Impaired pathogen-induced autophagy and increased IL-1β and TNFα release in response to pathogenic triggers in secretory phase endometrial stromal cells of endometriosis patients

2020 ◽  
Vol 41 (5) ◽  
pp. 767-781
Author(s):  
Sachiko Matsuzaki ◽  
Anne-Sophie Gremeau ◽  
Jean-Luc Pouly
Keyword(s):  
Stromal Cells ◽  
Secretory Phase ◽  
Endometrial Stromal Cells

ÜBER DIE BILDUNG VON ENDOMETRIALEN KÖRNCHENZELLEN BEI KASTRATINNEN UNTER HORMONEINFLUSS

1960 ◽  
Vol XXXIII (II) ◽  
pp. 261-276 ◽  
Author(s):  
G. Hellweg ◽  
J. Ferin ◽  
K. G. Ober
Keyword(s):  
Hormone Therapy ◽  
Stromal Cells ◽  
Sex Hormone ◽  
Substitution Therapy ◽  
Secretory Phase ◽  
Hormone Substitution ◽  
Endometrial Stromal Cells ◽  
Endometrial Stroma ◽  
K Cells

ABSTRACT 65 endometrial biopsies from castrated women who had received either natural or artificial sex hormone therapy were studied microscopically. Attention was paid to various histologic criteria, especially to the number of endometrial granulocytes (»K« cells, KZ). The following was obtained: The »K« cells are completely absent when no hormone substitution therapy is given. They were also lacking when the castrated patients were treated only with oestrogens, even if the dose given was ten-times that found in women during the reproductive ages. In contrast, the »K« cells developed from the endometrial stromal cells only under influence of progesterone, usually appearing first 8–10 days after the administration of the gestagen. The »K« cells were demonstrable in the number corresponding to a normal secretory phase only then, when the oestrogen-progesterone dosage ratio had induced a fully-developed secretory change, as measured by the usual histologic criteria. With an overdosage of oestrogen the »K« cells were either absent or were very sparse. Contrarily, an overdosage of progesterone had no influence on their number. The development of endometrial glands does not always entirely parallel that of the stroma in castrated patients following hormone therapy. A more exact indicator for the proper dose for the production of a secretory phase by hormone therapy seems to be the number of »K« cells in the endometrial stroma.

scholarly journals Expression of Wilms’ Tumor Suppressor Gene (WT1) in Human Endometrium: Regulation through Decidual Differentiation

2001 ◽  
Vol 86 (12) ◽  
pp. 5964-5972
Author(s):  
Antonis Makrigiannakis ◽  
George Coukos ◽  
Anastasia Mantani ◽  
Prokopis Prokopakis ◽  
Geoffrey Trew ◽  
...  
Keyword(s):  
Menstrual Cycle ◽  
Stromal Cells ◽  
Wilms Tumor ◽  
Suppressor Gene ◽  
Secretory Phase ◽  
Endometrial Stromal Cells ◽  
Protein Levels ◽  
Decidual Cells ◽  
Wt1 Protein

The Wilms’ tumor suppressor gene (WT1) encodes a zinc-finger containing transcription factor that is selectively expressed in the developing urogenital tract and functions as a tissue-specific developmental regulator. In addition to its gene-regulatory function through DNA binding properties, WT-1 also regulates transcription by formation of protein-protein complexes. These properties place WT-1 as a major regulator of cell growth and differentiation. In view of these observations, we studied WT1 mRNA and protein in human endometrial extracts and in endometrial stromal cells (ESCs) differentiating into decidual cells in vitro, by RT-PCR and Western blotting, respectively. WT1 protein expression was also studied in situ in the proliferative and the secretory phase of the menstrual cycle in the early pregnant state. Analysis by PCR of total RNA prepared from human ESCs demonstrated the presence of WT1 mRNA and four WT1 mRNA splice variants. Western blot analysis of nuclear protein extracts from ESCs yielded one immunoreactive protein of the expected size (approximately 52–54 kDa) recognized by the WT1 antibody. Immunohistochemical staining showed that WT1 protein is localized only to nuclei of human endometrial stromal cells. It remains constant in the proliferative and the secretory phase of the menstrual cycle and is increased remarkably during decidualization in early pregnancy. ESCs decidualized in vitro were investigated for WT-1 expression, which confirmed that decidualizing stimuli (E2, medroxy-progesterone-acetate, and relaxin for 12 d or cAMP and progesterone for 1–4 d) induced WT-1 mRNA (P < 0.05) and increased protein levels (P < 0.05). These data indicate that in humans the WT1 gene is expressed in ESCs and its mRNA and protein levels remain constant in the proliferative and the secretory phase of the menstrual cycle and that WT1 mRNA and protein expression increases significantly in ESCs when these cells differentiate into decidual cells.

