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However, how their proteome is regulated throughout the menstrual cycle is not known. Such information can provide novel insights into biological processes critical for embryo development, implantation, and successful pregnancy. Using mass spectrometry\u2010based quantitative proteomics, we show that small EVs (sEVs) isolated from uterine lavage of fertile women (UL\u2010sEV), compared to infertile women, are laden with proteins implicated in antioxidant activity (SOD1, GSTO1, MPO, CAT). Functionally, sEVs derived from endometrial cells enhance antioxidant function in trophectoderm cells. Moreover, there was striking enrichment of invasion\u2010related proteins (LGALS1\/3, S100A4\/11) in fertile UL\u2010sEVs in the secretory (estrogen plus progesterone\u2010driven, EP) versus proliferative (estrogen\u2010driven, E) phase, with several players downregulated in infertile UL\u2010sEVs. Consistent with this, sEVs from EP\u2010 versus E\u2010primed endometrial epithelial cells promote invasion of trophectoderm cells. Interestingly, UL\u2010sEVs from fertile versus infertile women carry known players\/predictors of embryo implantation (PRDX2, IDHC), endometrial receptivity (S100A4, FGB, SERPING1, CLU, ANXA2), and implantation success (CAT, YWHAE, PPIA), highlighting their potential to inform regarding endometrial status\/pregnancy outcomes. Thus, this study provides novel insights into proteome reprograming of sEVs and soluble secretome in uterine fluid, with potential to enhance embryo implantation and hence fertility.<\/jats:p>","DOI":"10.1002\/pmic.202000211","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T04:11:49Z","timestamp":1614312709000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Proteomic profiling of human uterine extracellular vesicles reveal dynamic regulation of key players of embryo implantation and fertility during menstrual cycle"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7994-5151","authenticated-orcid":false,"given":"Alin","family":"Rai","sequence":"first","affiliation":[{"name":"Baker Heart and Diabetes Institute Molecular Proteomics  Melbourne Victoria Australia"},{"name":"Central Clinical School Monash University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi Hui","family":"Poh","sequence":"additional","affiliation":[{"name":"Baker Heart and Diabetes Institute Molecular Proteomics  Melbourne Victoria Australia"},{"name":"Department of Biochemistry and Genetics La Trobe Institute for Molecular Science La Trobe University  Bundoora Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"Fatmous","sequence":"additional","affiliation":[{"name":"Baker Heart and Diabetes Institute Molecular Proteomics  Melbourne Victoria Australia"},{"name":"Department of Biochemistry and Genetics La Trobe Institute for Molecular Science La Trobe University  Bundoora Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyun","family":"Fang","sequence":"additional","affiliation":[{"name":"Baker Heart and Diabetes Institute Molecular Proteomics  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanti","family":"Gurung","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research  Clayton Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverley","family":"Vollenhoven","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology Monash University  Clayton Victoria Australia"},{"name":"Monash IVF  Clayton Victoria Australia"},{"name":"Women's and Newborn Program Monash Health  Clayton Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0558-7325","authenticated-orcid":false,"given":"Lois A.","family":"Salamonsen","sequence":"additional","affiliation":[{"name":"Hudson Institute of Medical Research  Clayton Victoria Australia"},{"name":"Department of Molecular and Translational Science Monash University  Clayton Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7516-485X","authenticated-orcid":false,"given":"David W.","family":"Greening","sequence":"additional","affiliation":[{"name":"Baker Heart and Diabetes Institute Molecular Proteomics  Melbourne Victoria Australia"},{"name":"Central Clinical School Monash University  Melbourne Victoria Australia"},{"name":"Department of Biochemistry and Genetics La Trobe Institute for Molecular Science La Trobe University  Bundoora Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,3,19]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1530\/rep.0.1240289"},{"key":"e_1_2_9_3_1","first-page":"85","article-title":"Sheep Uterine Gland Knockout (UGKO) model","volume":"121","author":"Spencer T. 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