scholarly journals Extracellular vesicles, lipids, and lipoproteins in early pregnant sheep

2021 ◽  
Author(s):  
◽  
Eleanore V. O'Neil
Keyword(s):  
Extracellular Vesicles ◽  
Early Pregnancy ◽  
Functional Roles ◽  
Dynamic Composition ◽  
Central Hypothesis ◽  
Pregnant Sheep ◽  
Conceptus Development ◽  
Endometrial Epithelium ◽  
Critical Components ◽  
Lipids And Lipoproteins

In sheep, pregnancy establishment encompasses conceptus elongation, implantation, and placentation. These events are regulated by factors present within the uterine luminal fluid (ULF) from the endometrial epithelium and the conceptus itself that affect proliferation, migration, attachment, and adhesion of the conceptus trophectoderm. As the peri-implantation period is especially susceptible to pregnancy loss, it is essential to understand the various components and functional roles of substances within the ULF. The central hypothesis of this dissertation is that lipids and lipid associated macromolecules are components of the ULF and mediate endometrial-embryonic crosstalk and regulate conceptus development. This work sought to identify, characterize, and/or determine the roles of: (1) extracellular vesicles (EVs); (2) lipids and metabolites; (3) prostaglandins (PGs); and (4) apolipoproteins present within the ULF of ewes during early gestation. Collectively, the present studies established that: (1) EVs increase within the ULF during the estrous cycle but are depleted in the uterine lumen of pregnant ewes due to uptake by the elongating conceptus; (2) the lipid and protein cargo of uterine EVs is diverse and altered by pregnancy; (3) uterine EVs regulate cellular processes in the conceptus trophectoderm and endometrium including cell proliferation and secretions; (4) various lipids (specifically phospholipids, ceramides, and triglycerides) and metabolites are elevated in the ULF of pregnant ewes; (5) the conceptus lipidome and metabolome is distinct from the ULF and endometrium suggesting selective uptake of ULF substances; (6) the production of PGs by PTGS2 in the conceptus is not required for conceptus elongation; (7) the secretion of APOA1 by the conceptus does not mobilize endometrial lipids into the ULF and is not required for early pregnancy development or survival. Collectively, these studies highlight the complex and dynamic composition of the ULF and support the overall hypothesis that lipids and lipid-associated macromolecules are critical components of the ULF that mediate conceptus-endometrial crosstalk and regulate important developmental processes in the conceptus. Future investigation and expansion of these findings will fill crucial gaps in our knowledge of early pregnancy events and may provide biomarkers or help develop therapies to improve pregnancy outcomes and reproductive efficiency in agricultural species.

scholarly journals 003.Uterine and placental factors regulating conceptus growth: insights from the ewe

2004 ◽  
Vol 16 (9) ◽  
pp. 3
Author(s):  
T. E. Spencer
Keyword(s):  
Branching Morphogenesis ◽  
Domestic Animals ◽  
Placental Lactogen ◽  
Apical Surface ◽  
Interferon Tau ◽  
Knock Out ◽  
Pregnant Sheep ◽  
Conceptus Development ◽  
Endometrial Epithelium ◽  
Extraembryonic Membranes

Uterine adenogenesis is the process whereby endometrial glands differentiate and develop and is primarily a postnatal event in all mammals. In domestic animals and humans, adenogenesis involves initial differentiation and budding of glandular epithelium followed by invagination and extensive tubular coiling and branching morphogenesis through the endometrial stroma to the myometrium. Transient exposure of the neonatal ewe to a progestin from birth to postnatal Day 56 resulted in a uterine gland knock out (UGKO) phenotype in the adult. UGKO ewes exhibit a peri-implantation defect in conceptus (embryo/fetus and associated extraembryonic membranes) survival, indicating the functional importance of uterine glands and their secretions. Genomic and proteomic analysis of uterine endometrium from UGKO ewes has identified many candidate genes that regulate conceptus development and implantation, including endogenous Jaagsiekte sheep retroviruses (enJSRVs), glycosylated cell adhesion molecule one (GlyCAM-1), osteopontin and galectin-15. Galectin-15, also known as OVGAL11, and a previously uncharacterised member of the galectin family of secreted β-galactoside lectins, was discovered in the endometrium of sheep. In endometria of cyclic and pregnant sheep, galectin-15 mRNA was expressed specifically in the endometrial luminal epithelium but not in the conceptus. In pregnant sheep, galectin-15 mRNA expression appeared in the epithelia between Days 10 and 12 and increased between Days 12 and 16. Progesterone induced and interferon tau stimulated galectin-15 mRNA in the endometrial epithelium. Galectin-15 protein was concentrated near and on the apical surface of the endometrial luminal epithelia and localised within discrete cytoplasmic crystalline structures of conceptus trophectoderm. Galectin-15 is hypothesised to function extracellularly to regulate trophectoderm migration and adhesion to the endometrial epithelium and intracellularly to regulate cell survival, growth and differentiation. In sheep, the sequential actions of ovarian steroid hormones (oestrogen and progesterone), interferon tau, placental lactogen and placental growth hormone constitute a servomechanism that directly regulates endometrial gland morphogenesis and terminal differentiated function to provide increasing histotrophic nutrition for conceptus growth and development. Knowledge gained from this research will be used to prevent or treat infertility, fetal growth retardation and disease in domestic animals and humans.

