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Molecular Mechanisms of Uterine Receptivity for Embryo Implantation
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Molecular Mechanisms of Uterine Receptivity for Embryo Implantation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 December 2023) | Viewed by 16600

Special Issue Editor

Dr. Jan Tesarik

E-Mail Website
Guest Editor
MARGen Clinic, Molecular Assisted Reproducion and Genetics, 18006 Granada, Spain
Interests: human infertility; assisted reproduction; endocrinology; diagnosis; treatment; embryo developmental potential; sperm quality; oocyte quality
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There is no doubt that contemporary diagnostic and treatment strategies aimed at resolving human infertility issues must be based on molecular medicine. Thus, the conventional schemes of diagnostic and therapeutic actions, which have been used for several decades, are to be abandoned in favour of patient-tailored interventions, considering the search for probable molecular issues hindering the establishment and further continuation of pregnancy until the birth of a healthy infant.

This approach revolves around a deep understanding of the molecular mechanisms involved in both embryo development and uterine function. In this Special Issue, we wish to analyse those issues related to uterine function that might cause implantation failure, miscarriage or late spontaneous abortion. Topics related to the molecular mechanisms of implantation, including the actions of the four major human chorionic gonadotropin (hCG) isoforms, classical hCG, hyperglycosylated hCH, free β subunit and sulphated hCG, in the essential events related to embryo implantation, including the function of the ovarian corpus luteum, restructuring of the endometrium, uterine angiogenesis, modification of the immune system and the prevention of early pregnancy loss, are of particular interest. Special attention should be paid to the ovarian–placental transition of progesterone production and possible effects of its alteration on pregnancy outcome. Both studies dealing with humans and those performed in relevant animal models will be considered.

Finally, new ideas about the choice of appropriate treatment methods adapted to specific molecular deficiencies of the female reproductive system are especially needed.

Dr. Jan Tesarik
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • uterine receptivity
  • embryo implantation
  • molecular control
  • miscarriage prevention
  • translational molecular medicine

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Published Papers (8 papers)

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Editorial

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3 pages, 184 KiB  
Editorial
Multiple Mechanisms Controlling Uterine Function: Editorial to Special Issue “Molecular Mechanisms of Uterine Receptivity for Embryo Implantation”
by Jan Tesarik
Int. J. Mol. Sci. 2023, 24(24), 17629; https://doi.org/10.3390/ijms242417629 - 18 Dec 2023
Viewed by 958
Abstract
Uterine (endometrial) receptivity is the ability of the endometrium to successfully attach to the embryo, to promote its implantation, to nourish it and keep it alive [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms of Uterine Receptivity for Embryo Implantation)

