scholarly journals Tripeptidyl peptidase I promotes human endometrial epithelial cell adhesive capacity implying a role in receptivity

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Leilani L. Santos ◽  
Cheuk Kwan Ling ◽  
Evdokia Dimitriadis
Keyword(s):  
Menstrual Cycle ◽  
Epithelial Cell ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Unexplained Infertility ◽  
Implantation Failure ◽  
Secretory Phase ◽  
Endometrial Epithelial Cell ◽  
Tripeptidyl Peptidase ◽  
Adhesive Capacity

AbstractThe endometrium undergoes cyclic remodelling throughout the menstrual cycle in preparation for embryo implantation which occurs in a short window during the mid-secretory phase. It is during this short ‘receptive window’ that the endometrial luminal epithelium acquires adhesive capacity permitting blastocysts firm adhesion to the endometrium to establish pregnancy. Dysregulation in any of these steps can compromise embryo implantation resulting in implantation failure and infertility. Many factors contribute to these processes including TGF-β, LIF, IL-11 and proteases. Tripeptidyl peptidase 1 (TPP1) is a is a lysosomal serine-type protease however the contribution of the TPP1 to receptivity is unknown. We aimed to investigate the role of TPP1 in receptivity in humans.In the current study, TPP1 was expressed in both epithelial and stromal compartments of the endometrium across the menstrual cycle. Expression was confined to the cytoplasm of luminal and glandular epithelial cells and stromal cells. Staining of mid-secretory endometrial tissues of women with normal fertility and primary unexplained infertility showed reduced immunostaining intensity of TPP1 in luminal epithelial cells of infertile tissues compared to fertile tissues. By contrast, TPP1 levels in glandular epithelial and stromal cells were comparable in both groups in the mid-secretory phase. Inhibition of TPP1 using siRNA compromised HTR8/SVneo (trophoblast cell line) spheroid adhesion on siRNA-transfected Ishikawa cells (endometrial epithelial cell line) in vitro. This impairment was associated with decreased sirtuin 1 (SIRT1), BCL2 and p53 mRNA and unaltered, CD44, CDH1, CDH2, ITGB3, VEGF A, OSTEOPONTIN, MDM2, CASP4, MCL1, MMP2, ARF6, SGK1, HOXA-10, LIF, and LIF receptor gene expression between treatment groups. siRNA knockdown of TPP1 in primary human endometrial stromal cells did not affect decidualization nor the expression of decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1). Taken together, our data strongly suggests a role for TPP1 in endometrial receptivity via its effects on epithelial cell adhesion and suggests reduced levels associated with unexplained infertility may contribute to implantation failure.

Soluble Delta-like ligand 1 alters human endometrial epithelial cell adhesive capacity

2017 ◽  
Vol 29 (4) ◽  
pp. 694 ◽  
Author(s):  
Michelle Van Sinderen ◽  
Jennifer Oyanedel ◽  
Ellen Menkhorst ◽  
Carly Cuman ◽  
Katarzyna Rainczuk ◽  
...  
Keyword(s):  
Menstrual Cycle ◽  
Embryo Implantation ◽  
Notch Signalling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Secretory Phase ◽  
Functional Changes ◽  
Infertile Women ◽  
Potential Biomarker ◽  
Adhesive Capacity

The endometrium undergoes substantial morphological and functional changes to become receptive to embryo implantation and to enable establishment of a successful pregnancy. Reduced Delta-like ligand 1 (DLL1, Notch ligand) in the endometrium is associated with infertility. DLL1 can be cleaved by ‘a disintegrin and metalloprotease’ (ADAM) proteases to produce a soluble ligand that may act to inhibit Notch signalling. We used an enzyme-linked immunosorbent assay to quantify soluble DLL1 in uterine lavages from fertile and infertile women in the secretory phase of the menstrual cycle. We also determined the cellular location and immunostaining intensity of ADAM12 and 17 in human endometrium throughout the cycle. Functional effects of soluble DLL1 in receptivity were analysed using in vitro adhesion and proliferation assays and gene expression analysis of Notch signalling targets. Soluble DLL1 was significantly increased in uterine lavage samples of infertile women compared with fertile women in the secretory phase of the menstrual cycle. This coincided with significantly increased ADAM17 immunostaining detected in the endometrial luminal epithelium in the mid-secretory phase in infertile women. Soluble DLL1 significantly inhibited the adhesive capacity of endometrial epithelial cells via downregulation of helix–loop–helix and hairy/enhancer of split family member HES1 mRNA. Thus, soluble DLL1 may serve as a suitable target or potential biomarker for receptivity.

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.