scholarly journals Glycosylation of Cancer Extracellular Vesicles: Capture Strategies, Functional Roles and Potential Clinical Applications

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 109
Author(s):  
Álvaro M. Martins ◽  
Cátia C. Ramos ◽  
Daniela Freitas ◽  
Celso A. Reis
Keyword(s):  
Extracellular Vesicles ◽  
Biomarker Discovery ◽  
De Novo ◽  
Recipient Cell ◽  
Cell Communication ◽  
Cancer Biomarkers ◽  
Functional Roles ◽  
Molecular Information ◽  
Glycosylation Pathway ◽  
Organ Tropism

Glycans are major constituents of extracellular vesicles (EVs). Alterations in the glycosylation pathway are a common feature of cancer cells, which gives rise to de novo or increased synthesis of particular glycans. Therefore, glycans and glycoproteins have been widely used in the clinic as both stratification and prognosis cancer biomarkers. Interestingly, several of the known tumor-associated glycans have already been identified in cancer EVs, highlighting EV glycosylation as a potential source of circulating cancer biomarkers. These particles are crucial vehicles of cell–cell communication, being able to transfer molecular information and to modulate the recipient cell behavior. The presence of particular glycoconjugates has been described to be important for EV protein sorting, uptake and organ-tropism. Furthermore, specific EV glycans or glycoproteins have been described to be able to distinguish tumor EVs from benign EVs. In this review, the application of EV glycosylation in the development of novel EV detection and capture methodologies is discussed. In addition, we highlight the potential of EV glycosylation in the clinical setting for both cancer biomarker discovery and EV therapeutic delivery strategies.

scholarly journals Differential Expression Pattern of Goat Uterine Fluids Extracellular Vesicles miRNAs during Peri-Implantation

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2308
Author(s):  
Yanshe Xie ◽  
Guangbin Liu ◽  
Xupeng Zang ◽  
Qun Hu ◽  
Chen Zhou ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Small Rnas ◽  
Target Genes ◽  
Embryo Implantation ◽  
Mature Embryo ◽  
Luciferase Reporter ◽  
Small Rna Sequencing ◽  
Transmission Electron ◽  
Differential Expression Pattern ◽  
Endometrial Epithelium

Early pregnancy failure occurs when a mature embryo attaches to an unreceptive endometrium. During the formation of a receptive endometrium, extracellular vesicles (EVs) of the uterine fluids (UFs) deliver regulatory molecules such as small RNAs to mediate intrauterine communication between the embryo and the endometrium. However, profiling of small RNAs in goat UFs’ EVs during pregnancy recognition (day 16) has not been carried out. In this study, EVs were isolated from UFs on day 16 of the estrous cycle or gestation. They were isolated by Optiprep™ Density G radient (ODG) and verified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. Immunostaining demonstrated that CD63 was present both in the endometrial epithelium and glandular epithelium, and stain intensity was greater in the pregnant endometrium compared to the non-pregnant endometrium. Small RNA sequencing revealed that UFs’ EVs contained numerous sRNA families and a total of 106 differentially expressed miRNAs (DEMs). Additionally, 1867 target genes of the DEMs were obtained, and miRNA–mRNA interaction networks were constructed. GO and KEGG analysis showed that miRNAs were significantly associated with the formation of a receptive endometrium and embryo implantation. In addition, the fluorescence in situ hybridization assay (FISH) showed that chi-miR-451-5p was mainly expressed in stromal cells of the endometrium and a higher level was detected in the endometrial luminal epithelium in pregnant states. Moreover, the dual-luciferase reporter assay showed that chi-miR-451-5p directly binds to PSMB8 and may play an important role in the formation of a receptive endometrium and embryo implantation. In conclusion, these results reveal that UFs’ EVs contain various small RNAs that may be vital in the formation of a receptive endometrium and embryo implantation.