Research

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18 pages, 7923 KiB  
Article
An Assessment of the Mechanophysical and Hormonal Impact on Human Endometrial Epithelium Mechanics and Receptivity
by Anna K. Sternberg, Liubov Izmaylova, Volker U. Buck, Irmgard Classen-Linke and Rudolf E. Leube
Int. J. Mol. Sci. 2024, 25(7), 3726; https://doi.org/10.3390/ijms25073726 - 27 Mar 2024
Viewed by 1547
Abstract
The endometrial epithelium and underlying stroma undergo profound changes to support and limit embryo adhesion and invasion, which occur in the secretory phase of the menstrual cycle during the window of implantation. This coincides with a peak in progesterone and estradiol production. We [...] Read more.
The endometrial epithelium and underlying stroma undergo profound changes to support and limit embryo adhesion and invasion, which occur in the secretory phase of the menstrual cycle during the window of implantation. This coincides with a peak in progesterone and estradiol production. We hypothesized that the interplay between hormone-induced changes in the mechanical properties of the endometrial epithelium and stroma supports this process. To study it, we used hormone-responsive endometrial adenocarcinoma-derived Ishikawa cells growing on substrates of different stiffness. We showed that Ishikawa monolayers on soft substrates are more tightly clustered and uniform than on stiff substrates. Probing for mechanical alterations, we found accelerated stress–relaxation after apical nanoindentation in hormone-stimulated monolayers on stiff substrates. Traction force microscopy furthermore revealed an increased number of foci with high traction in the presence of estradiol and progesterone on soft substrates. The detection of single cells and small cell clusters positive for the intermediate filament protein vimentin and the progesterone receptor further underscored monolayer heterogeneity. Finally, adhesion assays with trophoblast-derived AC-1M-88 spheroids were used to examine the effects of substrate stiffness and steroid hormones on endometrial receptivity. We conclude that the extracellular matrix and hormones act together to determine mechanical properties and, ultimately, embryo implantation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Uterine Receptivity for Embryo Implantation)
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18 pages, 6457 KiB  
Article
EGF-Enhanced GnRH-II Regulation in Decidual Stromal Cell Motility through Twist and N-Cadherin Signaling
by Hsien-Ming Wu, Liang-Hsuan Chen, Hong-Yuan Huang, Hsin-Shih Wang and Chia-Lung Tsai
Int. J. Mol. Sci. 2023, 24(20), 15271; https://doi.org/10.3390/ijms242015271 - 17 Oct 2023
Cited by 2 | Viewed by 1559
Abstract
Crucial roles in embryo implantation and placentation in humans include the invasion of the maternal decidua by extravillous trophoblasts and the motile behavior of decidual endometrial stromal cells. The effects of the epidermal growth factor (EGF) and GnRH-II in the endometrium take part [...] Read more.
Crucial roles in embryo implantation and placentation in humans include the invasion of the maternal decidua by extravillous trophoblasts and the motile behavior of decidual endometrial stromal cells. The effects of the epidermal growth factor (EGF) and GnRH-II in the endometrium take part in early pregnancy. In the present study, we demonstrated the coaction of EGF- and GnRH-II-promoted motility of human decidual endometrial stromal cells, indicating the possible roles of EGF and GnRH-II in embryo implantation and early pregnancy. After obtaining informed consent, we obtained human decidual endometrial stromal cells from decidual tissues from normal pregnancies at 6 to 12 weeks of gestation in healthy women undergoing suction dilation and curettage. Cell motility was evaluated with invasion and migration assays. The mechanisms of EGF and GnRH-II were performed using real-time PCR and immunoblot analysis. The results showed that human decidual tissue and stromal cells expressed the EGF and GnRH-I receptors. GnRH-II-mediated cell motility was enhanced by EGF and was suppressed by the knockdown of the endogenous GnRH-I receptor and EGF receptor with siRNA, revealing that GnRH-II promoted the cell motility of human decidual endometrial stromal cells through the GnRH-I receptor and the activation of Twist and N-cadherin signaling. This new concept regarding the coaction of EGF- and GnRH-promoted cell motility suggests that EGF and GnRH-II potentially affect embryo implantation and the decidual programming of human pregnancy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Uterine Receptivity for Embryo Implantation)
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17 pages, 4887 KiB  
Article
Exosomal miR-205-5p Improves Endometrial Receptivity by Upregulating E-Cadherin Expression through ZEB1 Inhibition
by Seong-Lan Yu, Da-Un Jeong, Eui-Jeong Noh, Hye Jin Jeon, Dong Chul Lee, Minho Kang, Tae-Hyun Kim, Sung Ki Lee, Ae Ra Han, Jaeku Kang and Seok-Rae Park
Int. J. Mol. Sci. 2023, 24(20), 15149; https://doi.org/10.3390/ijms242015149 - 13 Oct 2023
Cited by 4 | Viewed by 1823
Abstract
Endometrial receptivity is a complex process that prepares the uterine endometrium for embryo implantation; insufficient endometrial receptivity is one of the causes of implantation failure. Here, we analyzed the microRNA expression profiles of exosomes derived from both receptive (RL95-2) and non-receptive (AN3-CA) endometrial [...] Read more.
Endometrial receptivity is a complex process that prepares the uterine endometrium for embryo implantation; insufficient endometrial receptivity is one of the causes of implantation failure. Here, we analyzed the microRNA expression profiles of exosomes derived from both receptive (RL95-2) and non-receptive (AN3-CA) endometrial epithelial cell (EEC) lines to identify exosomal miRNAs closely linked to endometrial receptivity. Among the 466 differentially expressed miRNAs, miR-205-5p was the most highly expressed in exosomes secreted from receptive RL95-2 cells. miR-205-5p, enriched at the adhesive junction, was closely related to endometrial receptivity. ZEB1, a transcriptional repressor of E-cadherin associated with endometrial receptivity, was identified as a direct target of miR-205-5p. miR-205-5p expression was significantly lower in the endometrial tissues of infertile women than in that of non-infertile women. In vivo, miR-205-5p expression was upregulated in the post-ovulatory phase, and its inhibitor reduced embryo implantation. Furthermore, administration of genetically modified exosomes overexpressing miR-205-5p mimics upregulated E-cadherin expression by targeting ZEB1 and improved spheroid attachment of non-receptive AN3-CA cells. These results suggest that the miR-205-5p/ZEB1/E-cadherin axis plays an important role in regulating endometrial receptivity. Thus, the use of exosomes harboring miR-205-5p mimics can be considered a potential therapeutic approach for improving embryo implantation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Uterine Receptivity for Embryo Implantation)
