Spatiotemporally distinct roles of cyclooxygenase-1 and cyclooxygenase-2 at fetomaternal interface in mice.

Embryo implantation is crucial for ensuring a successful pregnancy outcome and subsequent child health. The intrauterine environment during the peri-implantation period shows drastic changes in gene expression and cellular metabolism in response to hormonal stimuli and reciprocal communication with embryos. Here, we performed spatial transcriptomic analysis to elucidate the mechanisms underlying embryo implantation. Transcriptome data revealed that lipid metabolism pathways, especially arachidonic acid-related (AA-related) ones, were enriched in the embryo-receptive luminal epithelia. Cyclooxygenases (COXs), rate-limiting enzymes involved in prostaglandin production by AA, were spatiotemporally regulated in the vicinity of embryos during implantation, but the role of each COX isozyme in the uterus for successful pregnancy was unclear. We established uterine-specific COX2-knockout (uKO) and COX1/uterine COX2-double-KO (COX1/COX2-DKO) mice. COX2 uKO caused deferred implantation with failed trophoblast invasion, resulting in subfertility with reduced pregnancy rates and litter sizes. COX1/COX2 DKO induced complete infertility, owing to abrogated embryo attachment. These results demonstrate that both isozymes have distinct roles during embryo implantation. Spatial transcriptome and lipidome analyses revealed unique profiles of prostaglandin synthesis by each COX isozyme and spatiotemporal expression patterns of downstream receptors throughout the endometrium. Our findings reveal previously unappreciated roles of COXs at the fetomaternal interface to establish early pregnancy.

Spatial and molecular anatomy of the endometrium during embryo implantation: a current overview of key regulators of blastocyst invasion.

Embryo implantation is composed of three steps: blastocyst apposition, adhesion/attachment and invasion. Blastocyst invasion has been studied less extensively than the other two events. Historically, studies conducted using electron microscopy have shown the removal of epithelial cells in the vicinity of the attached blastocysts in rodents, although the underlying mechanisms have remained unclear. Here, we describe recent studies using mice with uterine-specific gene deletion that demonstrated important roles for nuclear proteins such as progesterone receptor, hypoxia inducible factor and retinoblastoma in the regulation of embryo invasion. In these mouse models, the detachment of the endometrial luminal epithelium, decidualization in the stroma, and the activation of trophoblasts have been found to be important in ensuring embryo invasion. This review summarizes the molecular signaling associated with these cellular events, mainly evidenced by mouse models.

Pregnancy is associated with reduced progression of symptomatic adenomyosis: a retrospective pilot study.

BACKGROUND: Adenomyosis is a common gynecological disease in women of reproductive age and causes various symptoms such as dysmenorrhea and heavy menstrual bleeding. However, the influence of pregnancy on the progression of adenomyosis remains unclear. The insight into whether the size of adenomyosis is increased, decreased, or unchanged during pregnancy is also undetermined. The current study aimed to evaluate the influence of pregnancy in patients with symptomatic adenomyosis. METHODS: This study retrospectively enrolled patients diagnosed with adenomyosis by magnetic resonance imaging between 2015 and 2022 at The University of Tokyo Hospital. Uterine size changes were evaluated by two imaging examinations. In the pregnancy group, the patients did not receive any hormonal and surgical treatments, except cesarean section, but experienced pregnancy and delivery between the first and second imaging examinations. In the control group (nonpregnancy group), the patients experienced neither hormonal and surgical treatments nor pregnancy from at least 1 year before the first imaging to the second imaging. The enlargement rate of the uterine size per year (percentage) was calculated by the uterine volume changes (cm3) divided by the interval (years) between two imaging examinations. The enlargement rate of the uterine size per year was compared between the pregnancy group and the control group. RESULTS: Thirteen and 11 patients with symptomatic adenomyosis were included in the pregnancy group and in the control group, respectively. The pregnancy group had a lower enlargement rate per year than the control group (mean ± SE: -7.4% ± 3.6% vs. 48.0% ± 18.5%, P < 0.001), indicating that the size of the uterus with adenomyosis did not change in the pregnancy group. CONCLUSIONS: Pregnancy is associated with reduced progression of symptomatic adenomyosis.

