{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T04:24:32Z","timestamp":1792211072465,"version":"4.4.0"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,7,12]],"date-time":"2017-07-12T00:00:00Z","timestamp":1499817600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,7,12]],"date-time":"2017-07-12T00:00:00Z","timestamp":1499817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Communication between embryo and maternal endometrium occurs during a specific time frame in which implantation is possible. Here we demonstrate for the first time that conditioned media from non-manipulated human embryos cultured <jats:italic>in vitro<\/jats:italic> for 3 days or up to the blastocyst stage contain extracellular vesicles (EVs) with a diameter of 50 to 200\u2009nm and bearing the traditional microvesicle and exosome marker proteins CD63, CD9 and ALIX. The embryonic origin of these EVs has been confirmed by the presence of stemness gene transcripts and their enrichment in the non-classical HLA-G protein. <jats:italic>NANOG<\/jats:italic> and <jats:italic>POU5F1<\/jats:italic> transcripts were shown to be contained in vesicles deriving from embryos at different stages of development. In line with a higher detection rate of the HLA-G protein in blastocysts compared to cleavage stage embryos, a significantly higher amount of HLA-G was found in vesicles accumulated in spent media from day 3 to day 5 of development compared to those isolated from the earlier stage. Uptake of dye-labeled embryo-derived EVs by human primary endometrial epithelial and stromal cells was also demonstrated with a fluorescence intensity signal significantly higher for cells treated with vesicles derived from blastocysts. Based on these findings, EV exchange may be suggested as an emerging way of communication at the maternal-fetal interface.<\/jats:p>","DOI":"10.1038\/s41598-017-05549-w","type":"journal-article","created":{"date-parts":[[2017,7,6]],"date-time":"2017-07-06T10:09:45Z","timestamp":1499335785000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":145,"title":["Secretome of in vitro cultured human embryos contains extracellular vesicles that are uptaken by the maternal side"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3289-3221","authenticated-orcid":false,"given":"Elisa","family":"Giacomini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Vago","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Maria","family":"Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Podini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasa","family":"Zarovni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Murdica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Rizzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Bortolotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Candiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Vigan\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,7,12]]},"reference":[{"issue":"7965","key":"5549_CR1","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1016\/S0140-6736(76)92096-1","volume":"1","author":"PC Steptoe","year":"1976","unstructured":"Steptoe, P. C. & Edwards, R. G. Reimplantation of a human embryo with subsequent tubal pregnancy. Lancet \n                           1(7965), 880 (1976).","journal-title":"Lancet"},{"issue":"4","key":"5549_CR2","doi-asserted-by":"publisher","first-page":"355","DOI":"10.2147\/tcrm.2006.2.4.355","volume":"2","author":"J Wang","year":"2006","unstructured":"Wang, J. & Sauer, M. V. In vitro fertilization (IVF): a review of 3 decades of clinical innovation and technological advancement. Ther. Clin. Risk. Manag. \n                           2(4), 355\u201364 (2006).","journal-title":"Ther. Clin. Risk. Manag."},{"issue":"5","key":"5549_CR3","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1111\/ajo.12356","volume":"55","author":"JJ Wade","year":"2015","unstructured":"Wade, J. J., MacLachlan, V. & Kovacs, G. The success rate of IVF has significantly improved over the last decade. Aust. N. Z. J. Obstet. Gynaecol. \n                           55(5), 473\u20136 (2015).","journal-title":"Aust. N. Z. J. Obstet. Gynaecol."