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12 pages, 1127 KiB  
Article
Closer to the Reality—Proteome Changes Evoked by Endometrial Scratching in Fertile Females
by Iwona Scheliga, Dunja M. Baston-Buest, Gereon Poschmann, Kai Stuehler, Jan-Steffen Kruessel and Alexandra P. Bielfeld
Int. J. Mol. Sci. 2023, 24(17), 13577; https://doi.org/10.3390/ijms241713577 - 1 Sep 2023
Cited by 1 | Viewed by 1499
Abstract
Endometrial scratching (ES) has been widely used in assisted reproductive technology to possibly improve pregnancy rates, but its exact mechanism is still not understood or investigated, and its benefits are controversially discussed. Hypothetically, ES may trigger a local immune response, leading to an [...] Read more.
Endometrial scratching (ES) has been widely used in assisted reproductive technology to possibly improve pregnancy rates, but its exact mechanism is still not understood or investigated, and its benefits are controversially discussed. Hypothetically, ES may trigger a local immune response, leading to an improved endometrial receptivity. So far, it has been shown that ES affects the gene expression of cytokines, growth factors, and adhesive proteins, potentially modulating inflammatory pathways and adhesion molecule expression. Our pilot study applying proteomic analysis reveals that ES probably has an impact on the proteins involved in immune response pathways and cytoskeleton formation, which could potentially increase endometrial receptivity. Specifically, proteins that are involved in the immune response and cytoskeleton regulation showed a trend toward higher abundance after the first ES. On the other hand, proteins with a decreasing abundance after the first ES play roles in the regulation of the actin cytoskeleton and cellular processes such as intracellular transport, apoptosis, and autophagy. These trends in protein changes suggest that ES may affect endometrial tissue stiffness and extracellular matrix remodeling, potentially enhancing the embryos’ implantation. To our knowledge, this pilot study provides, for the first time, data investigating potential changes in the endometrium due to the scratching procedure that might explain its possible benefit for patients in infertility treatment. Furthermore, the proteome of a group of patients suffering from repeated implantation failure was compared to that of the fertile group in order to transfer the basic science to clinical routine and application. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Uterine Receptivity for Embryo Implantation)
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12 pages, 1912 KiB  
Article
Comparing Vaginal and Endometrial Microbiota Using Culturomics: Proof of Concept
by Robin Vanstokstraeten, Ellen Callewaert, Susanne Blotwijk, Eleni Rombauts, Florence Crombé, Kristof Emmerechts, Oriane Soetens, Kristof Vandoorslaer, Deborah De Geyter, Camille Allonsius, Leonore Vander Donck, Christophe Blockeel, Ingrid Wybo, Denis Piérard, Thomas Demuyser and Shari Mackens
Int. J. Mol. Sci. 2023, 24(6), 5947; https://doi.org/10.3390/ijms24065947 - 21 Mar 2023
Cited by 7 | Viewed by 3021
Abstract
It is generally accepted that microorganisms can colonize a non-pathological endometrium. However, in a clinical setting, endometrial samples are always collected by passing through the vaginal–cervical route. As such, the vaginal and cervical microbiomes can easily cross-contaminate endometrial samples, resulting in a biased [...] Read more.
It is generally accepted that microorganisms can colonize a non-pathological endometrium. However, in a clinical setting, endometrial samples are always collected by passing through the vaginal–cervical route. As such, the vaginal and cervical microbiomes can easily cross-contaminate endometrial samples, resulting in a biased representation of the endometrial microbiome. This makes it difficult to demonstrate that the endometrial microbiome is not merely a reflection of contamination originating from sampling. Therefore, we investigated to what extent the endometrial microbiome corresponds to that of the vagina, applying culturomics on paired vaginal and endometrial samples. Culturomics could give novel insights into the microbiome of the female genital tract, as it overcomes sequencing-related bias. Ten subfertile women undergoing diagnostic hysteroscopy and endometrial biopsy were included. An additional vaginal swab was taken from each participant right before hysteroscopy. Both endometrial biopsies and vaginal swabs were analyzed using our previously described WASPLab-assisted culturomics protocol. In total, 101 bacterial and two fungal species were identified among these 10 patients. Fifty-six species were found in endometrial biopsies and 90 were found in vaginal swabs. On average, 28 % of species were found in both the endometrial biopsy and vaginal swab of a given patient. Of the 56 species found in the endometrial biopsies, 13 were not found in the vaginal swabs. Of the 90 species found in vaginal swabs, 47 were not found in the endometrium. Our culturomics-based approach sheds a different light on the current understanding of the endometrial microbiome. The data suggest the potential existence of a unique endometrial microbiome that is not merely a presentation of cross-contamination derived from sampling. However, we cannot exclude cross-contamination completely. In addition, we observe that the microbiome of the vagina is richer in species than that of the endometrium, which contradicts the current sequence-based literature. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Uterine Receptivity for Embryo Implantation)
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Review