Sulfated glycoprotein-1 (SGP-1) expression in ovine endometrium during the oestrous cycle and early pregnancy

1995 ◽  
Vol 7 (5) ◽  
pp. 1053 ◽  
Author(s):  
TE Spencer ◽  
GH Graf ◽  
FW Bazer
Keyword(s):  
Early Pregnancy ◽  
Blot Hybridization ◽  
Immunohistochemical Localization ◽  
Oestrous Cycle ◽  
Northern Hybridization ◽  
Mrna Levels ◽  
Slot Blot ◽  
Slot Blot Hybridization ◽  
Endometrial Epithelium ◽  
Sulfated Glycoprotein

This study determined effects of day of oestrous cycle and early pregnancy on sulfated glycoprotein-1 (SGP-1) expression in ovine endometrium. A 364-bp clone of the ovine SGP-1 mRNA was amplified from reverse transcribed Day-15 cyclic endometrial mRNA using the polymerase chain reaction (PCR) and primers specific for the rat SGP-1 mRNA sequence. Nucleotide sequence of the ovine SGP-1 cDNA shared significant identity with rat SGP-1 and human prosaposin. Ewes (n = 40) were hysterectomized on either Day 1, 6, 11, 13 or 15 of the oestrous cycle or on Day 11, 13, 15, 17 or 25 of early pregnancy. Total cellular RNA was isolated from endometrium and subjected to Northern and slot blot hybridization analyses using an antisense cRNA probe transcribed from the ovine SGP-1 cDNA clone. A single 2.6-kb mRNA transcript was detected by Northern hybridization analyses. Slot blot hybridization analyses indicated that steady-state levels of endometrial SGP-1 mRNA varied during the oestrous cycle (cubic, P < 0.02) and increased between Day 11 and Day 25 of early pregnancy (linear, P < 0.01). On Days 11, 13 and 15, endometrial SGP-1 mRNA levels were greater in pregnant ewes than in cyclic ewes (day x pregnancy status, P < 0.01). Immunohistochemical localization of SGP-1 in uterine tissues with rabbit anti-rat SGP-1 antibody revealed intense immunoreactivity associated primarily with the endometrial epithelium. These results indicate that the ovine endometrium expresses SGP-1, a prosaposin, and that SGP-1 expression varies during the oestrous cycle and is enhanced by the conceptus. The presence of SGP-1 in the endometrium suggests intracellular and extracellular roles for this protein in glycosphingolipid metabolism or transport in the uterine environment.

scholarly journals Extracellular Vesicles in Inflammatory Bowel Disease: Small Particles, Big Players

2020 ◽  
Author(s):  
M Valter ◽  
S Verstockt ◽  
J A Finalet Ferreiro ◽  
I Cleynen
Keyword(s):  
Inflammatory Bowel Disease ◽  
Extracellular Vesicles ◽  
Bowel Disease ◽  
Intestinal Barrier ◽  
Cell Types ◽  
Physiological Status ◽  
Intestinal Epithelial ◽  
Functional Roles ◽  
Physiological Processes ◽  
Inflammatory Bowel

Abstract Extracellular vesicles are nanovesicles released by many cell types into the extracellular space. They are important mediators of intercellular communication, enabling the functional transfer of molecules from one cell to another. Moreover, their molecular composition reflects the physiological status of the producing cell and tissue. Consequently, these vesicles have been involved in many [patho]physiological processes such as immunomodulation and intestinal epithelial repair, both key processes involved in inflammatory bowel disease. Given that these vesicles are present in many body fluids, they also provide opportunities for diagnostic, prognostic, and therapeutic applications. In this review, we summarise functional roles of extracellular vesicles in health and disease, with a focus on immune regulation and intestinal barrier integrity, and review recent studies on extracellular vesicles and inflammatory bowel disease. We also elaborate on their clinical potential in inflammatory bowel disease.

scholarly journals Oral extracellular vesicles in early pregnancy can identify patients at risk of developing gestational diabetes mellitus