},{"issue":"5","key":"5549_CR4","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/j.mam.2012.12.011","volume":"34","author":"S Zhang","year":"2013","unstructured":"Zhang, S. et al. Physiological and molecular determinants of embryo implantation. Mol. Aspects Med. \n                           34(5), 939\u201380 (2013).","journal-title":"Mol. Aspects Med."},{"issue":"12","key":"5549_CR5","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1038\/nm.3012","volume":"18","author":"J Cha","year":"2012","unstructured":"Cha, J., Sun, X. & Dey, S. K. Mechanisms of implantation: strategies for successful pregnancy. Nat. Med. \n                           18(12), 1754\u201367 (2012).","journal-title":"Nat. Med."},{"key":"5549_CR6","first-page":"103","volume":"8","author":"IM Saadeldin","year":"2015","unstructured":"Saadeldin, I. M., Oh, H. J. & Lee, B. C. Embryonic\u2013maternal cross-talk via exosomes: potential implications. Stem Cells Cloning. \n                           8, 103\u2013107 (2015).","journal-title":"Stem Cells Cloning."},{"key":"5549_CR7","first-page":"2","volume":"5","author":"P Cameo","year":"2004","unstructured":"Cameo, P., Srisuparp, S., Strakova, Z. & Fazleabas, A. T. Chorionic gonadotropin and uterine dialogue in the primate. Reprod. Biol. Endocrinol. \n                           5, 2\u201350 (2004).","journal-title":"Reprod. Biol. Endocrinol."},{"issue":"Suppl A","key":"5549_CR8","doi-asserted-by":"publisher","first-page":"S26","DOI":"10.1016\/j.placenta.2004.01.014","volume":"25","author":"AT Fazleabas","year":"2004","unstructured":"Fazleabas, A. T., Kim, J. J. & Strakova., Z. Implantation: embryonic signals and the modulation of the uterine environment\u2014a review. Placenta \n                           25(Suppl A), S26\u2013S31 (2004).","journal-title":"Placenta"},{"key":"5549_CR9","doi-asserted-by":"publisher","first-page":"4097","DOI":"10.1210\/en.2005-0380","volume":"146","author":"Z Strakova","year":"2005","unstructured":"Strakova, Z. et al. In vivo infusion of interleukin-1beta and chorionic gonadotropin induces endometrial changes that mimic early pregnancy events in the baboon. Endocrinology \n                           146, 4097\u20134104 (2005).","journal-title":"Endocrinology"},{"issue":"3","key":"5549_CR10","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1210\/endo.132.3.7679981","volume":"132","author":"QJ Shi","year":"1993","unstructured":"Shi, Q. J., Lei, Z. M., Rao, C. V. & Lin, J. Novel role of human chorionic gonadotropin in differentiation of human cytotrophoblasts. Endocrinology \n                           132(3), 1387\u201395 (1993).","journal-title":"Endocrinology"},{"issue":"4","key":"5549_CR11","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1093\/molehr\/gah160","volume":"11","author":"M Zygmunt","year":"2005","unstructured":"Zygmunt, M., McKinnon, T., Herr, F., Lala, P. K. & Han, V. K. HCG increases trophoblast migration in vitro via the insulin-like growth factor-II\/mannose-6 phosphate receptor. Mol. Hum. Reprod. \n                           11(4), 261\u20137 (2005).","journal-title":"Mol. Hum. Reprod."},{"key":"5549_CR12","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.fertnstert.2005.02.033","volume":"84","author":"M Filicori","year":"2005","unstructured":"Filicori, M. et al. Novel concepts of human chorionic gonadotropin: reproductive system interactions and potential in the management of infertility. Fertil. Steril. \n                           84, 275\u2013284 (2005).","journal-title":"Fertil. Steril."},{"key":"5549_CR13","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1096\/fj.04-2078rev","volume":"19","author":"JS Hunt","year":"2005","unstructured":"Hunt, J. S., Petroff, M. G., McIntire, R. H. & Ober, C. HLA-G and immune tolerance in pregnancy. FASEB J. \n                           19, 681\u2013693 (2005).","journal-title":"FASEB J."},{"key":"5549_CR14","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1002\/1521-4141(200202)32:2<311::AID-IMMU311>3.0.CO;2-8","volume":"32","author":"B Fuzzi","year":"2002","unstructured":"Fuzzi, B. et al. HLA-G expression in early embryos is a fundamental prerequisite for the obtainment of pregnancy. Eur. J. Immunol. \n                           32, 311\u2013315 (2002).","journal-title":"Eur. J. Immunol."