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Connective Tissue Research Jun 2015The embryo-implantation promotes deep changes in the uterus resulting in the formation of a new structure at the maternal-fetal interface, the decidua. Decidualization...
The embryo-implantation promotes deep changes in the uterus resulting in the formation of a new structure at the maternal-fetal interface, the decidua. Decidualization can also be induced in pseudopregnant rodents resulting in a structure called deciduoma that is morphologically and functionally similar to the decidua. Previous studies from our and other laboratories demonstrate that in rodents, decidualization of the endometrium requires remarkable remodeling of the endometrial extracellular matrix (ECM) that is mainly coordinated by estradiol and progesterone. The influence of the embryo in this process, however, has not yet been investigated. To enlarge the knowledge on this subject, the present study investigates the behavior of a set of ECM molecules, in the absence of paracrine cues originated from the embryo. For that deciduoma was induced in pseudopregnant Swiss mice, and the distribution of collagen types I, III, IV, V and the proteoglycans decorin and biglycan was investigated by immunolabeling from the fifth to the eighth day of pseudopregnancy. It was observed the deposition of collagen types III and IV as well as decorin and biglycan was similar to that previously described by our group in the decidua. However, in the absence of the embryo, some differences occur in the distribution of collagen types I and V, suggesting that beside the major role of ovarian hormones on the endometrial ECM remodeling, molecular signals originated from the conceptus may influence this process.
Topics: Animals; Biglycan; Collagen Type I; Collagen Type III; Decidua; Embryo Implantation; Extracellular Matrix; Female; Mice; Pseudopregnancy; Uterus
PubMed: 25738597
DOI: 10.3109/03008207.2015.1023432 -
Human Reproduction (Oxford, England) Oct 2016Does nm23 have functional significance in decidualization in mice and humans?
STUDY QUESTION
Does nm23 have functional significance in decidualization in mice and humans?
SUMMARY ANSWER
nm23 affects decidualization via the phosphoinositide 3 kinase/mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathways in mouse endometrial stromal cells (ESCs; mESCs) and human ESCs.
WHAT IS KNOWN ALREADY
The function of nm23 in suppressing metastasis has been demonstrated in a variety of cancer types. nm23 also participates in the control of DNA replication and cell proliferation and differentiation.
STUDY DESIGN, SIZE AND DURATION
We first analyzed the expression profile of nm23 in mice during early pregnancy (n = 6/group), pseudopregnancy (n = 6/group) and artificial decidualization (n = 6/group) and in humans during the menstrual cycle phases and the first trimester. We then used primary cultured mESCs and a human ESC line, T-HESC, to explore the hormonal regulation of nm23 and the roles of nm23 in in vitro decidualization, and as a possible mediator of downstream PI3K-Akt-mTOR signaling pathways.
PARTICIPANTS/MATERIALS, SETTINGS AND METHODS
We evaluated the dynamic expression of nm23 in mice and humans using immunohistochemistry, western blot and real-time quantitative RT-PCR (RT-qPCR). Regulation of nm23 by steroid hormones was investigated in isolated primary mESCs and T-HESCs by western blot. The effect of nm23 knockdown (using siRNA) on ESC proliferation was analyzed by 5-ethynyl-2'-deoxyuridine staining (EdU) and proliferating cell nuclear antigen protein (PCNA) expression. The influence of nm23 expression on the differentiation of ESCs was determined by RT-qPCR using the mouse differentiation markers decidual/trophoblast PRL-related protein (dtprp, also named prl8a2) and prolactin family 3 subfamily c member 1 (prl3c1) and the human differentiation markers insulin-like growth factor binding protein 1 (IGFBP1) and prolactin (PRL). The effects of nm23 siRNA (si-nm23) and the PI3K inhibitor LY294002 on the downstream effects of nm23 on the PI3K-Akt-mTOR signaling pathway were estimated by western blot.