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14 pages, 856 KiB  
Review
Expression of HOXA10 Gene in Women with Endometriosis: A Systematic Review
by Nurunnajah Lazim, Marjanu Hikmah Elias, Zulazmi Sutaji, Abdul Kadir Abdul Karim, Mohammad Azrai Abu, Azizah Ugusman, Saiful Effendi Syafruddin, Mohd Helmy Mokhtar and Mohd Faizal Ahmad
Int. J. Mol. Sci. 2023, 24(16), 12869; https://doi.org/10.3390/ijms241612869 - 17 Aug 2023
Cited by 8 | Viewed by 2580
Abstract
The homeobox A10 (HOXA10) gene is known to be related to endometriosis; however, due to a lack of knowledge/evidence in the pathogenesis of endometriosis, the mechanisms that link HOXA10 to endometriosis still need to be clarified. This review addresses the difference [...] Read more.
The homeobox A10 (HOXA10) gene is known to be related to endometriosis; however, due to a lack of knowledge/evidence in the pathogenesis of endometriosis, the mechanisms that link HOXA10 to endometriosis still need to be clarified. This review addresses the difference in the expression of the HOXA10 gene in endometriotic women versus non-endometriotic women across populations by country and discusses its influences on women’s fertility. An organized search of electronic databases was conducted in Scopus, ScienceDirect, PubMed, and Web of Science. The keywords used were (HOXA10 OR “homeobox A10” OR PL OR HOX1 OR HOX1H OR HOX1.8) AND (“gene expression”) AND (endometriosis). The initial search resulted in 623 articles, 10 of which were included in this review. All ten papers included in this study were rated fair in terms of the quality of the studies conducted. The expression of the HOXA10 gene was found to be downregulated in most studies. However, one study provided evidence of the downregulation and upregulation of HOXA10 gene expression due to the localization of endometriotic lesions. Measuring the expression of the HOXA10 gene in women is clinically essential to predicting endometriosis, endometrial receptivity, and the development of pinopodes in the endometrium during the luteal phase. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Uterine Receptivity for Embryo Implantation)
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16 pages, 2521 KiB  
Review
Non-Coding RNAs as Biomarkers for Embryo Quality and Pregnancy Outcomes: A Systematic Review and Meta-Analysis
by Wen Huang, Andy Chun Hang Chen, Ernest Hung Yu Ng, William Shu Biu Yeung and Yin Lau Lee
Int. J. Mol. Sci. 2023, 24(6), 5751; https://doi.org/10.3390/ijms24065751 - 17 Mar 2023
Cited by 1 | Viewed by 2808
Abstract
Despite advances in in vitro fertilization (IVF), there is still a lack of non-invasive and reliable biomarkers for selecting embryos with the highest developmental and implantation potential. Recently, small non-coding RNAs (sncRNAs) have been identified in biological fluids, and extracellular sncRNAs are explored [...] Read more.
Despite advances in in vitro fertilization (IVF), there is still a lack of non-invasive and reliable biomarkers for selecting embryos with the highest developmental and implantation potential. Recently, small non-coding RNAs (sncRNAs) have been identified in biological fluids, and extracellular sncRNAs are explored as diagnostic biomarkers in the prediction of IVF outcomes. To determine the predictive role of sncRNAs in embryo quality and IVF outcomes, a systematic review and meta-analysis was performed. Articles were retrieved from PubMed, EMBASE, and Web of Science from 1990 to 31 July 2022. Eighteen studies that met the selection criteria were analyzed. In total, 22 and 47 different sncRNAs were found to be dysregulated in follicular fluid (FF) and embryo spent culture medium (SCM), respectively. MiR-663b, miR-454 and miR-320a in FF and miR-20a in SCM showed consistent dysregulation in two different studies. The meta-analysis indicated the potential predictive performance of sncRNAs as non-invasive biomarkers, with a pooled area under curve (AUC) value of 0.81 (95% CI 0.78, 0.844), a sensitivity of 0.79 (95% CI 0.72, 0.85), a specificity of 0.67 (95% CI 0.52, 0.79) and a diagnostic odds ratio (DOR) of 8 (95% CI 5, 12). Significant heterogeneity was identified among studies in sensitivity (I2  =  46.11%) and specificity (I2  =  89.73%). This study demonstrates that sncRNAs may distinguish embryos with higher developmental and implantation potentials. They can be promising non-invasive biomarkers for embryo selection in ART. However, the significant heterogeneity among studies highlights the demand for prospective multicenter studies with optimized methods and adequate sample sizes in the future. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Uterine Receptivity for Embryo Implantation)
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