Embryo-maternal interactions through EVs IN VIVO
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Oviductal fluid |
Isthmus-derived EVs enhance embryo quality and induce significant differences in gene expression related to metabolism, epigenetics, and water channel traffic. |
UC |
CD9, TSG101 and ERM (WB) |
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(Lopera-Vasquez et al., 2017Lopera-Vasquez R, Hamdi M, Maillo V, Gutierrez-Adan A, Bermejo-Alvarez P, Angel Ramirez M, et al. Effect of bovine oviductal extracellular vesicles on embryo development and quality in vitro. Reproduction. 2017;153(4):461-70. http://doi.org/10.1530/REP-16-0384. PMid:28104825. http://doi.org/10.1530/REP-16-0384...
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EVs were internalized by the embryo during in vitro culture and enhanced their ability to reach the blastocyst stage. |
UC |
HSP70 (WB) |
Proteins |
(Almiñana et al., 2017Almiñana C, Corbin E, Tsikis G, Alcântara-Neto AS, Labas V, Reynaud K, Galio L, Uzbekov R, Garanina AS, Druart X, Mermillod P. Oviduct extracellular vesicles protein content and their role during oviduct–embryo cross-talk. Reproduction. 2017;154(3):153-68. http://doi.org/10.1530/REP-17-0054. PMid:28630101. http://doi.org/10.1530/REP-17-0054...
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Changes in EV cargo across the estrous cycle are potentially related to gamete/embryo-oviductal interactions. |
UC |
HSP70 (WB) |
mRNAs, ncRNAs, and proteins |
(Almiñana et al., 2018Almiñana C, Tsikis G, Labas V, Uzbekov R, da Silveira JC, Bauersachs S, Mermillod P. Deciphering the oviductal extracellular vesicles content across the estrous cycle: implications for the gametes-oviduct interactions and the environment of the potential embryo. BMC Genomics. 2018;19(1):622. http://doi.org/10.1186/s12864-018-4982-5. PMid:30134841. http://doi.org/10.1186/s12864-018-4982-5...
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The metabolite content of EVs is regulated across the estrous cycle in cattle. |
UC |
CD81 and HSP70 (WB) |
Metabolites |
(Gatien et al., 2019Gatien J, Mermillod P, Tsikis G, Bernardi O, Janati Idrissi S, Uzbekov R, Le Bourhis D, Salvetti P, Almiñana C, Saint-Dizier M. Metabolomic Profile of Oviductal Extracellular Vesicles across the Estrous Cycle in Cattle. Int. J. Mol. Sci. 2019;20(24):6339. PMid: 31888194.) |
OF-EVs cargo regulates the embryonic transcriptome. |
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mRNAs and miRNAs |
(Bauersachs et al., 2020Bauersachs S, Mermillod P, Almiñana C. The oviductal extracellular vesicles’ RNA cargo regulates the bovine embryonic transcriptome. Int J Mol Sci. 2020;21(4):1303. http://doi.org/10.3390/ijms21041303. PMid:32075098. http://doi.org/10.3390/ijms21041303...
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The embryo presence modulates miRNA contents of EVs and BOECs in vivo. |
UC |
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miRNAs |
(Mazzarella et al., 2021Mazzarella R, Bastos NM, Bridi A, del Collado M, Andrade GM, Pinzon J, Prado CM, Silva LA, Meirelles FV, Pugliesi G, Perecin F, da Silveira JC. Changes in oviductal cells and small extracellular vesicles miRNAs in pregnant cows. Front Vet Sci. 2021;8:639752. http://doi.org/10.3389/fvets.2021.639752. PMid:33748215. http://doi.org/10.3389/fvets.2021.639752...
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Protein signature in pregnant animals' OF-EVs suggests interactions between the mother and the embryo through EVs in the oviduct. |
SEC |
CD63, CD81, and CD44 (FC) |
Proteins |
(Mazzarella et al., 2023bMazzarella R, Cajas YN, Cañón-Beltrán K, Gascón D, Martinez CA, Millán de la Blanca MG, Beltrán-Breña P, Nuñez-Puente C, González E, Rizos D. Impact of bta-mir-483-3p carried within oviductal fluid’s extracellular vesicles of pregnant cows on in vitro embryo development and quality. Reprod Fertil Dev. 2023b;36(2):196-196. http://doi.org/10.1071/RDv36n2Ab89. http://doi.org/10.1071/RDv36n2Ab89...