Polo-like kinase expression in normal human endometrium during the menstrual cycle

2000 ◽  
Vol 12 (2) ◽  
pp. 59 ◽  
Author(s):  
Noriyuki Takai ◽  
Tami Miyazaki ◽  
Isao Miyakawa ◽  
Ryoji Hamanaka
Keyword(s):  
Menstrual Cycle ◽  
Stromal Cells ◽  
Cellular Proliferation ◽  
Secretory Phase ◽  
Ki 67 ◽  
Normal Endometrium ◽  
Proliferative Phase ◽  
Normal Human ◽  
Late Secretory Phase

The enzyme, polo-like kinase (PLK), is a mammalian serine/threonine kinase involved in cell cycle regulation. A great deal of evidence regarding the role of PLK in the cell cycle has been obtained through studies of cultured cells, though little is known about its function or even expression in vivo. The endometrium undergoes rapid proliferation and differentiation under ovarian steroid hormone control during the 28-day cycle. Thus, normal endometrium provides an excellent model in which to study the hormone dependency of PLK expression. In the present study, we examined the features of PLK expression in 20 samples of normal human endometrium during the menstrual cycle. The expression of Ki-67 and proliferating cell nuclear antigen (PCNA) were also examined as markers of proliferation. Immunohistochemical studies showed that PLK staining was detected in the basement membrane of many endometrial glands, stromal cells, and some endothelial cells. The number of PLK-positive endometrial gland cells was significantly higher in the late proliferative phase (19.16% 4.98%) and the early secretory phase (19.28% 4.99%) than in the early proliferative phase (2.60% 2.33%) or the late secretory phase (5.76% 2.16%) (P<0.0001). PLK expression seemed to be correlated with the expression of Ki-67 and PCNA in many endometrial glands and stromal cells particularly in the late proliferative phase, reflecting a role of PLK in cellular proliferation. Nevertheless, in the early secretory phase, at which point the expression of Ki-67 and PCNA decreased in endometrial glands, PLK was strongly expressed. This finding suggests that PLK may have some post-mitotic functions in certain specialized cell types. Although the highest expression of PLK was observed in the late proliferative and the early secretory phases, the expression drastically decreased in the late secretory phase. These findings, taken together, indicate that the expression of PLK in normal endometrium fluctuates over the course of the menstrual cycle, suggesting in turn that PLK is associated with hormone-dependent cellular proliferation and that hormone functions may be involved in its regulation.

scholarly journals Human Decidual Stromal Cells as a Component of the Implantation Niche and a Modulator of Maternal Immunity

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Kameliya Vinketova ◽  
Milena Mourdjeva ◽  
Tsvetelina Oreshkova
Keyword(s):  
Menstrual Cycle ◽  
Immune Tolerance ◽  
Immune Cells ◽  
Stromal Cells ◽  
Secretory Phase ◽  
Lymph Vessels ◽  
Uterine Mucosa ◽  
Specialized Tissue ◽  
The Relationship ◽  
Human Decidua

The human decidua is a specialized tissue characterized by embryo-receptive properties. It is formed during the secretory phase of menstrual cycle from uterine mucosa termed endometrium. The decidua is composed of glands, immune cells, blood and lymph vessels, and decidual stromal cells (DSCs). In the process of decidualization, which is controlled by oestrogen and progesterone, DSCs acquire specific functions related to recognition, selection, and acceptance of the allogeneic embryo, as well as to development of maternal immune tolerance. In this review we discuss the relationship between the decidualization of DSCs and pathological obstetrical and gynaecological conditions. Moreover, the critical influence of DSCs on local immune cells populations as well as their relationship to the onset and maintenance of immune tolerance is described.

scholarly journals MiR-184 Combined with STC2 Promotes Endometrial Epithelial Cell Apoptosis in Dairy Goats via RAS/RAF/MEK/ERK Pathway

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1052
Author(s):  
Jiuzeng Cui ◽  
Xiaorui Liu ◽  
Lichun Yang ◽  
Sicheng Che ◽  
Hongran Guo ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Embryo Implantation ◽  
Animal Husbandry ◽  
Dairy Goat ◽  
Marker Genes ◽  
Erk Pathway ◽  
Dairy Goats ◽  
Endometrial Epithelial Cell ◽  
Forkhead Box M1 ◽  
Epithelial Cell Apoptosis

The endometrium undergoes a series of complex changes to form a receptive endometrium (RE) that allows the embryo to be implanted. The inability to establish endometrial receptivity of livestock causes embryo implantation failure and considerable losses to animal husbandry. MicroRNAs (miRNAs) are a class of noncoding RNAs. Studies have found that miRNAs can regulate many critical physiological processes, including the establishment of RE during embryo implantation. miR-184 is highly expressed in the endometrial receptive period of dairy goats. This study aimed to explore the effect of miR-184 on endometrial epithelial cell (EEC) apoptosis and RE establishment. Stanniocalcin2 (STC2) is a direct target of miR-184, and miR-184 decreases the expression of STC2 in dairy goat EECs. miR-184 can activate EECs apoptosis through the RAS/RAF/MEK/ERK pathway. Additionally, miR-184 increases the expression levels of RE marker genes, such as forkhead box M1 (FOXM1) and vascular endothelial growth factor (VEGF). These findings indicate that miR-184 promotes the apoptosis of endometrial epithelial cells in dairy goats by downregulating STC2 via the RAS/RAF/MEK/ERK pathway, and that it may also regulate the establishment of RE in dairy goats.

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 &lt; 0.05) and increased protein levels (P &lt; 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.

Sign in / Sign up

Export Citation Format

Share Document