scholarly journals The SARS-CoV-2 receptor, Angiotensin converting enzyme 2 (ACE2) is required for human endometrial stromal cell decidualization

2020 ◽  
Author(s):  
Sangappa B. Chadchan ◽  
Vineet K. Maurya ◽  
Pooja Popli ◽  
Ramakrishna Kommagani
Keyword(s):  
Menstrual Cycle ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Converting Enzyme ◽  
Endometrial Stromal Cell ◽  
Secretory Phase ◽  
Endometrial Stromal Cells ◽  
Angiotensin Converting Enzyme 2 ◽  
Proliferative Phase ◽  
Human Endometrial Stromal Cell

AbstractSTUDY QUESTIONIs SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE 2) expressed in the human endometrium during the menstrual cycle, and does it participate in endometrial decidualization?SUMMARY ANSWERACE2 protein is highly expressed in human endometrial stromal cells during the secretory phase and is essential for human endometrial stromal cell decidualization.WHAT IS KNOWN ALREADYACE2 is expressed in numerous human tissues including the lungs, heart, intestine, kidneys and placenta. ACE2 is also the receptor by which SARS-CoV-2 enters human cells.STUDY DESIGN, SIZE, DURATIONProliferative (n = 9) and secretory (n = 6) phase endometrium biopsies from healthy reproductive-age women and primary human endometrial stromal cells from proliferative phase endometrium were used in the study.PARTICIPANTS/MATERIALS, SETTING, METHODSACE2 expression and localization were examined by qRT-PCR, Western blot, and immunofluorescence in both human endometrial samples and mouse uterine tissue. The effect of ACE2 knockdown on morphological and molecular changes of human endometrial stromal cell decidualization were assessed. Ovariectomized mice were treated with estrogen or progesterone to determine the effects of these hormones on ACE2 expression.MAIN RESULTS AND THE ROLE OF CHANCEIn human tissue, ACE2 protein is expressed in both endometrial epithelial and stromal cells in the proliferative phase of the menstrual cycle, and expression increases in stromal cells in the secretory phase. The ACE2 mRNA (P < 0.0001) and protein abundance increased during primary human endometrial stromal cell (HESC) decidualization. HESCs transfected with ACE2-targeting siRNA were less able to decidualize than controls, as evidenced by a lack of morphology change and lower expression of the decidualization markers PRL and IGFBP1 (P < 0.05). In mice during pregnancy, ACE2 protein was expressed in uterine epithelial and stromal cells increased through day six of pregnancy. Finally, progesterone induced expression of Ace2 mRNA in mouse uteri more than vehicle or estrogen (P < 0.05).LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONExperiments assessing the function of ACE2 in human endometrial stromal cell decidualization were in vitro. Whether SARS-CoV-2 can enter human endometrial stromal cells and affect decidualization have not been assessed.WIDER IMPLICATIONS OF THE FINDINGSExpression of ACE2 in the endometrium allow SARS-CoV-2 to enter endometrial epithelial and stromal cells, which could impair in vivo decidualization, embryo implantation, and placentation. If so, women with COVID-19 may be at increased risk of early pregnancy loss.STUDY FUNDINGS/COMPETING INTEREST(S)This study was supported by National Institutes of Health / National Institute of Child Health and Human Development grants R01HD065435 and R00HD080742 to RK and Washington University School of Medicine start-up funds to RK. The authors declare that they have no conflicts of interest.

scholarly journals Estrogen promotes the survival of human secretory phase endometrial stromal cells via CXCL12/CXCR4 up-regulation-mediated autophagy inhibition

2015 ◽  
Vol 30 (7) ◽  
pp. 1677-1689 ◽  
Author(s):  
Jie Mei ◽  
Xiao-Yong Zhu ◽  
Li-Pin Jin ◽  
Zhong-Liang Duan ◽  
Da-Jin Li ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Secretory Phase ◽  
Endometrial Stromal Cells ◽  
Autophagy Inhibition

scholarly journals FKBP4 is regulated by HOXA10 during decidualization and in endometriosis

Reproduction ◽  
2012 ◽  
Vol 143 (4) ◽  
pp. 531-538 ◽  
Author(s):  
Huan Yang ◽  
Yuping Zhou ◽  
Benjiamin Edelshain ◽  
Frederick Schatz ◽  
Charles J Lockwood ◽  
...  
Keyword(s):  
Menstrual Cycle ◽  
Stromal Cells ◽  
Secretory Phase ◽  
Endometrial Stromal Cells ◽  
Eutopic Endometrium ◽  
Protein Levels ◽  
Proliferative Phase ◽  
Progestin Receptor ◽  
Fertile Women