MAIN RESULTS AND THE ROLE OF CHANCE
NM23-M1 was specifically expressed in the decidual zone during early pregnancy and in artificially induced deciduoma, and NM23-H1 was strongly expressed in human first trimester decidua. The expression of nm23 was upregulated by oestradiol and progesterone (P < 0.05 versus control) in vitro in mESCs and T-HESC, and this was inhibited by their respective receptor antagonists, ICI 182,780 and RU486. Mouse and human nm23 knockdown decreased ESC proliferation and differentiation (P < 0.05 versus control). The PI3K-Akt-mTOR signaling pathways were downstream mediators of nm23 in mESCs and T-HESCs decidualization.
LIMITATIONS AND REASONS FOR CAUTION
Whether the nm23 regulates decidualization via the activation of AMPK, RAS, PKA, STAT3 or other signaling molecules remains to be determined. The role of nm23 in decidualization was tested in vitro only.
WIDER IMPLICATIONS OF THE FINDINGS
Results demonstrate that nm23 plays a vital role in decidualization in mice and humans and that nm23 gene expression is hormonally regulated. The downregulation of nm23 in decidua during the first trimester may be associated with infertility in women.
STUDY FUNDING/COMPETING INTERESTS
This study was supported by the National Natural Science Foundation of China (grant nos. 81370731, 31571551 and 31571190), the Science and Technology Project of Chongqing Education Committee (KJ130309), open funding by the Chongqing Institute for Family Planning (1201) and the Excellent Young Scholars of Chongqing Medical University (CQYQ201302). The authors have no conflicts of interest to declare.
Topics: Animals; Cell Differentiation; Cell Line; Cell Proliferation; Decidua; Endometrium; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Mice; NM23 Nucleoside Diphosphate Kinases; Phosphatidylinositol 3-Kinases; Pregnancy; Pregnancy Trimester, First; Proto-Oncogene Proteins c-akt; Signal Transduction; Stromal Cells; TOR Serine-Threonine Kinases
PubMed: 27604954
DOI: 10.1093/humrep/dew191 -
Development, Growth & Differentiation Feb 2019Ubiquitin-specific protease 7 (USP7), a member of the deubiquitinating (DUB) enzyme family, regulates protein stability and has a well-characterized function in...
Ubiquitin-specific protease 7 (USP7), a member of the deubiquitinating (DUB) enzyme family, regulates protein stability and has a well-characterized function in tumorigenesis. Given its critical role in growth and development, it was speculated to be involved in modulating processes in the female reproductive system but its exact role has not been elucidated. Decidualization is one of the key processes in pregnancy and aberrant decidualization is a cause of pregnancy failure. The uterine endometrium layer undergoes significant structural and functional changes during decidualization in preparation for and after embryo implantation. Here, we hypothesized that USP7 could be involved in mediating endometrial stromal cell (ESC) decidualization and set out to determine its function with a primary stromal cell culture. Using in situ hybridization and immunohistochemical techniques, we observed increased USP7 expression during uterine decidualization and found that it was predominantly localized to the decidual zone in the post-implantation uterus. Since the ovarian hormones, progesterone (P4) and estrogen (E2), function in promoting stroma decidualization, we investigated their relationship with USP7 expression and found that they exert minimal influence. Moreover, increased USP7 expression observed during deciduoma development was found to be independent of blastocyst attachment. Using a specific USP7 inhibitor, HBX19818, we demonstrated an additional novel role for USP7 in endometrial stroma decidualization in mice during early pregnancy. Our findings could potentially be applied towards future research and development in female infertility.
Topics: Animals; Cells, Cultured; Endometrium; Enzyme Inhibitors; Female; Male; Mice; Stromal Cells; Ubiquitin-Specific Peptidase 7
PubMed: 30628051
DOI: 10.1111/dgd.12594 -
Cell Biochemistry and Function Dec 2014Endometrial decidualization is highly important for successful construction and maintenance of embryo implantation and pregnancy. Lefty gene at different menstrual cycle...
