Mouse model of human infertility: Transient and local inhibition of endometrial STAT‐3 activation results in implantation failure

Nakamura, Hitomi; Kimura, Tadashi; Koyama, Shinsuke; Ogita, Kazuhide; Tsutsui, Tateki; Shimoya, Koichiro; Taniguchi, Takeshi; Koyama, Masayasu; Kaneda, Yasufumi; Murata, Yuji

doi:10.1016/j.febslet.2006.04.029

Cited by 56 publications

(42 citation statements)

References 31 publications

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“…In contrast, some studies suggest that RacGAP1 is able to mediate some of its functions independently of its GAP activity (38). Recently, RacGAP1 has also been implicated in regulating the localization and transcriptional activity of signal transducer and activation of transcription (STAT) proteins (39,40), a family of proteins that have been strongly implicated in the stromal decidualization response and embryo implantation (41). Here, we have shown that hESC Rac-GAP1 levels are down-regulated in response to human embryos and that this correlates with an increase in Rac1 activity observed in hESCs.…”

Section: Discussionmentioning

confidence: 97%

Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration

Grewal

Carver

Ridley

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

162

140

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Failure of the human embryo to implant into the uterine wall during the early stages of pregnancy is a major cause of infertility. Implantation involves embryo apposition and adhesion to the endometrial epithelium followed by penetration through the epithelium and invasion of the embryonic trophoblast through the endometrial stroma. Although gene-knockdown studies have highlighted several molecules that are important for implantation in the mouse, the molecular mechanisms controlling implantation in the human are unknown. Here, we demonstrate in an in vitro model for human implantation that the Rho GTPases Rac1 and RhoA in human endometrial stromal cells modulate invasion of the human embryo through the endometrial stroma. We show that knockdown of Rac1 expression in human endometrial stromal cells inhibits human embryonic trophoblast invasion into stromal cell monolayers, whereas inhibition of RhoA activity promotes embryo invasion. Furthermore, we demonstrate that Rac1 is required for human endometrial stromal cell migration and that the motility of the stromal cells increases at implantation sites. This increased motility correlates with a localized increase in Rac1 activation and a reciprocal decrease in RacGAP1 levels. These results reveal embryo-induced and localized endometrial responses that may govern implantation of the human embryo.human trophoblast invasion ͉ implantation in vitro ͉ Rac-1 activation ͉ RacGAP1 ͉ Rho GTPases

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Section: Discussionmentioning

confidence: 97%

Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration

Grewal

Carver

Ridley

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

162

140

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“…Anti-LIF polyclonal antibodies administered directly into the uterus interfere with blastocyst implantation in the rhesus monkey (24) and in the mouse (25), but neither method completely prevents implantation. Intrauterine injection of a cell-permeable STAT3 peptide inhibitor (26) or a STAT3 decoy oligodeoxynucleotide (27) achieved Ϸ70% reduction in implantation rates. In contrast, both forms of our highly potent LIF antagonist were 100% effective in blocking implantation and were effective via the systemic i.p.…”

Section: Discussionmentioning

confidence: 99%

Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy

White¹,

Zhang

Salamonsen³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Blastocyst implantation is a critical stage in the establishment of pregnancy. Leukemia inhibitory factor (LIF) is essential for mouse blastocyst implantation and also plays a role in human pregnancy. We examined the effect of a potent LIF antagonist (LA) on mouse implantation. In mice, LIF expression peaks on day 3.5 of pregnancy (D3.5) (D0.5 ‫؍‬ day of mating plug detection) in the uterine glandular epithelium. LA (7 mg/kg per day) administered from D2.5 to D4.5 via four hourly i.p. injections plus continuous administration via miniosmotic pump resulted in complete implantation failure. To improve its pharmacokinetic properties, we conjugated LA to polyethylene glycol (PEG), achieving a significant increase in serum levels. PEGylated LA (PEGLA) (37.5 mg/kg per day) administered via three i.p. injections between D2.5 and D3.5 also resulted in complete implantation failure. PEGLA immunolocalized to the uterine luminal epithelium at the time of blastocyst implantation. Both LA and PEGLA reduced phosphorylation of the downstream signaling molecule STAT3 in luminal epithelial cells on D3.5. The effects of PEGLA were found to be endometrial, with no embryolethal effects observed. These data demonstrate that administration of a PEGylated LIF antagonist is an effective method of targeting LIF signaling in the endometrium and a promising novel approach in the development of nonhormonal contraceptives for women.embryo implantation ͉ leukemia inhibitory factor ͉ mouse

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“…indicating that STAT3 activation in endometrium was associated with endometrial receptivity to implantation in rodents (Liu & Ogle 2002, Catalano et al 2005, Nakamura et al 2006). It appears therefore apparently contradictory that the relative abundance of transcripts for JAK1 and STAT3 were higher in anti-progestin (mifepristone)-treated endometrium in the present study.…”

Section: Implantation-stage Endometrial Transcript Profilesmentioning

confidence: 99%

Effect of low-dose mifepristone administration on day 2 after ovulation on transcript profiles in implantation-stage endometrium of rhesus monkeys

Ghosh¹,

Sharkey²,

Charnock-Jones³

et al. 2009

Reproduction

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Progesterone is essential for endometrial receptivity in primates. In studies previously performed using global gene profiling based on microarray technology, attempts have been made to identify changes in gene expression between early luteal-phase and mid-luteal-phase endometria. However, the issue of the putative impact of preimplantation embryo-derived signal in the process of endometrial receptivity was missing in the previous studies. In the present study, an attempt has been made to delineate the transcripts profile in implantation-stage endometrium under combinatorial regulation of progesterone and embryo-derived signal in the rhesus monkey. To this effect, we have compared transcript profiles for 409 known genes between control receptive stage (nZ13), and mifepristone-induced desynchronized and non-receptive stage (nZ12) monkey endometrial samples collected on days 4 (nZ12) and 6 (nZ13) after ovulation from mated, potential conception cycles, using cDNA arrays containing sequence-verified clones. Statistical analysis of correlation of estimated transcript abundance between arrays and qRT-PCR for nine selected gene products yielded significant (P!0.05) concordance. Of 409 genes, a total of 40 gene transcripts were seen to be affected, nine gene transcripts in endometrial samples were found to progressively increase between days 4 and 6 following mifepristone treatment, while an additional five genes showed differential expression profile depending on the day after treatment. Additionally, different sets of 12 and 14 gene products showed changes in days 4 and 6 post-ovulation samples respectively. A new cohort of 28 gene products in implantation-stage endometrium was seen to be affected by luteal-phase mifepristone.

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Mouse model of human infertility: Transient and local inhibition of endometrial STAT‐3 activation results in implantation failure

Cited by 56 publications

References 31 publications

Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration

Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration

Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy

Effect of low-dose mifepristone administration on day 2 after ovulation on transcript profiles in implantation-stage endometrium of rhesus monkeys

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