PLoS ONE ◽  
2019 ◽  
Vol 14 (6) ◽  
pp. e0218616 ◽  
Author(s):  
Lara J. Monteiro ◽  
Manuel Varas-Godoy ◽  
Max Monckeberg ◽  
Ornella Realini ◽  
Marcela Hernández ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
At Risk ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Extracellular Vesicles ◽  
Early Pregnancy ◽  
Patients At Risk

scholarly journals Cortisol and Interferon Tau Regulation of Endometrial Function and Conceptus Development in Female Sheep

Endocrinology ◽  
2012 ◽  
Vol 154 (2) ◽  
pp. 931-941 ◽  
Author(s):  
Piotr Dorniak ◽  
Thomas H. Welsh ◽  
Fuller W. Bazer ◽  
Thomas E. Spencer
Keyword(s):  
Early Pregnancy ◽  
Reductase Activity ◽  
In Utero ◽  
Selective Inhibitor ◽  
Biological Role ◽  
Interferon Tau ◽  
Uterine Lumen ◽  
Conceptus Development ◽  
Female Sheep ◽  
Expression And Activity

During early pregnancy in sheep, the elongating conceptus secretes interferon-τ (IFNT) and the conceptus as well as endometrial epithelia produce prostaglandins (PG) via PG synthase 2 (PTGS2) and cortisol via hydroxysteroid (11-β) dehydrogenase 1 (HSD11B1). Ovarian progesterone induces and PG and IFNT stimulates endometrial HSD11B1 expression and keto-reductase activity as well as many epithelial genes that govern trophectoderm proliferation, migration, and attachment during elongation. The primary aim of these studies was to test the hypothesis that HSD11B1-derived cortisol has a biological role in endometrial function and conceptus development during early pregnancy in sheep. In study 1, cyclic ewes received vehicle, cortisol, PF 915275 (PF; a selective inhibitor of HSD11B1), cortisol and PF, meloxicam (a selective inhibitor of PTGS2), cortisol and meloxicam, recombinant ovine IFNT, or IFNT and PF into the uterus from day 10 to day14 after estrus. Cortisol and IFNT stimulated endometrial HSD11B1 expression and activity, increased endometrial PTGS2 activity and the amount of PG in the uterine lumen, and up-regulated many conceptus elongation-related genes in the endometrium. Some effects of cortisol and IFNT were mediated by PTGS2-derived PG. In study 2, bred ewes received PF 915275 or recombinant ovine IFNT and into the uterus from day 10 to day 14 after mating. Inhibition of HSD11B1 activity in utero prevented conceptus elongation, whereas IFNT rescued conceptus elongation in PF-infused ewes. These results suggest that HSD11B1-derived cortisol mediates, in part, actions of ovarian progesterone and the conceptus on endometrial function and support the hypothesis that IFNT, PG, and cortisol coordinately regulate endometrial functions important for conceptus elongation and implantation during early pregnancy in sheep.

scholarly journals Endometrial epithelial ARID1A is critical for uterine gland function in early pregnancy establishment

2020 ◽  
Author(s):  
Ryan M. Marquardt ◽  
Tae Hoon Kim ◽  
Jung-Yoon Yoo ◽  
Hanna E. Teasley ◽  
Asgerally T. Fazleabas ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Adult Mouse ◽  
Endometrial Receptivity ◽  
Pathophysiological Mechanism ◽  
Endometrial Gland ◽  
Uterine Gland ◽  
Endometrial Epithelium ◽  
Gland Function ◽  
Gland Development ◽  
Specific Deletion

AbstractThough endometriosis and infertility are clearly associated, the pathophysiological mechanism remains unclear. Previous work has linked endometrial ARID1A loss to endometriosis-related endometrial non-receptivity. Here, we show in mice that ARID1A binds and regulates transcription of the Foxa2 gene required for endometrial gland function. Uterine specific deletion of Arid1a compromises gland development and diminishes Foxa2 and Lif expression. Deletion of Arid1a with Ltf-iCre in the adult mouse endometrial epithelium preserves gland development while still compromising gland function. Mice lacking endometrial epithelial Arid1a are severely sub-fertile due to defects in implantation, decidualization, and endometrial receptivity from disruption of the LIF-STAT3-EGR1 pathway. FOXA2 is also reduced in the endometrium of women with endometriosis in correlation with diminished ARID1A, and both ARID1A and FOXA2 are reduced in non-human primates induced with endometriosis. Our findings describe a role for ARID1A in the endometrial epithelium supporting early pregnancy establishment through the maintenance of gland function.

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