Endometrial decidualization is highly important for successful construction and maintenance of embryo implantation and pregnancy. Lefty gene at different menstrual cycle phases has different expressions, indicating its regulatory significance. To study the mechanism of Lefty in decidualization, human endometrial stromal cells (hESCs) were cultured and induced with medroxyprogesterone acetate (MPA) and 8-bromoadenosine-cAMP (8-Br-cAMP) in vitro as a research model. Our results showed that Lefty1 overexpression inhibited MPA- and 8-Br-cAMP-induced hESC decidualization and significantly reduced the secretion of prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP-1). With the inhibition of Lefty1 expression, hESC decidualization induced by MPA and 8-Br-cAMP became more remarkable, and the secretions of PRL and IGFBP-1 were higher too. Further tests indicated that during the process of decidualization, P57 expression increased, whereas cyclin D1 expression decreased. Although Lefty1 overexpression did not significantly change the expressions of P57 and cyclin D1, inhibition of Lefty1 expression resulted in more evident changes in P57 and cyclin D1 expressions. Meanwhile, cell cycle examination showed that Lefty1 overexpression reduced the cell cycle arrest at G1/S phase in the in vitro hESC decidualization model. Therefore, Lefty1 could regulate the cell cycle via modulating the expressions of P57 and cyclin D1 and then inhibit the decidualization in vitro.
Topics: Adenosine; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p57; Deciduoma; Endometrium; Female; G1 Phase Cell Cycle Checkpoints; Humans; Left-Right Determination Factors; Medroxyprogesterone; S Phase Cell Cycle Checkpoints; Stromal Cells
PubMed: 25339094
DOI: 10.1002/cbf.3069 -
Human Reproduction (Oxford, England) Jun 2016What effect does diet-induced obesity have on endometrial stromal cell (ESC) decidualization?
STUDY QUESTION
What effect does diet-induced obesity have on endometrial stromal cell (ESC) decidualization?
SUMMARY ANSWER
Diet-induced obesity impairs ESC decidualization.
WHAT IS KNOWN ALREADY
Decidualization is important for successful implantation and subsequent health of the pregnancy. Compared with normal-weight women, obese women have lower pregnancy rates (both spontaneous and by assisted reproductive technology), higher rates of early pregnancy loss and poorer oocyte quality.
STUDY DESIGN, SIZE, DURATION
Beginning at 6 weeks of age, female C57Bl/6J mice were fed either a high-fat/high-sugar diet (HF/HS; 58% Fat Energy/Sucrose) or a diet of standard mouse chow (CON; 13% Fat) for 12 weeks. At this point, metabolic parameters were measured. Some of the mice (n = 9 HF/HS and 9 CON) were mated with reproductively competent males, and implantation sites were assessed. Other mice (n = 11 HF/HS and 10 CON) were mated with vasectomized males, and artificial decidualization was induced. For in vitro human studies of primary ESCs, endometrial tissue was obtained via biopsy from normo-ovulatory patients without history of infertility (obese = BMI > 30 kg/m(2), n = 11 and lean = BMI < 25 kg/m(2), n = 7) and from patients consented for hysterectomies for a benign indication (n = 4). In vitro studies were also performed with immortalized human ESCs. ESCs were decidualized in culture for nine 9 days in the presence or absence of palmitic acid (PA), and the degree of decidualization was assessed by measuring expression of decidualization markers.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The sizes of implantation sites and fetuses were analyzed in mice mated with reproductively competent males. In mice mated with vasectomized males, decidualization was induced, and uterine tissues were analyzed via hematoxylin and eosin staining, quantitative RT-PCR (RT-qPCR), and western blots. Human ESCs were cultured in vitro and induced to decidualize by treatment with cAMP and medroxyprogesterone. The level of expression of decidualization markers was assessed by RT-qPCR (mRNA) and western blotting (protein). ATP content of ESCs was measured, and levels of autophagy were assessed by western blotting of the autophagy regulators acetyl coa carboxylase (ACC) and ULK1 (Ser 317). Autophagic flux was measured by western blot of the marker LC3b-II.
MAIN RESULTS AND THE ROLE OF CHANCE
Mice exposed to an HF/HS diet became obese and metabolically impaired. HF/HS-exposed mice mated to reproductively competent males had smaller implantation sites in early pregnancy (P <0.001) and larger fetuses at term (P <0.05) than CON-exposed mice. In the artificial decidualization experiments, mice exposed to the HF/HS diet developed 50% smaller deciduomas than mice exposed to CON diet (P< 0.001). Human ESCs cultured in the presence of PA had markedly decreased mRNA expression of the decidualization markers, decidual prolactin (PRL) (P< 0.0001) and insulin-like growth factor binding protein 1 (IGFBP1) (P< 0.0001). Expression of PRL and IGFBP1 by mRNA were also significantly lower in early follicular phase ESCs of obese women than in those of normal-weight women (P< 0.05). Protein expression of phosphorylated ACC and phosphorylated ULK1, both activated forms, were lower in deciduomas of HF/HS mice than in those of control mice (P < 0.01). In immortalized human ESCs, LC3b-II levels were higher in decidualized cells than in controls, indicating increased autophagy. PA treatment abrogated this increase.