},{"issue":"1","key":"5549_CR15","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.fertnstert.2015.09.014","volume":"105","author":"A Capalbo","year":"2016","unstructured":"Capalbo, A. et al. MicroRNAs in spent blastocyst culture medium are derived from trophectoderm cells and can be explored for human embryo reproductive competence assessment. Fertil. Steril. \n                           105(1), 225\u201335 (2016).","journal-title":"Fertil. Steril."},{"key":"5549_CR16","doi-asserted-by":"publisher","first-page":"22519","DOI":"10.1038\/srep22519","volume":"6","author":"E Willms","year":"2016","unstructured":"Willms, E. et al. Cells release subpopulations of exosomes with distinct molecular and biological properties. Sci. Rep. \n                           6, 22519, doi:10.1038\/srep22519 (2016).","journal-title":"Sci. Rep."},{"issue":"6","key":"5549_CR17","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.tcb.2015.01.004","volume":"25","author":"E Cocucci","year":"2015","unstructured":"Cocucci, E. & Meldolesi, J. Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. \n                           25(6), 364\u201372 (2015).","journal-title":"Trends Cell Biol."},{"key":"5549_CR18","doi-asserted-by":"publisher","first-page":"27066","DOI":"10.3402\/jev.v4.27066","volume":"4","author":"M Yanez-Mo","year":"2015","unstructured":"Yanez-Mo, M. et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles \n                           4, 27066 (2015).","journal-title":"J. Extracell. Vesicles"},{"key":"5549_CR19","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/j.phrs.2016.07.006","volume":"111","author":"SA Kooijmans","year":"2016","unstructured":"Kooijmans, S. A., Schiffelers, R. M., Zarovni, N. & Vago, R. Modulation of tissue tropism and biological activity of exosomes and other extracellular vesicles: New nanotools for cancer treatment. Pharmacol Res. \n                           111, 487\u2013500 (2016).","journal-title":"Pharmacol Res."},{"key":"5549_CR20","first-page":"649161","volume":"2015","author":"Z Qian","year":"2015","unstructured":"Qian, Z., Shen, Q., Yang, X., Qiu, Y. & Zhang, W. The Role of Extracellular Vesicles: An Epigenetic View of the Cancer Microenvironment. Biomed Res Int. \n                           2015, 649161 (2015).","journal-title":"Biomed Res Int."},{"key":"5549_CR21","doi-asserted-by":"publisher","first-page":"11958","DOI":"10.1038\/ncomms11958","volume":"7","author":"LM Desrochers","year":"2016","unstructured":"Desrochers, L. M., Bordeleau, F., Reinhart-King, C. A., Cerione, R. A. & Antonyak, M. A. Microvesicles provide a mechanism for intercellular communication by embryonic stem cells during embryo implantation. Nat. Commun. \n                           7, 11958, doi:10.1038\/ncomms11958 (2016).","journal-title":"Nat. Commun."},{"issue":"3","key":"5549_CR22","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1089\/cell.2014.0003","volume":"16","author":"IM Saadeldin","year":"2014","unstructured":"Saadeldin, I. M., Kim, S. J., Choi, Y. B. & Lee, B. C. Improvement of Cloned Embryos Development by Co-Culturing with Parthenotes: A Possible Role of Exosomes\/Microvesicles for Embryos Paracrine Communication. Cell Reprogram. \n                           16(3), 223\u2013234 (2014).","journal-title":"Cell Reprogram."},{"key":"5549_CR23","doi-asserted-by":"publisher","first-page":"26913","DOI":"10.3402\/jev.v3.26913","volume":"3","author":"J L\u00f6tvall","year":"2014","unstructured":"L\u00f6tvall, J. et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell. Vesicles \n                           3, 26913 (2014).","journal-title":"J Extracell. Vesicles"},{"issue":"6","key":"5549_CR24","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1038\/ncb3347","volume":"18","author":"MN Shahbazi","year":"2016","unstructured":"Shahbazi, M. N. et al. Self-organization of the human embryo in the absence of maternal tissues. Nat. Cell Biol. \n                           18(6), 700\u20138 (2016).","journal-title":"Nat. Cell Biol."