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CXCL12 enhances pregnancy outcome via improvement of endometrial receptivity in mice.

ABSTRACT: Successful pregnancy inevitably depends on the implantation of a competent embryo into a receptive endometrium. Although many substances have been suggested to improve the rate of embryo implantation targeting enhancement of endometrial receptivity, currently there rarely are effective evidence-based treatments to prevent or cure this condition. Here we strongly suggest minimally-invasive intra-uterine administration of embryo-secreted chemokine CXCL12 as an effective therapeutic intervention. Chemokine CXCL12 derived from pre- and peri-implanting embryos significantly enhances the rates of embryo attachment and promoted endothelial vessel formation and sprouting in vitro. Consistently, intra-uterine CXCL12 administration in C57BL/6 mice improved endometrial receptivity showing increased integrin β3 and its ligand osteopontin, and induced endometrial angiogenesis displaying increased numbers of vessel formation near the lining of endometrial epithelial layer with higher CD31 and CD34 expression. Furthermore, intra-uterine CXCL12 application dramatically promoted the rates of embryo implantation with no morphologically retarded embryos. Thus, our present study provides a novel evidence that improved uterine endometrial receptivity and enhanced angiogenesis induced by embryo-derived chemokine CXCL12 may aid to develop a minimally-invasive therapeutic strategy for clinical treatment or supplement for the patients with repeated implantation failure with less risk.

SUBMITTER: Koo HS

PROVIDER: S-EPMC8016928 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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CXCL12 enhances pregnancy outcome via improvement of endometrial receptivity in mice.

Koo Hwa Seon HS Yoon Min-Ji MJ Hong Seon-Hwa SH Ahn Jungho J Cha Hwijae H Lee Danbi D Ko Ji-Eun JE Kwon Hwang H Choi Dong Hee DH Lee Kyung-Ah KA Ko Jung-Jae JJ Kang Youn-Jung YJ

Scientific reports 20210401 1

Successful pregnancy inevitably depends on the implantation of a competent embryo into a receptive endometrium. Although many substances have been suggested to improve the rate of embryo implantation targeting enhancement of endometrial receptivity, currently there rarely are effective evidence-based treatments to prevent or cure this condition. Here we strongly suggest minimally-invasive intra-uterine administration of embryo-secreted chemokine CXCL12 as an effective therapeutic intervention. C ...[more]

PMID: 33795831

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Project description:PurposeAdenomyosis has a negative impact on female fertility. GnRH agonist treatment can improve pregnancy outcomes in women with adenomyosis. However, the impact of GnRH agonist upon endometrium receptivity of patients with adenomyosis remains unclear. In this study, endometrial receptivity and pregnancy outcome were investigated using a mouse model of adenomyosis.Materials and methodsAdenomyosis was induced in 12 female ICR mice, neonatally treated with tamoxifen, while another six female mice (control group) received solvent only. At 75 days, the induced adenomyosis group was randomly divided into two groups: an untreated group and a group treated with GnRH agonist (n = 6 each). Sixty days later, the mice were mated and pregnancy outcomes were observed and compared among the three groups (n = 6 each). In a parallel experiment using the same treatment regimes, uterus samples were collected on day 4 of pregnancy for immunohistochemistry, gene (quantitative polymerase chain reaction) and protein expression (Western blot), and scanning electron microscopy analyses.ResultsWe found that the average live litter size was reduced in the adenomyosis compared with control group (8 ± 0.56 versus 13 ± 0.71; P = 0.03). However, the litter size was significantly increased in the treated with GnRH agonist group compared with the untreated group (12 ± 0.35 versus 8 ± 0.56; P = 0.04). The uterine expression levels of Hoxa10, Hoxa11, Lif and integrin b3 mRNA and protein were decreased in the adenomyosis group, and were significantly increased after GnRH agonist treatment. Additionally, pinopodes were reduced in number and poorly developed in mice with induced adenomyosis. However, pinopodes were abundant and well-developed in the GnRH agonist treatment group.ConclusionAdenomyosis may have an adverse impact on endometrial receptivity and reduce pregnancy outcomes in mice. However, GnRH agonist may improve the pregnancy outcome by partially restoring endometrial receptivity.