LIMITATIONS, REASONS FOR CAUTION
Many aspects of obesity and metabolic impairment could contribute to the decidualization defects observed in the HF/HS-exposed mice. Although our findings suggest that both autophagy and decidualization are impaired by exposure to PA, the underlying mechanisms should be elucidated. Finally, our human patient sample size was small.
WIDER IMPLICATIONS OF THE FINDINGS
Although many factors contribute to poor reproductive outcome and early pregnancy loss in obese women, our study suggests the importance of decidualization defects. Such defects may contribute to compromised endometrial receptivity and poor implantation. If defects in autophagy contribute to impaired decidualization, therapeutics could be developed to improve this process and thus improve implantation and pregnancy outcomes in obese women.
STUDY FUNDING/COMPETING INTERESTS
Grants include NIH 5T32HD040135-12 (J.S.R.), R01 HD065435 (K.H.M.), NIH T32 HD049305 (J.L.S.) and ACOG Research Grant (M.B.S.). The authors report no conflicts of interest.
Topics: Animals; Autophagy; Biomarkers; Decidua; Diet, High-Fat; Embryo Implantation; Female; Humans; Male; Mice, Inbred C57BL; Obesity; Palmitic Acid; Phosphorylation; RNA, Messenger; Stromal Cells
PubMed: 27052498
DOI: 10.1093/humrep/dew048 -
Endocrinology Feb 2016The most significant increase in metabolic syndrome over the previous decade occurred in women of reproductive age, which is alarming given that metabolic syndrome is...
The most significant increase in metabolic syndrome over the previous decade occurred in women of reproductive age, which is alarming given that metabolic syndrome is associated with reproductive problems including subfertility and early pregnancy loss. Individuals with metabolic syndrome often consume excess fructose, and several studies have concluded that excess fructose intake contributes to metabolic syndrome development. Here, we examined the effects of increased fructose consumption on pregnancy outcomes in mice. Female mice fed a high-fructose diet (HFrD) for 6 weeks developed glucose intolerance and mild fatty liver but did not develop other prominent features of metabolic syndrome such as weight gain, hyperglycemia, and hyperinsulinemia. Upon mating, HFrD-exposed mice had lower pregnancy rates and smaller litters at midgestation than chow-fed controls. To explain this phenomenon, we performed artificial decidualization experiments and found that HFrD consumption impaired decidualization. This appeared to be due to decreased circulating progesterone as exogenous progesterone administration rescued decidualization. Furthermore, HFrD intake was associated with decreased bone morphogenetic protein 2 expression and signaling, both of which were restored by exogenous progesterone. Finally, expression of forkhead box O1 and superoxide dismutase 2 [Mn] proteins were decreased in the uteri of HFrD-fed mice, suggesting that HFrD consumption promotes a prooxidative environment in the endometrium. In summary, these data suggest that excess fructose consumption impairs murine fertility by decreasing steroid hormone synthesis and promoting an adverse uterine environment.
Topics: Abortion, Spontaneous; Animals; Bone Morphogenetic Protein 2; Decidua; Deciduoma; Embryo Culture Techniques; Embryo Transfer; Endometrium; Fatty Liver; Female; Fertilization in Vitro; Forkhead Box Protein O1; Forkhead Transcription Factors; Fructose; Glucose Intolerance; Immunohistochemistry; Litter Size; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Oxidative Stress; Pregnancy; Pregnancy Rate; Progesterone; Superovulation; Superoxide Dismutase; Sweetening Agents
PubMed: 26677880
DOI: 10.1210/en.2015-1618 -
Reproductive Biomedicine Online Feb 2017The molecular mechanisms underlying endometrial stromal cell proliferation and differentiation (decidualization) are still not fully understood. This study revealed that...
