Development of a vaginally applied, non-hormonal contraceptive: the contraceptive efficacy and impact on bone turnover of PEGLA, a long-acting LIF antagonist

Menkhorst, Ellen; Zhang, J.G.; Morgan, Phillip O.; Poulton, Ingrid J; Metcalf, Donald; Salamonsen, Lois A.; Sims, Natalie A.; Nicola, N.A.

doi:10.1016/j.jri.2010.06.062

Cited by 3 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, E-cadherin (ECAD) mRNA was not regulated by MDM2 in the endometrial epithelium. LIF is reported to regulate implantation in humans (Cullinan et al 1996;Vogiagis et al 1996;Laird et al 1997) and is required for implantation in mice (Stewart et al 1992;White et al 2007;Menkhorst et al 2010Menkhorst et al , 2011. LIF mRNA was significantly reduced in Ishikawa cells and HEECs in response to MDM2 knockdown, which further supports a role for MDM2 in endometrial receptivity and implantation.…”

Section: Discussionsupporting

confidence: 52%

Mouse double minute homologue 2 (MDM2) downregulation by miR-661 impairs human endometrial epithelial cell adhesive capacity

Winship

Ton

Sinderen

et al. 2018

Reprod. Fertil. Dev.

View full text Add to dashboard Cite

Human blastocysts that fail to implant following IVF secrete elevated levels of miR-661, which is taken up by primary human endometrial epithelial cells (HEECs) and impairs their adhesive capability. MicroRNA miR-661 downregulates mouse double minute homologue 2 (MDM2) and MDM4 in other epithelial cell types to activate p53; however, this has not been examined in the endometrium. In this study MDM2 protein was detected in the luminal epithelium of the endometrium, the site of blastocyst attachment, during the mid secretory receptive phase of the menstrual cycle. The effects of miR-661 on gene expression in and adhesion of endometrial cells was also examined. MiR-661 overexpression consistently downregulated MDM2 but not MDM4 or p53 gene expression in the Ishikawa endometrial epithelial cell line and primary HEEC. Adhesion assays were performed on the real-time monitoring xCELLigence system and by co-culture using Ishikawa cells and HEECs with HTR8/SVneo trophoblast spheroids. Targeted siRNA-mediated knockdown of MDM2 in endometrial epithelial cells reduced Ishikawa cell adhesion (P<0.001) and also reduced HTR8/SVneo trophoblast spheroid adhesion to Ishikawa cells (P<0.05) and HEECs (P<0.05). MDM2 overexpression using recombinant protein treatment resulted in enhanced HTR8/SVneo trophoblast spheroid adhesion to Ishikawa cells (P<0.01) and HEECs (P<0.05). This study highlights a potential new mechanism by which human blastocyst-secreted miR-661 reduces endometrial epithelial cell adhesion; via downregulation of MDM2. These findings suggest that MDM2 contributes to endometrial-blastocyst adhesion, implantation and infertility in women.

show abstract

Section: Discussionsupporting

confidence: 52%

Mouse double minute homologue 2 (MDM2) downregulation by miR-661 impairs human endometrial epithelial cell adhesive capacity

Winship

Ton

Sinderen

et al. 2018

Reprod. Fertil. Dev.

View full text Add to dashboard Cite

show abstract

“…LA was covalently conjugated to PEG (PEGLA) to increase the period of serum retention [ 28 ]. To inhibit LIF action, mated female mice were administered by intraperitoneal (IP) injection with 600μg/dose PEGLA (20mg/kg/dose) or equal molarity PEG as a control (as optimized previously [ 17 , 29 , 30 ]), twice daily at E8-10 or E10-13 (n = 4 mice/group). Mice were killed at E10 or E13 of pregnancy respectively, on the final day of PEGLA treatment.…”

