reproduction. 2017;153(6):749–58.  https://doi.org/10.1530/REP-16-0574.Google Scholar
  72. 72.
    Wang H, Pilla F, Anderson S, Martinez-Escribano S, Herrer I, Moreno-Moya JM, et al. A novel model of human implantation: 3D endometrium-like culture system to study attachment of human trophoblast (Jar) cell spheroids. Mol Hum Reprod. 2012;18(1):33–43.  https://doi.org/10.1093/molehr/gar064.Google Scholar
  73. 73.
    Altmae S, Martinez-Conejero JA, Salumets A, Simon C, Horcajadas JA, Stavreus-Evers A. Endometrial gene expression analysis at the time of embryo implantation in women with unexplained infertility. Mol Hum Reprod. 2010;16(3):178–87.  https://doi.org/10.1093/molehr/gap102.Google Scholar
  74. 74.
    Enciso M, Carrascosa JP, Sarasa J, Martinez-Ortiz PA, Munne S, Horcajadas JA, et al. Development of a new comprehensive and reliable endometrial receptivity map (ER map/ER grade) based on RT-qPCR gene expression analysis. Hum Reprod. 2018;33(2):220–8.  https://doi.org/10.1093/humrep/dex370.Google Scholar
  75. 75.
    Krjutskov K, Katayama S, Saare M, Vera-Rodriguez M, Lubenets D, Samuel K, et al. Single-cell transcriptome analysis of endometrial tissue. Hum Reprod. 2016;31(4):844–53.  https://doi.org/10.1093/humrep/dew008.Google Scholar
  76. 76.
    Hannan NJ, Paiva P, Dimitriadis E, Salamonsen LA. Models for study of human embryo implantation: choice of cell lines? Biol Reprod. 2010;82(2):235–45.  https://doi.org/10.1095/biolreprod.109.077800.Google Scholar
  77. 77.
    Huang X, Luthi M, Ontsouka EC, Kallol S, Baumann MU, Surbek DV, et al. Establishment of a confluent monolayer model with human primary trophoblast cells: novel insights into placental glucose transport. Mol Hum Reprod. 2016;22(6):442–56.  https://doi.org/10.1093/molehr/gaw018.Google Scholar
  78. 78.
    Rothbauer M, Patel N, Gondola H, Siwetz M, Huppertz B, Ertl P. A comparative study of five physiological key parameters between four different human trophoblast-derived cell lines. Sci Rep. 2017;7(1):5892.  https://doi.org/10.1038/s41598-017-06364-z.Google Scholar
  79. 79.
    McConkey CA, Delorme-Axford E, Nickerson CA, Kim KS, Sadovsky Y, Boyle JP, et al. A three-dimensional culture system recapitulates placental syncytiotrophoblast development and microbial resistance. Sci Adv. 2016;2(3):e1501462.  https://doi.org/10.1126/sciadv.1501462.Google Scholar
  80. 80.
    Dassen H, Punyadeera C, Kamps R, Klomp J, Dunselman G, Dijcks F, et al. Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007;64(7–8):1009–32.  https://doi.org/10.1007/s00018-007-6553-9.Google Scholar
  81. 81.
    Paiva P, Menkhorst E, Salamonsen L, Dimitriadis E. Leukemia inhibitory factor and interleukin-11: critical regulators in the establishment of pregnancy. Cytokine Growth Factor Rev. 2009;20(4):319–28.  https://doi.org/10.1016/j.cytogfr.2009.07.001.Google Scholar
  82. 82.
    Franasiak JM, Holoch KJ, Yuan L, Schammel DP, Young SL, Lessey BA. Prospective assessment of midsecretory endometrial leukemia inhibitor factor expression versus alphanubeta3 testing in women with unexplained infertility. Fertil Steril. 2014;101(6):1724–31.  https://doi.org/10.1016/j.fertnstert.2014.02.027.Google Scholar
  83. 83.
    Lessey BA, Castelbaum AJ. Integrins and implantation in the human. Rev Endocr Metab Disord. 2002;3(2):107–17.Google Scholar
  84. 84.
    Hirota Y, Osuga Y, Hasegawa A, Kodama A, Tajima T, Hamasaki K, et al. Interleukin (IL)-1beta stimulates migration and survival of first-trimester villous cytotrophoblast cells through endometrial epithelial cell-derived IL-8. Endocrinology. 2009;150(1):350–6.  https://doi.org/10.1210/en.2008-0264.Google Scholar
  85. 85.
    Plaks V, Rinkenberger J, Dai J, Flannery M, Sund M, Kanasaki K, et al. Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction. Proc Natl Acad Sci U S A. 2013;110(27):11109–14.  https://doi.org/10.1073/pnas.1309561110.Google Scholar
  86. 86.
    Kurarmoto H, Hamano M, Imai M. HEC-1 cells. Hum Cell. 2002;15(2):81–95.  https://doi.org/10.1111/j.1749-0774.2002.tb00103.x.Google Scholar
  87. 87.
    Thie M, Denker HW. In vitro studies on endometrial adhesiveness for trophoblast: cellular dynamics in uterine epithelial cells. Cells Tissues Organs. 2002;172(3):237–52.  https://doi.org/10.1159/000066963.Google Scholar
  88. 88.
    Rahimipour M, Salehnia M, Jafarabadi M. Morphological, ultrastructural, and molecular aspects of in vitro mouse embryo implantation on human endometrial mesenchymal stromal cells in the presence of steroid hormones as an implantation model. Cell J. 2018;20(3):369–76.  https://doi.org/10.22074/cellj.2018.5221.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Paula Vergaro
    • 1
    • 2
  • Gustavo Tiscornia
    • 1
    • 3
  • Amelia Rodríguez
    • 1
  • Josep Santaló
    • 2
  • Rita Vassena
    • 1
    Email author
  1. 1.Clínica EUGINBarcelonaSpain
  2. 2.Facultat de Biociències, Departament de Biologia Cel·lular, de Fisiologia i d’ImmunologiaUniversitat Autònoma de BarcelonaBarcelonaSpain
  3. 3.Centro de Investigação em Biomedicina (CBMR)Universidade do AlgarveFaroPortugal

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