FKBP4 (FKBP52) and FKBP5 (FKBP51) are progestin receptor (PR) co-chaperone proteins that enhance and inhibit, respectively, progestin-mediated transcription by PR. Here, we examinedFKBP4andFKBP5expression in the eutopic endometrium of fertile women with endometriosis and effects of FKBP4 and FKBP5 on the decidualization of human endometrial stromal cells (HESCs), and assessed HOXA10 regulation of FKBP4. Expression ofFKBP4mRNA was increased in the late proliferative phase and remained elevated throughout the secretory phase.FKBP5expression was low and remained constant throughout the menstrual cycle. Compared with controls,FKBP4mRNA expression was decreased in the endometrium of women with endometriosis, whereas no significant endometriosis-related change was seen forFKBP5. Cultured HESCs were treated with eitherFKBP4orFKBP5siRNA and then decidualized by incubation with progesterone (P4) and 8-bromoadenosine cAMP. Treatment of HESCs withFKBP4siRNA resulted in 60% lowerIGFBP1expression. In contrast, incubation withFKBP5siRNA did not significantly decreaseIGFBP1expression duringin vitrodecidualization.HOXA10andFKBP4expression increased in parallel duringin vitrodecidualization. In HESCs, overexpressed HOXA10 enhanced FKBP4 mRNA and protein levels, whereas HOXA10 knockdown decreased FKBP4 mRNA and protein levels compared with controls. Similarly, duringin vitrodecidualization,FKBP4expression was decreased in HOXA10-silenced cells. EnhancedHOXA10expression in HESCs elicits a decidualization mediating increase inFKBP4expression. The findings are consistent with the observation that women with endometriosis have diminishedFKBP4expression leading to impaired decidualization and infertility. The P4resistance seen in endometriosis may be mediated through HOXA10-regulatedFKBP4expression.

scholarly journals Metformin inhibits growth of eutopic stromal cells from adenomyotic endometrium via AMPK activation and subsequent inhibition of AKT phosphorylation: a possible role in the treatment of adenomyosis

Reproduction ◽  
2013 ◽  
Vol 146 (4) ◽  
pp. 397-406 ◽  
Author(s):  
Jing Xue ◽  
Hui Zhang ◽  
Wei Liu ◽  
Ming Liu ◽  
Min Shi ◽  
...  
Keyword(s):  
Cell Growth ◽  
Stromal Cells ◽  
Primary Cultures ◽  
Akt Signaling ◽  
Dependent Manner ◽  
Ampk Activation ◽  
Secretory Phase ◽  
Endometrial Stromal Cells ◽  
Compound C ◽  
17Β Estradiol

Adenomyosis is a finding that is associated with dysmenorrhea and heavy menstrual bleeding, associated with PI3K/AKT signaling overactivity. To investigate the effect of metformin on the growth of eutopic endometrial stromal cells (ESCs) from patients with adenomyosis and to explore the involvement of AMP-activated protein kinase (AMPK) and PI3K/AKT pathways. Primary cultures of human ESCs were derived from normal endometrium (normal endometrial stromal cells (N-ESCs)) and adenomyotic eutopic endometrium (adenomyotic endometrial stroma cells (A-ESCs)). Expression of AMPK was determined using immunocytochemistry and western blot analysis. 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assays were used to determine the effects of metformin and compound C on ESCs and also to detect growth and proliferation of ESCs. AMPK and PI3K/AKT signaling was determined by western blotting. A-ECSs exhibited greater AMPK expression than N-ESCs. Metformin inhibited proliferation of ESCs in a concentration-dependent manner. The IC50was 2.45 mmol/l for A-ESCs and 7.87 mmol/l for N-ESCs. Metformin increased AMPK activation levels (p-AMPK/AMPK) by 2.0±0.3-fold in A-ESCs, 2.3-fold in A-ESCs from the secretory phase, and 1.6-fold in the proliferation phase. The average reduction ratio of 17β-estradiol on A-ESCs was 2.1±0.8-fold in proliferative phase and 2.5±0.5-fold in secretory phase relative to the equivalent groups not treated with 17β-estradiol. The inhibitory effects of metformin on AKT activation (p-AKT/AKT) were more pronounced in A-ESCs from the secretory phase (3.2-fold inhibition vs control) than in those from the proliferation phase (2.3-fold inhibition vs control). Compound C, a selective AMPK inhibitor, abolished the effects of metformin on cell growth and PI3K/AKT signaling. Metformin inhibits cell growth via AMPK activation and subsequent inhibition of PI3K/AKT signaling in A-ESCs, particularly during the secretory phase, suggesting a greater effect of metformin on A-ESCs from secretory phase.