The EZH2-PRC2-H3K27me3 axis governs the endometrial cell cycle and differentiation for blastocyst invasion.

Infertility occurs in 15% of couples worldwide. Recurrent implantation failure (RIF) is one of the major problems in in vitro fertilization and embryo transfer (IVF-ET) programs, and how to manage patients with RIF to achieve successful pregnancy outcomes remains unresolved. Here, a uterine polycomb repressive complex 2 (PRC2)-regulated gene network was found to control embryo implantation. Our RNA-seq analyses of the human peri-implantation endometrium obtained from patients with RIF and fertile controls revealed that PRC2 components, including its core enzyme enhancer of zeste homolog 2 (EZH2)-catalyzing H3K27 trimethylation (H3K27me3) and their target genes are dysregulated in the RIF group. Although fertility of uterine epithelium-specific knockout mice of Ezh2 (eKO mice) was normal, Ezh2-deleted mice in the uterine epithelium and stroma (uKO mice) exhibited severe subfertility, suggesting that stromal Ezh2 plays a key role in female fertility. The RNA-seq and ChIP-seq analyses revealed that H3K27me3-related dynamic gene silencing is canceled, and the gene expression of cell-cycle regulators is dysregulated in Ezh2-deleted uteri, causing severe epithelial and stromal differentiation defects and failed embryo invasion. Thus, our findings indicate that the EZH2-PRC2-H3K27me3 axis is critical to preparing the endometrium for the blastocyst invasion into the stroma in mice and humans.

Levonorgestrel-Releasing Intrauterine System Improves Menorrhagia-Related Quality of Life in Patients with Symptomatic Adenomyosis.

Levonorgestrel-releasing intrauterine system (LNG-IUS) relieves dysmenorrhea and heavy menstrual bleeding (HMB) in adenomyosis. However, its efficacy on health-related quality of life (HR-QOL) in patients with symptomatic adenomyosis remains unclear. The menorrhagia multi-attribute scale (MMAS), which measures HR-QOL improvement through the treatment of HMB, has never been used for evaluating menorrhagia-specific HR-QOL in patients with symptomatic adenomyosis. Hence, this study aimed to investigate the efficacy of LNG-IUS in improving menorrhagia-specific HR-QOL in these patients using the MMAS. The participants were diagnosed by magnetic resonance imaging. We also assessed the relationships between menorrhagia-specific HR-QOL, blood hemoglobin levels, and the degree of dysmenorrhea before and during LNG-IUS treatment. The LNG-IUS treatment improved the menorrhagia-specific HR-QOL more effectively in incipient type adenomyosis than in advanced type adenomyosis. The efficacy of LNG-IUS treatment on dysmenorrhea evaluated by the visual analog scale score tended to be better in the incipient type than in the advanced type. By the treatment of LNG-IUS, the blood hemoglobin level was not improved in the advanced type but in the incipient type. Furthermore, dysmenorrhea and HMB-related anemia were associated with HR-QOL impairment, and LNG-IUS treatment may improve the HR-QOL by relieving the symptoms. In conclusion, the effectiveness of LNG-IUS on HR-QOL is decreased by advanced adenomyosis. Thus, magnetic resonance imaging use should be reinforced to predict LNG-IUS efficacy in improving the HR-QOL of patients with adenomyosis.

DNA Methylation and Histone Modification Are the Possible Regulators of Preimplantation Blastocyst Activation in Mice.