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Oviductal fluid and Uterine Fluid |
miRNA profile changes in OF- and UF-EVs across the estrous cycle suggest miRNAs' role in cell signaling and reproductive functions. |
UC |
CD9 and HSP70 (WB) |
miRNAs |
(Hamdi et al., 2021Hamdi M, Cañon-Beltrán K, Mazzarella R, Cajas YN, Leal CLV, Gutierrez-Adan A, González EM, Da Silveira JC, Rizos D. Characterization and profiling analysis of bovine oviduct and uterine extracellular vesicles and their miRNA cargo through the estrous cycle. FASEB J. 2021;35(12):e22000. http://doi.org/10.1096/fj.202101023R. PMid:34731497. http://doi.org/10.1096/fj.202101023R...
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OF- and UF-EVs in sequential IVC enhanced blastocyst quality, survival rate, and lipid content and changed lipid metabolism gene expression. |
UC |
CD9 and HSP70 (WB) |
miRNAs |
(Leal et al., 2022Leal CLV, Cañón-Beltrán K, Cajas YN, Hamdi M, Yaryes A, Millán de la Blanca MG, Beltrán-Breña P, Mazzarella R, da Silveira JC, Gutiérrez-Adán A, González EM, Rizos D. Extracellular vesicles from oviductal and uterine fluids supplementation in sequential in vitro culture improves bovine embryo quality. J Anim Sci Biotechnol. 2022;13(1):116. http://doi.org/10.1186/s40104-022-00763-7. PMid:36280872. http://doi.org/10.1186/s40104-022-00763-...
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OF- and UF-EVs miRNA cargo may influence embryo development and quality and potentially regulate immune response and implantation. |
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miRNAs |
(Mazzarella et al., 2024Mazzarella R, Cañón-Beltrán K, Cajas YN, Hamdi M, González EM, da Silveira JC, Leal CLV, Rizos D. Extracellular vesicles-coupled miRNAs from oviduct and uterus modulate signaling pathways related to lipid metabolism and bovine early embryo development. J Anim Sci Biotechnol. 2024;15(1):51. http://doi.org/10.1186/s40104-024-01008-5. PMid:38570884. http://doi.org/10.1186/s40104-024-01008-...
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Uterine Fluid |
UF-EVs contain IFNT on days 17, 20, and 22 of pregnancy and can up-regulate apoptosis-related genes and adhesion molecules in BEECs. |
Exo-Quick® |
CD63 and HSP70 (WB) |
Proteins |
(Kusama et al., 2018Kusama K, Nakamura K, Bai R, Nagaoka K, Sakurai T, Imakawa K. Intrauterine exosomes are required for bovine conceptus implantation. Biochem Biophys Res Commun. 2018;495(1):1370-5. http://doi.org/10.1016/j.bbrc.2017.11.176. PMid:29196267. http://doi.org/10.1016/j.bbrc.2017.11.17...
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In vitro culture supplementation with UF-EVs in nuclear transfer embryos significantly increased blastocyst formation rates. |
UC |
CD9 (WB) |
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(Qiao et al., 2018Qiao F, Ge H, Ma X, Zhang Y, Zuo Z, Wang M, Zhang Y, Wang Y. Bovine uterus-derived exosomes improve developmental competence of somatic cell nuclear transfer embryos. Theriogenology. 2018;114:199-205. http://doi.org/10.1016/j.theriogenology.2018.03.027. PMid:29653387. http://doi.org/10.1016/j.theriogenology....
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The presence of multiple D7 embryos in the uterus can lead to significant changes in the protein and miRNA contents of UF-EVs. |
Exo-QuickTC
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HSP70, CD63, RAB5, among others (WB) |
Proteins and miRNAs |
(Kusama et al., 2021Kusama K, Rashid MB, Kowsar R, Marey MA, Talukder AK, Nagaoka K, Shimada M, Khatib H, Imakawa K, Miyamoto A. Day 7 embryos change the proteomics and exosomal Micro-RNAs content of bovine uterine fluid: involvement of innate immune functions. Front Genet. 2021;12:676791. http://doi.org/10.3389/fgene.2021.676791. PMid:34262596. http://doi.org/10.3389/fgene.2021.676791...
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Changes in UF-EV concentration and protein profile at follicular and luteal phases suggest EV modulation of uterine microenvironment across the estrous cycle. |
SEC |
ANXA4, CD63, CD1, among others (MS) |
Proteins |
(Piibor et al., 2023Piibor J, Dissanayake K, Midekessa G, Andronowska A, Kavak A, Waldmann A, Fazeli A. Characterization of bovine uterine fluid extracellular vesicles proteomic profiles at follicular and luteal phases of the oestrous cycle. Vet Res Commun. 2023;47(2):885-900. http://doi.org/10.1007/s11259-022-10052-3. PMid:36547796. http://doi.org/10.1007/s11259-022-10052-...