scholarly journals Regulated Expression of Signal Transducer and Activator of Transcription, Stat5, and its Enhancement of PRL Expression in Human Endometrial Stromal Cells in Vitro

2002 ◽  
Vol 87 (6) ◽  
pp. 2581-2588 ◽  
Author(s):  
I. Y. H. Mak ◽  
J. J. Brosens ◽  
M. Christian ◽  
F. A. Hills ◽  
L. Chamley ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Recurrent Miscarriage ◽  
Dominant Negative ◽  
Secretory Phase ◽  
Endometrial Stromal Cells ◽  
Signal Transducers ◽  
Regulated Expression ◽  
Functional Relevance

Differentiation of human endometrium during the secretory phase of the menstrual cycle is characterized by expression of a variety of genes implicated in the establishment and maintenance of pregnancy. An increased abundance of signal transducers and activators of transcription (Stats) in the secretory phase suggests Stat5 as a component of the differentiation of endometrium in response to ovarian hormone stimulation in vivo. Decidualization is initiated in a subset of endometrial stromal cells (ESC) in vivo during the secretory phase, but it is unclear whether regulated expression of Stat5 is a feature of these cells. Here, therefore, the abundance and subcellular distribution of Stat5 in ESC after a decidualization stimulus of cAMP plus medroxyprogesterone acetate (MPA) has been investigated in vitro. Western blotting revealed an increase in the apparent abundance of Stat5a and Stat5b, in the cytosolic and nuclear fractions, at 2, 3, and 4 d after stimulation. The potential functional relevance of this increase in Stat5 is suggested by the ability of transiently transfected Stat5a or Stat5b to significantly enhance the response of the decidual PRL promoter to cAMP/MPA and attenuation of the response to cAMP/MPA by dominant negative Stat5. Recent evidence suggests endometrial differentiation, including PRL production, as a possible target of antiphospholipid antibodies (aPL) prevalent in recurrent miscarriage. Monoclonal antibody, ID2, which has similar reactivity as human aPL, significantly decreased the apparent abundance of nuclear Stat5b in response to cAMP/MPA and was associated with decreased decidual PRL promoter activation and PRL secretion. Regulated expression of Stat5 is therefore a component of decidual differentiation of human ESC and contributes significantly to activation of the decidual PRL promoter. Alteration of this process by an aPL component suggests decidual differentiation as a potential clinical target in recurrent early miscarriages.

scholarly journals Decreased CD44v3 Expression Impairs Endometrial Stromal Cell Decidualization in Women With Recurrent Implantation Failure

2021 ◽  
Author(s):  
Xiaowei Zhou ◽  
Yi Cao ◽  
mingjuan Zhou ◽  
Mi Han ◽  
mengyu Liu ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Culture System ◽  
Embryo Implantation ◽  
Group Identification ◽  
Endometrial Receptivity ◽  
Implantation Failure ◽  
Recurrent Implantation Failure ◽  
Secretory Phase ◽  
Endometrial Stromal Cells ◽  
Cd44 Isoforms

Abstract BackgroundThe precise pathogenesis of poor endometrial receptivity in recurrent implantation failure (RIF) still remains unclear. This study aims to explore the effects of different CD44 isoforms in the mid-secretory phase endometrium on endometrial receptivity in women with RIF.MethodsMid-secretory phase endometrial tissue samples were obtained from two groups of women who had undergone IVF: a) 24 patients with RIF, b) 18 patients with infertility due to tubal obstruction, who had achieved a successful clinical pregnancy after the first embryo transfer in IVF (control group). Identification of differentially expressed CD44 isoforms in endometrial tissues was assessed with immunohistochemistry, qPCR and western blotting. Effects of CD44v3 overexpression and knockdown on proliferation and decidualization of Immortalized human endometrial stromal cells (T-HESCs) and primary HESCs were investigated by qPCR and Western blot. A heterologous co-culture system of embryo implantation was constructed to mimics the process of trophoblast invasion during implantation.ResultsCD44v3 was significantly higher expressed in mid-secretory phase of endometrial stromal cells than proliferation phase, but was notably lower in RIF patients. The expression of decidualization markers, prolactin (PRL) and insulin like growth factor binding protein-1 (IGFBP1), was notably decreased following CD44v3 knockdown, whereas the expression levels of both PRL and IGFBP1 increased after CD44v3 overexpression in HESCs. Furthermore, the CD44v3-knockdown HESCs displayed a significantly deficiency in supporting trophoblast outgrowth through a co-culture system of embryo implantation; however, CD44v3 overexpression in HESCs promoted trophoblast outgrowth.ConclusionThe reduced expression of CD44v3 suppresses HESCs proliferation and decidualization, which might play a pivotal role in poor endometrial receptivity in women with RIF.

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