Under ovarian hormone control, dormant blastocysts obtain implantation capacity (known as blastocyst activation) through their global gene expression. After the activated blastocysts communicate with the receptive uterus, the implantation-competent blastocysts start the implantation. Although dormant and activated blastocysts have different gene expression levels, the regulatory mechanisms underlying these transcriptions remain unclear. Hence, this study aimed to analyze epigenetic marks in dormant and activated blastocysts. In mice, blastocyst dormancy is artificially induced by daily progesterone injection without estrogen supplementation after peri-implantation ovariectomy; when estrogen is administered concomitantly, blastocyst activation and implantation occur. These phenomena demonstrate a mouse model of delayed implantation. We collected dormant and activated blastocysts from a delayed implantation mouse model. RNA-seq, methylated DNA immunoprecipitation (MeDIP)-seq, and chromatin immunoprecipitation (ChIP)-seq for H3K4 me3 and H3K27 me3 were performed using dormant and activated blastocysts. Cell cycle-related transcripts were affected during blastocyst activation. DNA methylations were accumulated in downregulated genes in the activated blastocysts. Histone H3 trimethylations were globally altered between the dormant and activated blastocysts. Dormant and activated blastocysts have unique methylation patterns on DNA and histone H3, with high correlation to gene expression. DNA methylation and histone modification can regulate preimplantation blastocyst activation.

A gene network of uterine luminal epithelium organizes mouse blastocyst implantation.

Purpose: The receptive endometrium is critical for blastocyst implantation. In mice, after blastocysts enter the uterine cavities on day 4 of pregnancy (day 1 = vaginal plug), blastocyst attachment is completed within 24 h, accompanied by dynamic interactions between the uterine luminal epithelium and the blastocysts. Any failures in this process compromise subsequent pregnancy outcomes. Here, we performed comprehensive analyses of gene expression at the luminal epithelium in the peri-implantation period. Methods: RNA-seq combined with laser microdissection (LMD) was used to reveal unique gene expression kinetics in the epithelium. Results: We found that the prereceptive epithelium on day 3 specifically expresses cell cycle-related genes. In addition, days 3 and 4 epithelia express glutathione pathway-related genes, which are protective against oxidative stresses. In contrast, day 5 epithelium expresses genes involved in glycolysis and the regulation of cell proliferation. The genes highly expressed on days 3 and 4 compared to day 5 are related to progesterone receptor signaling, and the genes highly expressed on day 5 compared to days 3 and 4 are associated with the ones regulated by H3K27me3. Conclusions: These results suggest that specific gene expression patterns govern uterine functions during early pregnancy, contributing to implantation success.

Constant Activation of STAT3 Contributes to the Development of Adenomyosis in Females.

Adenomyosis is a benign uterine disease that causes dysmenorrhea, heavy menstrual bleeding, and infertility; however, its pathophysiology remains unclear. Since signal transducer and activator of transcription 3 (STAT3) is crucial for endometrial regeneration, we hypothesized that STAT3 participates in adenomyosis pathophysiology. To investigate the influence of STAT3 on adenomyosis development, this study was performed using a novel mouse model of adenomyosis and human specimens of eutopic endometria and adenomyosis lesions. We established a novel mouse model of adenomyosis by puncturing entire mouse uterine layers with a thin needle. Mouse eutopic and ectopic endometria showed a positive immunoreactivity for phosphorylated STAT3 (pSTAT3), the active form of STAT3. Decreased numbers of adenomyotic lesions and reduced expression of Cxcl1, Icam1, and Spp1, which are associated with immune cell chemotaxis and tissue regeneration, were observed in uterine Stat3-deficient mice compared with the controls. In humans, pSTAT3 was intensely expressed at both the eutopic endometrium and the adenomyotic lesions regardless of the menstrual cycle phases. Conversely, it was limitedly expressed in the eutopic endometrium during the menstrual and proliferative phases in women without adenomyosis. Our findings indicate that continuous STAT3 activation promotes adenomyosis development. STAT3 inhibition can be a promising treatment strategy in patients with adenomyosis.

Uterine Receptivity is Reflected by LIF Expression in the Cervix.