Project description:BackgroundAdenomyosis is a common gynecological disease which seriously impacts female fertility and is increasing in incidence in women of childbearing age. Melatonin has beneficial effects on reproductive processes. However, its impact on the uterine receptivity of patients with adenomyosis remains unclear. In this study, we investigated the effect of melatonin on uterine receptivity and pregnancy outcomes in an adenomyosis mouse model.MethodsWe induced an adenomyosis mouse model by oral administration of tamoxifen to neonatal female CD-1 mice, then conducted a melatonin injection experiment to investigate its effect on implantation rates (n=6 each). In a second experiment, the endometrium in the implantation state was collected to identify the local action of melatonin on adenomyosis mice (n=6 each), and in a parallel study, the pregnancy rate and number of offspring were recorded (n=6 each).ResultsThe number of implantation sites in the adenomyosis model mice was much less than in control group (5.0±2.10 vs. 13.3±2.38, P<0.0001), and 30 mg/kg of melatonin significantly improved this (9.0±0.63 vs. 5.0±2.10, P=0.002). Additionally, melatonin administration ameliorated the impaired endometrial receptivity [leukemia inhibitory factor (LIF), integrin β3, homeobox A10 (HoxA10), and HoxA11], and improved the endometrium development [endometrial area (EA) and endometrial thickness index (ETI)] and pregnancy outcomes. Furthermore, the expression of implantation-related genes (Era, Pra, and P53), inflammatory factors [tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)], oxidative stress associated genes (Gpx1 and Sod1), and apoptosis-related genes or proteins (Bax, Bcl-2, caspase-3, and cleaved caspase-3) was detected. The results showed higher local levels of reactive oxygen species (ROS) and inflammatory cytokines in the uterus of an adenomyosis model mice induced endometrial cells apoptosis and tissue damage, changed the uterine microenvironment, affected embryo implantation, and reduced the fertility of adenomyosis. Interestingly, melatonin significantly mitigated adenomyosis-induced changes by inhibiting the nuclear factor kappa B (NF-κB) signaling pathway, increasing the vascular endothelial growth factor (VEGF) expression, decreasing the endometrial cells apoptosis, and improving pregnancy outcomes.ConclusionsMelatonin treatment restored impaired uterine development and endometrial receptivity of adenomyosis mice by improving the endometrial microenvironment via the NF-κB/apoptosis signaling pathway. Our results provided new insight into melatonin-based therapy for adenomyosis-related infertility.

Project description:BackgroundReceptivity of the uterus is essential for embryo implantation and progression of mammalian pregnancy. Acquisition of receptivity involves major molecular and cellular changes in the endometrial lining of the uterus from a non-receptive state at ovulation, to a receptive state several days later. The precise molecular mechanisms underlying this transition and their upstream regulators remain to be fully characterized. Here, we aimed to generate a comprehensive profile of the endometrial transcriptome in the peri-ovulatory and peri-implantation states, to define the genes and gene pathways that are different between these states, and to identify new candidate upstream regulators of this transition, in the mouse.ResultsHigh throughput RNA-sequencing was utilized to identify genes and pathways expressed in the endometrium of female C57Bl/6 mice at estrus and on day 3.5 post-coitum (pc) after mating with BALB/c males (n = 3-4 biological replicates). Compared to the endometrium at estrus, 388 genes were considered differentially expressed in the endometrium on day 3.5 post-coitum. The transcriptional changes indicated substantial modulation of uterine immune and vascular systems during the pre-implantation phase, with the functional terms Angiogenesis, Chemotaxis, and Lymphangiogenesis predominating. Ingenuity Pathway Analysis software predicted the activation of several upstream regulators previously shown to be involved in the transition to receptivity including various cytokines, ovarian steroid hormones, prostaglandin E2, and vascular endothelial growth factor A. Our analysis also revealed four candidate upstream regulators that have not previously been implicated in the acquisition of uterine receptivity, with growth differentiation factor 2, lysine acetyltransferase 6 A, and N-6 adenine-specific DNA methyltransferase 1 predicted to be activated, and peptidylprolyl isomerase F predicted to be inhibited.ConclusionsThis study confirms that the transcriptome of a receptive uterus is vastly different to the non-receptive uterus and identifies several genes, regulatory pathways, and upstream drivers not previously associated with implantation. The findings will inform further research to investigate the molecular mechanisms of uterine receptivity.

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CXCL12 enhances pregnancy outcome via improvement of endometrial receptivity in mice.

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CXCL12 enhances pregnancy outcome via improvement of endometrial receptivity in mice.

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