},{"issue":"6","key":"5549_CR25","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1016\/j.rbmo.2010.06.038","volume":"21","author":"T Ebner","year":"2010","unstructured":"Ebner, T. et al. Group culture of human zygotes is superior to individual culture in terms of blastulation, implantation and life birth. Reprod. Biomed. Online \n                           21(6), 762\u20138 (2010).","journal-title":"Reprod. Biomed. Online"},{"issue":"12","key":"5549_CR26","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.1007\/s10815-014-0350-9","volume":"31","author":"L Restelli","year":"2014","unstructured":"Restelli, L. et al. The strategy of group embryo culture based on pronuclear pattern on blastocyst development: a two center analysis. J. Assist. Reprod. Genet. \n                           31(12), 1629\u20131634 (2014).","journal-title":"J. Assist. Reprod. Genet."},{"issue":"7","key":"5549_CR27","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1007\/s10815-007-9148-3","volume":"24","author":"RG Roussev","year":"2007","unstructured":"Roussev, R. G. & Coulam, C. B. HLA-G and its role in implantation (review). J. Assist. Reprod. Genet. \n                           24(7), 288\u201395 (2007).","journal-title":"J. Assist. Reprod. Genet."},{"issue":"1","key":"5549_CR28","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.ydbio.2012.12.008","volume":"375","author":"KK Niakan","year":"2013","unstructured":"Niakan, K. K. & Eggan, K. Analysis of human embryos from zygote to blastocyst reveals distinct gene expression patterns relative to the mouse. Dev. Biol. \n                           375(1), 54\u201364 (2013).","journal-title":"Dev. Biol."},{"issue":"10","key":"5549_CR29","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1089\/scd.2009.0122","volume":"18","author":"AJ Harvey","year":"2009","unstructured":"Harvey, A. J., Armant, D. R., Bavister, B. D., Nichols, S. M. & Brenner, C. A. Inner cell mass localization of NANOG precedes OCT3\/4 in rhesus monkey blastocysts. Stem Cells Dev. \n                           18(10), 1451\u20138 (2009).","journal-title":"Stem Cells Dev."},{"key":"5549_CR30","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1093\/humrep\/den351","volume":"24","author":"G Cauffman","year":"2009","unstructured":"Cauffman, G., De Rycke, M., Sermon, K., Liebaers, I. & Van de Velde, H. Markers that define stemness in ESC are unable to identify the totipotent cells in human preimplantation embryos. Hum. Reprod. \n                           24, 63\u201370 (2009).","journal-title":"Hum. Reprod."},{"issue":"6","key":"5549_CR31","doi-asserted-by":"publisher","first-page":"4330","DOI":"10.4049\/jimmunol.180.6.4330","volume":"180","author":"VR Shaikly","year":"2008","unstructured":"Shaikly, V. R. et al. Analysis of HLA-G in maternal plasma, follicular fluid, and preimplantation embryos reveal an asymmetric pattern of expression. J. Immunol. \n                           180(6), 4330\u20137 (2008).","journal-title":"J. Immunol."},{"issue":"4","key":"5549_CR32","doi-asserted-by":"publisher","first-page":"2663","DOI":"10.4049\/jimmunol.1001081","volume":"186","author":"A Verloes","year":"2011","unstructured":"Verloes, A. et al. HLA-G expression in human embryonic stem cells and preimplantation embryos. J. Immunol. \n                           186(4), 2663\u201371 (2011).","journal-title":"J. Immunol."},{"key":"5549_CR33","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1073\/pnas.93.1.161","volume":"93","author":"A Jurisicova","year":"1996","unstructured":"Jurisicova, A., Casper, R. F., MacLusky, N. J., Mills, G. B. & Librach, C. L. HLA-G expression during preimplantation human embryo development. Proc. Natl. Acad. Sci. USA \n                           93, 161\u2013165 (1996).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"5549_CR34","doi-asserted-by":"publisher","first-page":"8379","DOI":"10.4049\/jimmunol.175.12.8379","volume":"175","author":"YQ Yao","year":"2005","unstructured":"Yao, Y. Q., Barlow, D. H. & Sargent, I. L. Differential expression of alternatively spliced transcripts of HLA-G in human preimplantation embryos and inner cell masses. J. Immunol. \n                           175, 8379\u20138385 (2005).","journal-title":"J. Immunol."