Recurrent implantation failure is a major problem in assisted reproductive technology (ART). Although ART systems have evolved rapidly over the decades, it is still difficult to diagnose uterine conditions suitable for embryo transfer (ET) without the use of invasive endometrial procedures. Previous studies in mice showed that leukemia inhibitory factor (LIF) is a well-known endometrial biomarker for uterine implantation capacity, also known as uterine receptivity. This study focused on LIF in the mouse and human cervix as a possible biomarker of implantation capacity. We found that high expression of LIF in the cervical epithelium is strongly correlated with that of the uterine epithelium during the peri-implantation period in mice. Likewise, human cervical epithelia also exhibit elevated levels of LIF in the peri-implantation period. In addition, cervical LIF is downregulated in mice with defective implantation caused by pharmacological treatments. These results indicated that cervical LIF is a possible biomarker that detected uterine receptivity without invasive endometrial damage.

Uterine Epithelial LIF Receptors Contribute to Implantation Chamber Formation in Blastocyst Attachment.

Recent studies have demonstrated that the formation of an implantation chamber composed of a uterine crypt, an implantation-competent blastocyst, and uterine glands is a critical step in blastocyst implantation in mice. Leukemia inhibitory factor (LIF) activates signal transducer and activator of transcription 3 (STAT3) precursors via uterine LIF receptors (LIFRs), allowing successful blastocyst implantation. Our recent study revealed that the role of epithelial STAT3 is different from that of stromal STAT3. However, both are essential for blastocyst attachment, suggesting the different roles of epithelial and stromal LIFR in blastocyst implantation. However, how epithelial and stromal LIFR regulate the blastocyst implantation process remains unclear. To investigate the roles of LIFR in the uterine epithelium and stroma, we generated Lifr-floxed/lactoferrin (Ltf)-iCre (Lifr eKO) and Lifr-floxed/antimüllerian hormone receptor type 2 (Amhr2)-Cre (Lifr sKO) mice with deleted epithelial and stromal LIFR, respectively. Surprisingly, fertility and blastocyst implantation in the Lifr sKO mice were normal despite stromal STAT3 inactivation. In contrast, blastocyst attachment failed, and no implantation chambers were formed in the Lifr eKO mice with epithelial inactivation of STAT3. In addition, normal responsiveness to ovarian hormones was observed in the peri-implantation uteri of the Lifr eKO mice. These results indicate that the epithelial LIFR-STAT3 pathway initiates the formation of implantation chambers, leading to complete blastocyst attachment, and that stromal STAT3 regulates blastocyst attachment without stromal LIFR control. Thus, uterine epithelial LIFR is critical to implantation chamber formation and blastocyst attachment.

Retinoblastoma protein promotes uterine epithelial cell cycle arrest and necroptosis for embryo invasion.

Retinoblastoma protein (RB) encoded by Rb1 is a prominent inducer of cell cycle arrest (CCA). The hormone progesterone (P4 ) promotes CCA in the uterine epithelium and previous studies indicated that P4 activates RB by reducing the phosphorylated, inactive form of RB. Here, we show that embryo implantation is impaired in uterine-specific Rb1 knockout mice. We observe persistent cell proliferation of the Rb1-deficient uterine epithelium until embryo attachment, loss of epithelial necroptosis, and trophoblast phagocytosis, which correlates with subsequent embryo invasion failure, indicating that Rb1-induced CCA and necroptosis of uterine epithelium are involved in embryo invasion. Pre-implantation P4 supplementation is sufficient to restore these defects and embryo invasion. In Rb1-deficient uterine epithelial cells, TNFα-primed necroptosis is impaired, which is rescued by the treatment with a CCA inducer thymidine or P4 through the upregulation of TNF receptor type 2. TNFα is expressed in the luminal epithelium and the embryo at the embryo attachment site. These results provide evidence that uterine Rb1-induced CCA is involved in TNFα-primed epithelial necroptosis at the implantation site for successful embryo invasion.

