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Owing to their transcriptionally and translationally inert state, this transformation into fertilization competent cells is driven by complex mechanisms of intercellular communication with the secretory epithelium that delineates the epididymal tubule. Chief among these mechanisms are the release of extracellular vesicles (EV), which have been implicated in the exchange of varied macromolecular cargo with spermatozoa. Here, we describe the optimization of a tractable cell culture model to study the mechanistic basis of sperm\u2013extracellular vesicle interactions. In tandem with receptor inhibition strategies, our data demonstrate the importance of milk fat globule\u2010EGF factor 8 (MFGE8) protein in mediating the efficient exchange of macromolecular EV cargo with mouse spermatozoa; with the MFGE8 integrin\u2010binding Arg\u2010Gly\u2010Asp (RGD) tripeptide motif identified as being of particular importance. Specifically, complementary strategies involving MFGE8 RGD domain ablation, competitive RGD\u2010peptide inhibition and antibody\u2010masking of alpha V integrin receptors, all significantly inhibited the uptake and redistribution of EV\u2010delivered proteins into immature mouse spermatozoa. These collective data implicate the MFGE8 ligand and its cognate integrin receptor in the mediation of the EV interactions that underpin sperm maturation.<\/jats:p>","DOI":"10.1002\/pmic.202000079","type":"journal-article","created":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T02:10:55Z","timestamp":1617243055000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A novel role for milk fat globule\u2010EGF factor 8 protein (MFGE8) in the mediation of mouse sperm\u2013extracellular vesicle interactions"],"prefix":"10.1002","volume":"21","author":[{"given":"Natalie A.","family":"Trigg","sequence":"first","affiliation":[{"name":"Priority Research Centre for Reproductive Science The University of Newcastle  Callaghan New South Wales Australia"},{"name":"Pregnancy and Reproduction Program Hunter Medical Research Institute  New Lambton Heights New South Wales 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The University of Newcastle  Callaghan New South Wales Australia"},{"name":"Cancer Research Program Hunter Medical Research Institute  New Lambton Heights New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Eamens","sequence":"additional","affiliation":[{"name":"Priority Research Centre for Reproductive Science The University of Newcastle  Callaghan New South Wales Australia"},{"name":"Pregnancy and Reproduction Program Hunter Medical Research Institute  New Lambton Heights New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffry N.","family":"De Iuliis","sequence":"additional","affiliation":[{"name":"Priority Research Centre for Reproductive Science The University of Newcastle  Callaghan New South Wales Australia"},{"name":"Pregnancy and Reproduction Program Hunter Medical Research Institute  New Lambton Heights New South Wales 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