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The presence of an embryo modulates the uterine environment, specifically the protein profile within UF-EVs. |
SEC |
CD63, CD81, and CD44 (FC) |
Proteins |
(Mazzarella et al., 2023aMazzarella R, Cajas YN, Cañón-Beltrán K, Gascón Collado D, Beltrán–Breña P, Sánchez JM, Fernandez-Fuertes B, Gutierrez-Adan A, González E, Rizos D. Effect of bta-miR-483-3p of extracellular vesicles from the oviductal fluid of pregnant cows on in vitro early embryo development. Anim. -. Sci. Proc. 2023a;14(3):467-8. http://doi.org/10.1016/j.anscip.2023.03.060. http://doi.org/10.1016/j.anscip.2023.03....
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OF-EVs increase embryo diameter and IFNT expression. |
ExoLutE® |
CD9, CD63, CD81 and CD40 (FC) |
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(Aguilera et al., 2024Aguilera C, Wong YS, Gutierrez-Reinoso MA, Velásquez AE, Melo-Báez B, Cabezas J, Caamaño D, Navarrete F, Castro FO, Rodriguez-Alvarez LL. Embryo-maternal communication mediated by extracellular vesicles in the early stages of embryonic development is modified by in vitro conditions. Theriogenology. 2024;214:43-56. http://doi.org/10.1016/j.theriogenology.2023.10.005. PMid:37852113. http://doi.org/10.1016/j.theriogenology....
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Embryo-maternal interactions through EVs IN VITRO
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BOECs |
BOECs-CM and BOECs-EVs improve embryo quality (number of cells and gene expression) and cryosurvival. |
UC |
CD9, CD63, TSG101 and ERM (FC) |
Proteins |
(Lopera-Vásquez et al., 2016Lopera-Vásquez R, Hamdi M, Fernandez-Fuertes B, Maillo V, Beltrán-Breña P, Calle A, Redruello A, López-Martín S, Gutierrez-Adán A, Yañez-Mó M, Ramirez MÁ, Rizos D. Extracellular vesicles from BOEC in in vitro embryo development and quality. PLoS One. 2016;11(2):e0148083. http://doi.org/10.1371/journal.pone.0148083. PMid:26845570. http://doi.org/10.1371/journal.pone.0148...
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In vivo (OF) and in vitro-derived (BOECs) EVs have different secretion/content. |
UC |
HSP70 (WB) |
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(Almiñana et al., 2017Almiñana C, Corbin E, Tsikis G, Alcântara-Neto AS, Labas V, Reynaud K, Galio L, Uzbekov R, Garanina AS, Druart X, Mermillod P. Oviduct extracellular vesicles protein content and their role during oviduct–embryo cross-talk. Reproduction. 2017;154(3):153-68. http://doi.org/10.1530/REP-17-0054. PMid:28630101. http://doi.org/10.1530/REP-17-0054...
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Oviductal explants |
Oviductal explants-EVs and OF-EVs share common proteins involved in early embryo development. |
SEC |
CD63, CD81, and CD44 (FC) |
Proteins |
(Mazzarella et al., 2023cMazzarella R, Sánchez JM, Egido SG, Álvarez-Barrientos A, González E, Falcón-Pérez JM, Azkargorta M, Elortza F, González ME, Lonergan P, Rizos D, Fernandez-Fuertes B. Profiling the protein cargo of uterine extracellular vesicles isolated from pregnant and cyclic heifers. Anim Reprod. 2023c;20(2):1-3.) |
BEECs |
BEECs-EVs improve the pre-implantation development of in vitro-produced embryos. |
ExoLutE® |
CD9, CD63, CD81 and CD40 (FC) |
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(Aguilera et al. 2024Aguilera C, Wong YS, Gutierrez-Reinoso MA, Velásquez AE, Melo-Báez B, Cabezas J, Caamaño D, Navarrete F, Castro FO, Rodriguez-Alvarez LL. Embryo-maternal communication mediated by extracellular vesicles in the early stages of embryonic development is modified by in vitro conditions. Theriogenology. 2024;214:43-56. http://doi.org/10.1016/j.theriogenology.2023.10.005. PMid:37852113. http://doi.org/10.1016/j.theriogenology....
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EMBRYO DERIVED EVS
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Blastocysts secrete EVs into the culture medium, and these EVs vary depending on embryo competence. |
UC |
CD63 and CD9 (FC) |
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(Mellisho et al., 2017Mellisho EA, Velásquez AE, Nuñez MJ, Cabezas JG, Cueto JA, Fader C, Castro FO, Rodríguez-Álvarez L. Identification and characteristics of extracellular vesicles from bovine blastocysts produced in vitro. PLoS One. 2017;12(5):e0178306. http://doi.org/10.1371/journal.pone.0178306. PMid:28542562. http://doi.org/10.1371/journal.pone.0178...
