Extracellular vesicles : novel mediators of conceptus-maternal interactions in sheep

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Infertility and pregnancy loss are common problems affecting reproductive efficiency, health and development in livestock. Pregnancy loss occurs most commonly during the first weeks of gestation and may arise due to asynchrony between the conceptus and uterus or endometrial dysfunction, resulting in defective conceptus elongation, implantation and/or placentation. Extracellular vesicles (EVs), a term including exosomes and microvesicles, are membrane-bound nanoparticles released from diverse cell types that deliver nucleic acids and proteins to target cells. Available studies support the central hypothesis that EVs are a component of uterine histotroph and mediate crosstalk between the developing conceptus and uterine endometrium prior to implantation. Studies were conducted here to: (1) identify and characterize EVs from uterine flush of cyclic and pregnant ewes; (2) examine potential of vesicle mediated communication during early pregnancy from endometrium and elongating conceptus derived EVs; and (3) determine progesterone regulation of EV cargo, endometrial gene expression, and total EV number in the uterine lumen of cyclic sheep. Results from these studies established that: (1) EVs are a component of the uterine histotroph in sheep with pregnancy associated differences; (2) EVs emanate from the uterine endometrium and elongating conceptus; (3) the endometrial epithelium and conceptus trophectoderm uptake labeled EVs indicating a role in intercellular communication during the establishment of pregnancy; (4) uterine EV content increases more than five-fold from day 10 to 14 of the estrous cycle; (5) the endometrial epithelia produce EVs with multivesicular endosomes, the progenitors of EVs, localized to the luminal and glandular epithelium; and (6) progesterone treatment increases the number of uterine EVs and alters their miRNA cargo. Collectively, these studies have established that EVs are a dynamic component of the uterine histotroph, produced by both the uterine epithelium and conceptus trophectoderm, with the ability to traffic between maternal and embryonic tissues and support the idea that EVs mediate communication that underpins conceptus development required for the successful establishment of pregnancy. These studies provide evidence of EVs as novel mediators of communication between the developing conceptus and endometrium. Uterine EVs may provide useful biomarkers for uterine receptivity or indicate endometrial dysfunction given their dynamic cargo and robust stability in biofluids.