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

Sinderen, Michelle Van; Oyanedel, Jennifer; Menkhorst, Ellen; Cuman, Carly; Rainczuk, Katarzyna; Winship, Amy; Salamonsen, Lois A.; Edgell, Tracey A.

doi:10.1071/rd15313

Cited by 10 publications

(10 citation statements)

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“…We have previously shown that Notch 1, DLL1 and Jagged1 are all significantly decreased in the endometrial epithelium of women with unexplained primary infertility [7,18]. Interestingly, loss of endometrial epithelial DLL1 in women with unexplained primary infertility may be due to excess cleavage of DLL1 by ADAM17, increasing soluble (s)DLL1 in the uterine lumen [59]. sDLL1 is increased in the uterine lavage of women with primary infertility and impairs blastocyst adhesion in our in vitro model of blastocyst implantation [59].…”

Section: Discussionmentioning

confidence: 65%

MAML1: a coregulator that alters endometrial epithelial cell adhesive capacity

Zafir

Zhou

Menkhorst

et al. 2021

Fertil Res and Pract

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Background Abnormalities in endometrial receptivity has been identified as a major barrier to successful embryo implantation. Endometrial receptivity refers to the conformational and biochemical changes occurring in the endometrial epithelial layer which make it adhesive and receptive to blastocyst attachment. This takes place during the mid-secretory phase of woman’s menstrual cycle and is a result of a delicate interplay between numerous hormones, cytokines and other factors. Outside of this window, the endometrium is refractory to an implanting blastocyst. It has been shown that Notch ligands and receptors are dysregulated in the endometrium of infertile women. Mastermind Like Transcriptional Coactivator 1 (MAML1) is a known coactivator of the Notch signaling pathway. This study aimed to determine the role of MAML1 in regulating endometrial receptivity. Methods The expression and localization of MAML1 in the fertile human endometrium (non-receptive proliferative phase versus receptive mid-secretory phase) were determined by immunohistochemistry. Ishikawa cells were used as an endometrial epithelial model to investigate the functional consequences of MAML1 knockdown on endometrial adhesive capacity to HTR8/SVneo (trophoblast cell line) spheroids. After MAML1 knockdown in Ishikawa cells, the expression of endometrial receptivity markers and Notch dependent and independent pathway members were assessed by qPCR. Two-tailed unpaired or paired student’s t-test were used for statistical analysis with a significance threshold of P < 0.05. Results MAML1 was localized in the luminal epithelium, glandular epithelium and stroma of human endometrium and the increased expression identified in the mid-secretory phase was restricted only to the luminal epithelium (P < 0.05). Functional analysis using Ishikawa cells demonstrated that knockdown of MAML1 significantly reduced epithelial adhesive capacity (P < 0.01) to HTR8/SVneo (trophoblast cell line) spheroids compared to control. MAML1 knockdown significantly affected the expression of classical receptivity markers (SPP1, DPP4) and this response was not directly via hormone receptors. The expression level of Hippo pathway target Ankyrin repeat domain-containing protein 1 (ANKRD1) was also affected after MAML1 knockdown in Ishikawa cells. Conclusion Our data strongly suggest that MAML1 is involved in regulating the endometrial adhesive capacity and may facilitate embryo attachment, either directly or indirectly through the Notch signaling pathway.

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Section: Discussionmentioning

confidence: 65%

MAML1: a coregulator that alters endometrial epithelial cell adhesive capacity

Zafir

Zhou

Menkhorst

et al. 2021

Fertil Res and Pract

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“…Greening et al (45) found a significant alteration in the intracellular protein profile and secretome of ECC-1 cells after supplementation with estrogen and progesterone compared to estrogen alone. Specifically, Van Sinderen et al (46) showed soluble delta-like ligand 1 (DLL1) was increased in the uterine lavage of infertile patients, which was associated with increased intracellular "a disintegrin and metalloprotease" protease-17 (ADAM17) expression in endometrial tissue and reduced epithelial adhesiveness of RL95 cells. ADAM17 cleaves DLL1 into its soluble form, which may inhibit Notch signaling and therefore interfere with endometrial receptivity (46)…”

Section: Resultsmentioning

confidence: 99%

“…To identify the role of specific molecules in endometrial cell adhesive capacity, the levels of the relevant factor is altered experimentally and their effect on adhesion determined. The xCELLigence technology which incorporates real-time monitoring of cell adhesion is also used as an approach to determine endometrial cell adhesive capacity (46). In this assay, endometrial epithelial cells adhesion is measured either directly on attachment to plastic plates or the plates are coated with various extracellular matrix (ECM) proteins and endometrial epithelial cell adhesion measured via electrical impedance in realtime (75).…”