The molecular mechanisms underlying endometrial stromal cell proliferation and differentiation (decidualization) are still not fully understood. This study revealed that increased Slp-2 expression is a significant factor modulating endometrial stromal cell proliferation and decidualization in both mice and humans. Our results showed a significant difference in the mRNA and protein levels between the implantation site and inter-implantation site on day 5 and day 6 of pregnancy in mice (all P < 0.05). Strong Slp-2 immunostaining was mainly localized within the decidual zone of mice through the post-implantation period. Mice with artificially induced deciduoma showed significantly higher expression of Slp-2 compared with uninduced controls (P < 0.005). Human stromal cells in the middle and late-secretory phases demonstrated significantly (all P < 0.05) upregulated SLP-2, compared with cells in the proliferative phase and early secretory phases. Further analyses of the SLP-2 gene knocked down revealed a significant (P < 0.005) repression of both the decidualization marker gene's expression (decidual/trophoblast prolactin-related protein in mice, insulin-like growth factor binding protein and prolactin in human) and the cell proliferation in in vitro-induced decidualized primary endometrial stromal cells in mice and humans.
Topics: Animals; Blood Proteins; Cell Differentiation; Cell Proliferation; Decidua; Deciduoma; Embryo Implantation; Endometrium; Female; Gene Expression Regulation, Developmental; Humans; Insulin-Like Growth Factor Binding Protein 1; Membrane Proteins; Menstrual Cycle; Mice; Pregnancy; Prolactin; RNA, Messenger; Stromal Cells
PubMed: 27986413
DOI: 10.1016/j.rbmo.2016.11.009 -
BMJ Case Reports Jul 2019We describe a case of a deciduoid mesothelioma, a rare variant of epithelioid mesothelioma, which is associated with a very poor prognosis. A review of the relevant...
We describe a case of a deciduoid mesothelioma, a rare variant of epithelioid mesothelioma, which is associated with a very poor prognosis. A review of the relevant literature is also included. The patient was a man with probable asbestos exposure and presented with classic features of pleural malignancy. Diagnosis was reached with close correlation between clinical, radiological and pathological findings.
Topics: Aged; Asbestos; Deciduoma; Environmental Exposure; Humans; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Palliative Care; Pleural Neoplasms; Prognosis; Thoracoscopy; Tomography, X-Ray Computed
PubMed: 31289169
DOI: 10.1136/bcr-2019-229945 -
Journal of Comparative Pathology May 2017Tumours and tumour-like lesions are rare findings in the genital system of guinea pigs. The aim of the present study was to characterize nodular lesions in the cervix...
Tumours and tumour-like lesions are rare findings in the genital system of guinea pigs. The aim of the present study was to characterize nodular lesions in the cervix and uterus of guinea pigs submitted for histopathological diagnosis. Samples from 83 pet animals were investigated. Cases included 64 surgically excised masses including complete uteri (n = 37), parts from uteri containing masses (n = 8), complete masses (n = 12) or samples from masses (n = 7) and 19 complete necropsy examinations. In 55 of the cases, only solitary changes were observed; in 28 cases two or more lesions were diagnosed. Histopathological diagnoses included polyps in the vagina, cervix or uterus (n = 8), hyperplastic lesions of the endocervix (n = 10) and seven adenomas and two adenocarcinomas of the endocervix. Endometrial alterations included single small glandular cysts (n = 3), nodular glandular-cystic hyperplasia (n = 8), adenoma (n = 20) and adenocarcinoma (n = 3). Four placentas, 10 focal decidualizations and six deciduomas were found. Furthermore, 18 leiomyomas and nine leiomyosarcomas were diagnosed. Uterine malignant mixed Müllerian tumours were observed in seven cases. Overall, benign lesions outnumbered malignant tumours in the female genital tract of pet guinea pigs. Therefore, surgical excision or ovariohysterectomy should be recommended as therapy.
Topics: Animals; Female; Guinea Pigs; Hyperplasia; Retrospective Studies; Uterine Cervical Neoplasms; Uterine Neoplasms
PubMed: 28427752
DOI: 10.1016/j.jcpa.2017.03.002