Uterine Epithelial Progesterone Receptor Governs Uterine Receptivity Through Epithelial Cell Differentiation.

Progesterone receptor (PGR) is indispensable for pregnancy in mammals. Uterine PGR responds to the heightened levels of ovarian progesterone (P4) after ovulation and regulates uterine gene transcription for successful embryo implantation. Although epithelial and stromal P4-PGR signaling may interact with each other to form appropriate endometrial milieu for uterine receptivity and the subsequent embryo attachment, it remains unclear what the specific roles of epithelial P4-PGR signaling in the adult uterus are. Here we generated mice with epithelial deletion of Pgr in the adult uterus (Pgrfl/flLtfCre/+ mice) by crossing Pgr-floxed and Ltf-Cre mice. Pgrfl/flLtfCre/+ mice are infertile due to the impairment of embryo attachment. Pgrfl/flLtfCre/+ uteri did not exhibit epithelial growth arrest, suggesting compromised uterine receptivity. Both epithelial and stromal expressions of P4-responsive genes decreased in Pgrfl/flLtfCre/+ mice during the peri-implantation period, indicating that epithelial Pgr deletion affects not only epithelial but stromal P4 responsiveness. In addition, uterine LIF, an inducer of embryo attachment, was decreased in Pgrfl/flLtfCre/+ mice. The RNA-seq analysis using luminal epithelial specimens dissected out by laser capture microdissection revealed that the signaling pathways related to extracellular matrix, cell adhesion, and cell proliferation are altered in Pgr fl/flLtf Cre/+ mice. These findings suggest that epithelial PGR controls both epithelial and stromal P4 responsiveness and epithelial cell differentiation, which provides normal uterine receptivity and subsequent embryo attachment.

Differential roles of uterine epithelial and stromal STAT3 coordinate uterine receptivity and embryo attachment.

Although it has been reported that uterine signal transducer and activator of transcription 3 (STAT3) is essential for embryo implantation, the exact roles of uterine epithelial and stromal STAT3 on embryo implantation have not been elucidated. To address this issue, we generated Stat3-floxed/Ltf-iCre (Stat3-eKO), Stat3-floxed/Amhr2-Cre (Stat3-sKO), and Stat3-floxed/Pgr-Cre (Stat3-uKO) mice to delete Stat3 in uterine epithelium, uterine stroma, and whole uterine layers, respectively. We found that both epithelial and stromal STAT3 have critical roles in embryo attachment because all the Stat3-eKO and Stat3-sKO female mice were infertile due to implantation failure without any embryo attachment sites. Stat3-eKO uteri showed indented structure of uterine lumen, indicating the role of epithelial STAT3 in slit-like lumen formation in the peri-implantation uterus. Stat3-sKO uteri exhibited hyper-estrogenic responses and persistent cell proliferation of the epithelium in the peri-implantation uterus, suggesting the role of stromal STAT3 in uterine receptivity. In addition, Stat3-uKO female mice possessed not only the characteristic of persistent epithelial proliferation but also that of indented structure of uterine lumen. These findings indicate that epithelial STAT3 controls the formation of slit-like structure in uterine lumen and stromal STAT3 suppresses epithelial estrogenic responses and cell proliferation. Thus, epithelial and stromal STAT3 cooperatively controls uterine receptivity and embryo attachment through their different pathways.

Levonorgestrel Inhibits Embryo Attachment by Eliminating Uterine Induction of Leukemia Inhibitory Factor.