},{"key":"5549_CR35","doi-asserted-by":"publisher","first-page":"02","DOI":"10.1111\/j.1600-0897.2006.00404.x","volume":"56","author":"R Rizzo","year":"2006","unstructured":"Rizzo, R. & Baricordi, O. H. L. A.-G. Expression and Regulation in early embryos. Am. J. Reprod. Immunol. \n                           56, 02\u201304 (2006).","journal-title":"Am. J. Reprod. Immunol."},{"key":"5549_CR36","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/332459a0","volume":"332","author":"P Braude","year":"1988","unstructured":"Braude, P., Bolton, V. & Moore, S. Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature \n                           332, 459\u2013461 (1988).","journal-title":"Nature"},{"key":"5549_CR37","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s12896-016-0262-0","volume":"16","author":"H Aswad","year":"2016","unstructured":"Aswad, H., Jalabert, A. & Rome, S. Depleting extracellular vesicles from fetal bovine serum alters proliferation and differentiation of skeletal muscle cells in vitro. BMC Biotechnol. \n                           16, 32 (2016).","journal-title":"BMC Biotechnol."},{"key":"5549_CR38","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1007\/BF02215726","volume":"12","author":"PS Weathersbee","year":"1995","unstructured":"Weathersbee, P. S., Pool, T. B. & Ord, T. Synthetic serum substitute (SSS): a globulin-enriched protein supplement for human embryo culture. J. Assist. Reprod. Genet. \n                           12, 354\u2013360 (1995).","journal-title":"J. Assist. Reprod. Genet."},{"key":"5549_CR39","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1093\/humrep\/den396","volume":"24","author":"M Meintjes","year":"2009","unstructured":"Meintjes, M. et al. A randomized controlled study of human serum albumin and serum substitute supplement as protein supplements for IVF culture and the effect on live birth rates. Hum. Reprod \n                           24, 782\u2013789 (2009).","journal-title":"Hum. Reprod"},{"issue":"10","key":"5549_CR40","doi-asserted-by":"publisher","first-page":"2174","DOI":"10.1093\/humrep\/dew157","volume":"31","author":"A Sunde","year":"2016","unstructured":"Sunde, A. et al. Time to take human embryo culture seriously. Hum. Reprod. \n                           31(10), 2174\u201382 (2016).","journal-title":"Hum. Reprod."},{"issue":"16","key":"5549_CR41","doi-asserted-by":"publisher","first-page":"30658","DOI":"10.1016\/j.placenta.2016.12.011","volume":"S0143\u20134004","author":"H Homer","year":"2016","unstructured":"Homer, H., Rice, G. E. & Salomon, C. Embryo and endometrium-derived exosomes and their potential role in assisted reproductive treatments-liquid biopsies for endometrial receptivity. Placenta \n                           S0143\u20134004(16), 30658\u20130, doi:10.1016\/j.placenta.2016.12.011 (2016).","journal-title":"Placenta"},{"issue":"2","key":"5549_CR42","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1095\/biolreprod.115.134890","volume":"94","author":"DW Greening","year":"2016","unstructured":"Greening, D. W., Nguyen, H. P., Elgass, K., Simpson, R. J. & Salamonsen, L. A. Human endometrial exosomes contain hormone-specific cargo modulating Trophoblast adhesive capacity. Biol. Reprod. \n                           94(2), 38 (2016).","journal-title":"Biol. Reprod."},{"issue":"9\u201310","key":"5549_CR43","first-page":"997","volume":"58","author":"F Calzi","year":"2012","unstructured":"Calzi, F. et al. Exposure of embryos to oxygen at low concentration in a cleavage stage transfer program: reproductive outcomes in a time-series analysis. Clin. Lab. \n                           58(9\u201310), 997\u20131003 (2012).","journal-title":"Clin. Lab."