Section: In Vitro Assays Used To Investigate Plasma Membrane Transformentioning

confidence: 99%

“…The importance of integrin avb3 and focal adhesion disruption on implantation has been confirmed in the animal models, as summarized in Table 3. (46). Therefore, both SUSD2 and DLL1 may play a role in Notch signaling in the endometrium, which, importantly, is also a well-known inducer of transcription program switching in the EMT.…”

Section: Comparison Of Cytoskeleton Regulation Between Plasma Membranmentioning

confidence: 99%

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Alterations in Epithelial Cell Polarity During Endometrial Receptivity: A Systematic Review

2020

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Background: Abnormal endometrial receptivity is one of the major causes of embryo implantation failure and infertility. The plasma membrane transformation (PMT) describes the collective morphological and molecular alterations occurring to the endometrial luminal epithelium across the mid-secretory phase of the menstrual cycle to facilitate implantation. Dysregulation of this process directly affects endometrial receptivity and implantation. Multiple parallels between these alterations to confer endometrial receptivity in women have been drawn to those seen during the epithelial-mesenchymal transition (EMT) in tumorigenesis. Understanding these similarities and differences will improve our knowledge of implantation biology, and may provide novel therapeutic targets to manage implantation failure. Methods: A systematic review was performed using the Medline (Ovid), Embase, and Web of Science databases without additional limits. The search terms used were "(plasma membrane* or cell membrane*) and transformation*" and "endometrium or endometrial." Research studies on the PMT or its regulation in women, discussing either the endometrial epithelium, decidualized stroma, or both, were eligible for inclusion. Results: A total of 198 articles were identified. Data were extracted from 15 studies that matched the inclusion criteria. Collectively, these included studies confirmed the alterations occurring to the endometrial luminal epithelium during the PMT are similar to those seen during the EMT. Such similarities included alterations to the actin cytoskeleton remodeling of adherens junctions, integrin expression and epithelial-stromal communication. These were also some differences between these processes, such as the regulation of tight junctions and mucins, which need to be further researched. Conclusions: This review raised the prospect of shared and distinct mechanisms existing in PMT and EMT. Further investigation into similarities between the PMT in the endometrium and the EMT in tumorigenesis may provide new mechanistic insights into PMT and new targets for the management of implantation failure and infertility.

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“…Staining intensity scores were determined by scorers blinded to the patient characteristics as previously published. 24 , 25 A score of 0 denoted no positive brown DROSHA or DICER staining and 3 was intense staining. Scores were averaged and plotted using Graphpad Prism 7.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA Biogenesis Machinery Is Dysregulated in the Endometrium of Infertile Women Suggesting a Role in Receptivity and Infertility

Loke

Rainczuk

Dimitriadis

2019

J Histochem Cytochem.

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MicroRNAs (miRs) regulate endometrial function and their dysregulation could underlie unexplained infertility in women. Ribonucleases including DICER and DROSHA, and the proteins, ARGONAUTE 1 (AGO 1) and 2 (AGO 2) regulate the biogenesis/maturation of miRs. We aimed to elucidate the expression and localization of miR biogenesis machinery components during the human menstrual cycle and compare their levels in endometrium from women with normal fertility and primary unexplained infertility. miR biogenesis components were measured by quantitative-RT-PCR and immunohistochemistry. In the endometrium of women with normal fertility, DROSHA immunolocalized maximally to the epithelium during the early and mid-secretory phases compared with the proliferative and late-secretory phases. Stromal DICER immunostaining intensity was higher in the late-secretory phase compared with all other phases in fertile women. DROSHA mRNA was reduced in the mid-secretory-infertile whole endometrial tissue (has all cells of the tissue), and primary epithelial and stromal cells while no differences were found in DICER, AGO1, and AGO2 mRNA. In the luminal epithelium, DROSHA staining intensity was reduced in early and mid-secretory-infertile while DICER staining was reduced in the early secretory-infertile compared with their respective fertile groups. DICER and DROSHA were dynamically regulated across the menstrual cycle and reduced levels during receptivity phase could underlie implantation failure/infertility.

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

Cited by 10 publications

References 58 publications

MAML1: a coregulator that alters endometrial epithelial cell adhesive capacity

MAML1: a coregulator that alters endometrial epithelial cell adhesive capacity

Alterations in Epithelial Cell Polarity During Endometrial Receptivity: A Systematic Review

MicroRNA Biogenesis Machinery Is Dysregulated in the Endometrium of Infertile Women Suggesting a Role in Receptivity and Infertility

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