Progestogens including progesterone (P4) and levonorgestrel (LNG) are clinically used for multiple purposes such as contraception and infertility treatment. The effects of progestogens on the uterus remains to be elucidated. Here we examine the effect of excessive progestogen administration on embryo implantation focusing on the function of uterine leukemia inhibitory factor (LIF), a cytokine that is induced by estrogen and essential for embryo attachment. Treatment of wild-type (WT) female mice with vehicle (control), LNG at the dose of 300 µg/kg/day and P4 at the dose of 10 mg/day from day 1 to day 4 of pregnancy was conducted. LNG-treated and P4-treated mice showed embryo attachment failure on day 5 of pregnancy (The rate of mice with embryo attachment sites [%MAS], 11% and 13%, respectively), while all the control mice had normal attachment sites. Uterine LIF expression was significantly reduced in LNG-treated and P4-treated mice on day 4 evening. Administration of recombinant LIF (rLIF) at the dose of 24 µg/day on day 4 significantly rescued embryo attachment failure in LNG-treated and P4-treated mice (%MAS, 80% and 75%, respectively). Estradiol (E2) administration also rescued embryo attachment failure in LNG-treated mice (%MAS, 83%). Furthermore, excess P4 treatment before implantation decreased decidual P4 receptor (PGR) expression and induced decidualization defect apart from LIF downregulation. These findings indicate that progestogens cause embryo attachment inhibition through downregulation of uterine LIF expression and compromised decidualization through downregulation of PGR independently of LIF reduction. This study may contribute to a better understanding of contraceptive action of progestogens.

Uterine receptivity, embryo attachment, and embryo invasion: Multistep processes in embryo implantation.

BACKGROUND: Recurrent implantation failure is a critical issue in IVF-ET treatment. Successful embryo implantation needs appropriate molecular and cellular communications between embryo and uterus. Rodent models have been used intensively to understand these mechanisms. METHODS: The molecular and cellular mechanisms of embryo implantation were described by referring to the previous literature investigated by us and others. The studies using mouse models of embryo implantation were mainly cited. RESULTS: Progesterone (P4) produced by ovarian corpus luteum provides the uterus with receptivity to the embryo, and uterine epithelial growth arrest and stromal proliferation, what we call uterine proliferation-differentiation switching (PDS), take place in the peri-implantation period before embryo attachment. Uterine PDS is a hallmark of uterine receptivity, and several genes such as HAND2 and BMI1, control uterine PDS by modulating P4-PR signaling. As the next implantation process, embryo attachment onto the luminal epithelium occurs. This process is regulated by FOXA2-LIF pathway and planar cell polarity signaling. Then, the luminal epithelium at the embryo attachment site detaches from the stroma, which enables trophoblast invasion. This process of embryo invasion is regulated by HIF2α in the stroma. CONCLUSION: These findings indicate that embryo implantation contains multistep processes regulated by specific molecular pathways.

Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality.

Functions of tumor suppressor p53 and its negative regulator mouse double minute 2 homolog (Mdm2) in ovarian granulosa cells remain to be elucidated, and the current study aims at clarifying this issue. Mice with Mdm2 deficiency in ovarian granulosa cells [ Mdm2-loxP/ progesterone receptor ( Pgr)-Cre mice] were infertile as a result of impairment of oocyte maturation, ovulation, and fertilization, and those with Mdm2/p53 double deletion in granulosa cells ( Mdm2-loxP/ p53-loxP/ Pgr-Cre mice) showed normal fertility, suggesting that p53 induction in the ovarian granulosa cells is detrimental to ovarian function by disturbing oocyte quality. Another model of Mdm2 deletion in ovarian granulosa cells ( Mdm2-loxP/ anti-Mullerian hormone type 2 receptor-Cre mice) also showed subfertility as a result of the failure of ovulation and fertilization, indicating critical roles of ovarian Mdm2 in ovulation and fertilization. Mdm2-p53 pathway in cumulus granulosa cells transcriptionally controlled an orphan nuclear receptor steroidogenic factor 1 (SF1), a key regulator of ovarian function. Importantly, MDM2 and SF1 levels in human cumulus granulosa cells were positively associated with the outcome of oocyte maturation and fertilization in patients undergoing infertility treatment. These findings suggest that the Mdm2-p53-SF1 axis in ovarian cumulus granulosa cells directs ovarian function by affecting their neighboring oocyte quality.-Haraguchi, H., Hirota, Y., Saito-Fujita, T., Tanaka, T., Shimizu-Hirota, R., Harada, M., Akaeda, S., Hiraoka, T., Matsuo, M., Matsumoto, L., Hirata, T., Koga, K., Wada-Hiraike, O., Fujii, T., Osuga, Y. Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality.

HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment.

Although it has been reported that hypoxia inducible factor 2 α (Hif2a), a major transcriptional factor inducible by low oxygen tension, is expressed in the mouse uterus during embryo implantation, its role in pregnancy outcomes remains unclear. This study aimed to clarify functions of uterine HIF using transgenic mouse models. Mice with deletion of Hif2a in the whole uterus (Hif2a-uKO mice) showed infertility due to implantation failure. Supplementation with progesterone (P4) and leukemia inhibitory factor (LIF) restored decidual growth arrest and aberrant position of implantation sites in Hif2a-uKO mice, respectively, but did not rescue pregnancy failure. Histological analyses in Hif2a-uKO mice revealed persistence of the intact luminal epithelium, which blocked direct contact between stroma and embryo, inactivation of PI3K-AKT pathway (embryonic survival signal), and failed embryo invasion. Mice with stromal deletion of Hif2a (Hif2a-sKO mice) showed infertility with impaired embryo invasion and those with epithelial deletion of Hif2a (Hif2a-eKO mice) showed normal fertility, suggesting the importance of stromal HIF2α in embryo invasion. This was reflected in reduced expression of membrane type 2 metalloproteinase (MT2-MMP), lysyl oxidase (LOX), VEGF, and adrenomedullin (ADM) in Hif2a-uKO stroma at the attachment site, suggesting that stromal HIF2α regulates these mediators to support blastocyst invasion. These findings provide new insight that stromal HIF2α allows trophoblast invasion through detachment of the luminal epithelium and activation of an embryonic survival signal.

F4/80+ Macrophages Contribute to Clearance of Senescent Cells in the Mouse Postpartum Uterus.

Cellular senescence, defined as an irreversible cell cycle arrest, exacerbates the tissue microenvironment. Our previous study demonstrated that mouse uterine senescent cells were physiologically increased according to gestational days and that their abnormal accumulation was linked to the onset of preterm delivery. We hypothesized that there is a mechanism for removal of senescent cells after parturition to maintain uterine function. In the current study, we noted abundant uterine senescent cells and their gradual disappearance in wild-type postpartum mice. F4/80+ macrophages were present specifically around the area rich in senescent cells. Depletion of macrophages in the postpartum mice using anti-F4/80 antibody enlarged the area of senescent cells in the uterus. We also found excessive uterine senescent cells and decreased second pregnancy success rate in a preterm birth model using uterine p53-deleted mice. Furthermore, a decrease in F4/80+ cells and an increase in CD11b+ cells with a senescence-associated inflammatory microenvironment were observed in the p53-deleted uterus, suggesting that uterine p53 deficiency affects distribution of the macrophage subpopulation, interferes with senescence clearance, and promotes senescence-induced inflammation. These findings indicate that the macrophage is a key player in the clearance of uterine senescent cells to maintain postpartum uterine function.

Ischemic heart disease due to compression of the coronary arteries by malignant lymphoma.

A 76-year-old man presented with a two-month history of angina pectoris. Computed tomography (CT) revealed a serial enlargement of the supraclavicular and mediastinal lymph nodes compressing the heart, pulmonary artery and aorta. CT angiography (CTA) showed stenosis of the coronary arteries as a result of compression by the enlarged lymph nodes. First-pass contrast-enhanced cardiac magnetic resonance imaging (MRI) at rest revealed a perfusion defect, thus indicating myocardial ischemia. Diffuse large B-cell lymphoma was diagnosed and multidrug combination chemotherapy led to prompt improvement of the symptoms. Relief of the stenosis in the coronary arteries and improvements in myocardial perfusion were noted on follow-up CTA and MRI.