},{"issue":"2","key":"5549_CR44","first-page":"194","volume":"22","author":"P Rubino","year":"2016","unstructured":"Rubino, P., Vigan\u00f2, P., Luddi, A. & Piomboni, P. The ICSI procedure from past to future: a systematic review of the more controversial aspects. Hum. Reprod. Update \n                           22(2), 194\u2013227 (2016).","journal-title":"Hum. Reprod. Update"},{"issue":"1","key":"5549_CR45","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.ejogrb.2013.08.017","volume":"171","author":"L Corti","year":"2013","unstructured":"Corti, L. et al. Fresh blastocyst transfer as a clinical approach to overcome the detrimental effect of progesterone elevation at hCG triggering: a strategy in the context of the Italian law. Eur. J. Obstet. Gynecol. Reprod. Biol. \n                           171(1), 73\u20137 (2013).","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"5549_CR46","doi-asserted-by":"crossref","unstructured":"Th\u00e9ry, C., Amigorena, S., Raposo, G. & Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell Biol. 3.22.1\u20133.22.29 (2006).","DOI":"10.1002\/0471143030.cb0322s30"},{"key":"5549_CR47","doi-asserted-by":"publisher","first-page":"20360","DOI":"10.3402\/jev.v2i0.20360","volume":"2","author":"KW Witwer","year":"2013","unstructured":"Witwer, K. W. et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell. Vesicles \n                           2, 20360, doi:10.3402\/jev.v2i0.20360 (2013).","journal-title":"J. Extracell. Vesicles"},{"key":"5549_CR48","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.ymeth.2015.05.028","volume":"87","author":"N Zarovni","year":"2015","unstructured":"Zarovni, N. et al. Integrated isolation and quantitative analysis of exosome shuttled proteins and nucleic acids using immunocapture approaches. Methods \n                           87, 46\u201358 (2015).","journal-title":"Methods"},{"key":"5549_CR49","doi-asserted-by":"publisher","first-page":"0414","DOI":"10.5966\/sctm.2015-0414","volume":"2015","author":"V Meneghini","year":"2016","unstructured":"Meneghini, V. et al. Generation of Human Induced Pluripotent Stem Cell-Derived Bona Fide Neural Stem Cells for Ex Vivo Gene Therapy of Metachromatic Leukodystrophy. Stem Cells Transl Med. \n                           2015, 0414, doi:10.5966\/sctm.2015-0414 (2016).","journal-title":"Stem Cells Transl Med."},{"issue":"4","key":"5549_CR50","first-page":"523","volume":"24","author":"R Rizzo","year":"2009","unstructured":"Rizzo, R. et al. Production of sHLA-G molecules by in vitro matured cumulus-oocyte complex. Int J Mol. Med. \n                           24(4), 523\u201330 (2009).","journal-title":"Int J Mol. Med."},{"issue":"1-2","key":"5549_CR51","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.jri.2007.02.005","volume":"74","author":"R Rizzo","year":"2007","unstructured":"Rizzo, R. et al. Soluble HLA-G molecules in follicular fluid: a tool for oocyte selection in IVF? J Reprod. Immunol. \n                           74(1-2), 133\u201342 (2007).","journal-title":"J Reprod. Immunol."},{"key":"5549_CR52","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3109\/00016349309023418","volume":"72","author":"P Vigan\u00f2","year":"1993","unstructured":"Vigan\u00f2, P., Di Blasio, A. M., Dell\u2019Antonio, G. & Vignali, M. Culture of endometrial cells: a new simple technique to completely separate epithelial glands. Acta Obstet. Gynecol. Scand. \n                           72, 87\u201392 (1993).","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"5549_CR53","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1007\/978-1-62703-547-7_37","volume":"1049","author":"I Nazarenko","year":"2013","unstructured":"Nazarenko, I., Rupp, A. K. & Altevogt, P. Exosomes as a potential tool for a specific delivery of functional molecules. Methods Mol. Biol. \n                           1049, 495\u2013511 (2013).","journal-title":"Methods Mol. Biol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05549-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05549-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05549-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T06:31:28Z","timestamp":1671777088000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05549-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,12]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["5549"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-05549-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,12]]},"assertion":[{"value":"12 December 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 May 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 July 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"5210"}}