Section: Methodsmentioning

confidence: 99%

Leukemia Inhibitory Factor (LIF) Inhibition during Mid-Gestation Impairs Trophoblast Invasion and Spiral Artery Remodelling during Pregnancy in Mice

et al. 2015

View full text Add to dashboard Cite

The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Trophoblast cell proliferation, migration and invasion into the endometrium are fundamental events in the initiation of placentation. Leukemia inhibitory factor (LIF) has been shown to promote trophoblast invasion in vitro, however its precise role in trophoblast invasion in vivo is unknown. We hypothesized that LIF would be required for normal trophoblast invasion and spiral artery remodeling in mice. Both LIF and its receptor (LIFRα) co-localized with cytokeratin-positive invasive endovascular extravillous trophoblasts (EVT) in mouse implantation sites during mid-gestation. Temporally blocking LIF action during specific periods of placental development via administration of our unique LIFRα antagonist, PEGLA, resulted in abnormal trophoblast invasion and impaired spiral artery remodeling compared to PEG control. PEGLA-treated mouse decidual vessels were characterized by retention of α-smooth muscle actin (αSMA)-positive vascular smooth muscle cells (VSMCs), while PEG control decidual vessels were remodelled by cytokeratin-positive trophoblasts. LIF blockade did not alter F4/80-positive decidual macrophage numbers between treatment groups, but resulted in down-regulation of decidual transcript levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10), which are important immune cell activation factors that promote spiral artery remodeling during pregnancy. Our data suggest that LIF plays an important role in trophoblast invasion in vivo and may facilitate trophoblast-decidual-immune cell cross talk to enable adequate spiral artery remodeling.

show abstract

“…LA was covalently bound to PEG (PEGLA) to increase the period of sera retention 49 . To inhibit LIF action in the placenta, mated female mice were injected IP with 600 μg/dose PEGLA (20 mg/kg/dose) or equal molarity PEG as a control (as optimized previously based on serum half life studies and in vivo dose response studies 18 35 55 , twice daily at E6–8, E8–10, E10–13 or E10–17) (n = 4 mice/group). Mice were weighed and killed at E10, E13 or E17 of pregnancy respectively, or allowed to deliver at term.…”

Section: Methodsmentioning

confidence: 99%

Blocking Endogenous Leukemia Inhibitory Factor During Placental Development in Mice Leads to Abnormal Placentation and Pregnancy Loss

Winship

Correia

Krishnan

et al. 2015

Sci Rep

View full text Add to dashboard Cite

The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Specialized trophoblast cells derived from the embryonic trophectoderm play a pivotal role in the establishment of the placenta. Leukemia inhibitory factor (LIF) is one of the predominant cytokines present in the placenta during early pregnancy. LIF has been shown to regulate trophoblast adhesion and invasion in vitro, however its precise role in vivo is unknown. We hypothesized that LIF would be required for normal placental development in mice. LIF and LIFRα were immunolocalized to placental trophoblasts and fetal vessels in mouse implantation sites during mid-gestation. Temporally blocking LIF action during specific periods of placental development via intraperitoneal administration of our specific LIFRα antagonist, PEGLA, resulted in abnormal placental trophoblast and vascular morphology and reduced activated STAT3 but not ERK. Numerous genes regulating angiogenesis and oxidative stress were altered in the placenta in response to LIF inhibition. Pregnancy viability was also significantly compromised in PEGLA treated mice. Our data suggest that LIF plays an important role in placentation in vivo and the maintenance of healthy pregnancy.

show abstract

Development of a vaginally applied, non-hormonal contraceptive: the contraceptive efficacy and impact on bone turnover of PEGLA, a long-acting LIF antagonist

Cited by 3 publications

References 0 publications

Mouse double minute homologue 2 (MDM2) downregulation by miR-661 impairs human endometrial epithelial cell adhesive capacity

Mouse double minute homologue 2 (MDM2) downregulation by miR-661 impairs human endometrial epithelial cell adhesive capacity

Leukemia Inhibitory Factor (LIF) Inhibition during Mid-Gestation Impairs Trophoblast Invasion and Spiral Artery Remodelling during Pregnancy in Mice

Blocking Endogenous Leukemia Inhibitory Factor During Placental Development in Mice Leads to Abnormal Placentation and Pregnancy Loss

Contact Info

Product

Resources

About