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Bovine somatic cell nuclear transfer (SCNT) embryos secrete EVs, which are essential for the subsequent development of these embryos. |
UC |
CD9 (IHC) |
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(Qu et al., 2017Qu P, Qing S, Liu R, Qin H, Wang W, Qiao F, Ge H, Liu J, Zhang Y, Cui W, Wang Y. Effects of embryo-derived exosomes on the development of bovine cloned embryos. PLoS One. 2017;12(3):e0174535. http://doi.org/10.1371/journal.pone.0174535. PMid:28350875. http://doi.org/10.1371/journal.pone.0174...
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Embryonic EVs act as autocrine embryotropins in embryo–embryo communication during in vitro embryo culture. |
OptiPrep™ |
CD63 and CD9 (WB) |
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(Pavani et al., 2019Pavani KC, Hendrix A, Van Den Broeck W, Couck L, Szymanska K, Lin X, De Koster J, Van Soom A, Leemans B. Isolation and characterization of functionally active extracellular vesicles from culture medium conditioned by bovine embryos in vitro. Int J Mol Sci. 2019;20(1):1–22. PMid: 30577682.) |
Individually cultured embryos secrete EVs that may indicate their developmental competency. |
SEC |
CD9, CD63, CD81, among others (MA) |
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(Dissanayake et al., 2020Dissanayake K, Nõmm M, Lättekivi F, Ressaissi Y, Godakumara K, Lavrits A, Midekessa G, Viil J, Bæk R, Jørgensen MM, Bhattacharjee S, Andronowska A, Salumets A, Jaakma Ü, Fazeli A. Individually cultured bovine embryos produce extracellular vesicles that have the potential to be used as non-invasive embryo quality markers. Theriogenology. 2020;149:104-16. http://doi.org/10.1016/j.theriogenology.2020.03.008. PMid:32259747. http://doi.org/10.1016/j.theriogenology....
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EVs released by individually cultured bovine embryos impact gene expression in BOECs based on the quality of the embryo. |
SEC |
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(Dissanayake et al., 2021Dissanayake K, Nõmm M, Lättekivi F, Ord J, Ressaissi Y, Godakumara K, Reshi QUA, Viil J, Jääger K, Velthut-Meikas A, Salumets A, Jaakma Ü, & Fazeli A. Oviduct as a sensor of embryo quality: deciphering the extracellular vesicle (EV)-mediated embryo-maternal dialogue. Journal of Molecular Medicine. 2021; 99(5), 685–697. PMid:33512581.) |
In vivo and in vitro‐produced bovine hatched blastocysts (Day 9) secret EVs with different miRNA profiles. |
Exo-QuickTC
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miRNAs |
(Bridi et al., 2021Bridi A, Andrade GM, Del Collado M, Sangalli JR, de Ávila ACFCM, Motta IG, da Silva JCB, Pugliesi G, Silva LA, Meirelles FV, da Silveira JC, Perecin F. Small extracellular vesicles derived from in vivo- or in vitro-produced bovine blastocysts have different miRNAs profiles-Implications for embryo-maternal recognition. Mol Reprod Dev. 2021;88(9):628-43. http://doi.org/10.1002/mrd.23527. PMid:34402123. http://doi.org/10.1002/mrd.23527...
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EVs from in vitro- and in vivo-produced embryos have different effects on the transcriptomic profiles of IFNT-stimulated genes in BEECs. |
ExoLutE® |
CD9, CD63, CD81 and CD40 (FC) |
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(Aguilera et al., 2023Aguilera C, Velásquez AE, Gutierrez-Reinoso MA, Wong YS, Melo-Baez B, Cabezas J, Caamaño D, Navarrete F, Rojas D, Riadi G, Castro FO, Rodriguez-Alvarez L. Extracellular vesicles secreted by pre-hatching bovine embryos produced in vitro and in vivo alter the expression of IFNtau-Stimulated Genes in Bovine endometrial cells. Int J Mol Sci. 2023;24(8):7438. http://doi.org/10.3390/ijms24087438. PMid:37108601. http://doi.org/10.3390/ijms24087438...
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EVs from in vitro-produced embryos induce non-classical ISGs in BEECs |
ExoLutE® |
CD9, CD63, CD81 and CD40 (FC) |
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(Aguilera et al., 2024Aguilera C, Wong YS, Gutierrez-Reinoso MA, Velásquez AE, Melo-Báez B, Cabezas J, Caamaño D, Navarrete F, Castro FO, Rodriguez-Alvarez LL. Embryo-maternal communication mediated by extracellular vesicles in the early stages of embryonic development is modified by in vitro conditions. Theriogenology. 2024;214:43-56. http://doi.org/10.1016/j.theriogenology.2023.10.005. PMid:37852113. http://doi.org/10.1016/j.theriogenology....
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