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Voros C, Varthaliti A, Athanasiou D, Mavrogianni D, Bananis K, Athanasiou A, Athanasiou A, Papahliou AM, Zografos CG, Kondili P, Daskalaki MA, Mazis Kourakos D, Vaitsis D, Theodora M, Antsaklis P, Loutradis D, Daskalakis G. MicroRNA Signatures in Endometrial Receptivity-Unlocking Their Role in Embryo Implantation and IVF Success: A Systematic Review. Biomedicines 2025; 13:1189. [PMID: 40427016 PMCID: PMC12109305 DOI: 10.3390/biomedicines13051189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/17/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Endometrial receptivity is crucial for successful embryo implantation in assisted reproductive technologies (ARTs). MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) have emerged as important post-transcriptional regulators of endometrial function, although their diagnostic and molecular functions are poorly understood. Methods: A systematic review was conducted following PRISMA 2020 principles and registered in PROSPERO (CRD420251001811). We looked at 28 peer-reviewed publications published between 2010 and 2025 that used endometrial tissue, blood, uterine fluid, saliva, and embryo culture medium to study miRNAs and other non-coding RNAs in endometrial receptivity, recurrent implantation failure (RIF), and infertility. Results: MiRNAs like miR-145, miR-30d, miR-223-3p, and miR-125b influence implantation-related pathways such as HOXA10, LIF-STAT3, PI3K-Akt, and Wnt/β-catenin. Dysregulated expression profiles were linked to inadequate decidualization, immunological imbalance, and poor angiogenesis. CeRNA networks that include lncRNAs (e.g., H19 and NEAT1) and circRNAs (e.g., circ_0038383) further regulate miRNA activity. Non-invasive biomarkers derived from plasma, uterine fluid, and embryo media showed high prediction accuracy for implantation outcomes. Conclusions: MiRNA signatures offer a functional and diagnostic blueprint for endometrial receptivity. This systematic review provides a timely and thorough synthesis of the existing literature, with the goal of bridging the gap between molecular discoveries and therapeutic applications. By emphasizing both the mechanistic importance and diagnostic value of certain miRNA signatures, it paves the way for future precision-based techniques in embryo transfer and endometrial assessment in ART.
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Affiliation(s)
- Charalampos Voros
- 1st Department of Obstetrics and Gynecology, ‘Alexandra’ General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece; (A.V.); (D.M.); (A.-M.P.); (P.K.); (M.A.D.); (M.T.); (P.A.); (G.D.)
| | - Antonia Varthaliti
- 1st Department of Obstetrics and Gynecology, ‘Alexandra’ General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece; (A.V.); (D.M.); (A.-M.P.); (P.K.); (M.A.D.); (M.T.); (P.A.); (G.D.)
| | - Diamantis Athanasiou
- IVF Athens Reproduction Center V. Athanasiou, 15123 Maroussi, Greece; (D.A.); (A.A.); (A.A.)
| | - Despoina Mavrogianni
- 1st Department of Obstetrics and Gynecology, ‘Alexandra’ General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece; (A.V.); (D.M.); (A.-M.P.); (P.K.); (M.A.D.); (M.T.); (P.A.); (G.D.)
| | - Kyriakos Bananis
- King’s College Hospitals NHS Foundation Trust, London SE5 9RS, UK;
| | - Antonia Athanasiou
- IVF Athens Reproduction Center V. Athanasiou, 15123 Maroussi, Greece; (D.A.); (A.A.); (A.A.)
| | - Aikaterini Athanasiou
- IVF Athens Reproduction Center V. Athanasiou, 15123 Maroussi, Greece; (D.A.); (A.A.); (A.A.)
| | - Anthi-Maria Papahliou
- 1st Department of Obstetrics and Gynecology, ‘Alexandra’ General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece; (A.V.); (D.M.); (A.-M.P.); (P.K.); (M.A.D.); (M.T.); (P.A.); (G.D.)
| | | | - Panagiota Kondili
- 1st Department of Obstetrics and Gynecology, ‘Alexandra’ General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece; (A.V.); (D.M.); (A.-M.P.); (P.K.); (M.A.D.); (M.T.); (P.A.); (G.D.)
| | - Maria Anastasia Daskalaki
- 1st Department of Obstetrics and Gynecology, ‘Alexandra’ General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece; (A.V.); (D.M.); (A.-M.P.); (P.K.); (M.A.D.); (M.T.); (P.A.); (G.D.)
| | - Dimitris Mazis Kourakos
- Rea Maternity Hospital S.A., Avenue Siggrou 383 & Pentelis 17, P. Faliro, 17564 Athens, Greece;
| | - Dimitrios Vaitsis
- Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece (D.L.)
| | - Marianna Theodora
- 1st Department of Obstetrics and Gynecology, ‘Alexandra’ General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece; (A.V.); (D.M.); (A.-M.P.); (P.K.); (M.A.D.); (M.T.); (P.A.); (G.D.)
| | - Panagiotis Antsaklis
- 1st Department of Obstetrics and Gynecology, ‘Alexandra’ General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece; (A.V.); (D.M.); (A.-M.P.); (P.K.); (M.A.D.); (M.T.); (P.A.); (G.D.)
| | - Dimitrios Loutradis
- Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece (D.L.)
- Fertility Institute—Assisted Reproduction Unit, Paster 15, 11528 Athens, Greece
| | - Georgios Daskalakis
- 1st Department of Obstetrics and Gynecology, ‘Alexandra’ General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece; (A.V.); (D.M.); (A.-M.P.); (P.K.); (M.A.D.); (M.T.); (P.A.); (G.D.)
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Mukherjee A, Verma A, Das T, Ghosh B, Ghosh Z. Circulating microRNAs in Body Fluid: "Fingerprint" RNA Snippets Deeply Impact Reproductive Biology. Reprod Sci 2025; 32:555-574. [PMID: 39658771 DOI: 10.1007/s43032-024-01753-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 11/22/2024] [Indexed: 12/12/2024]
Abstract
Circulating miRNAs (C-miRNAs) occuring in a cell-free form within body fluids and other extracellular environments have garnered attention in recent times. They offer deeper insight into various physiological and pathological processes which include reproductive health. This review delves into their diagnostic potential across a spectrum of reproductive disorders, including conditions affecting ovarian function, male infertility and post pregnancy issues. Through analysis of C-miRNA profiles in bodily fluids, researchers uncover crucial markers indicative of reproductive challenges. Dysregulated C-miRNAs emerge as important players in the progression of several reproductive disorders which is the main focus of this review. Advancements in technology, facilitate precise detection and quantification of C-miRNAs, paving the way for innovative diagnostic approaches. Challenges in studying C-miRNAs, such as their low abundance and variability in expression levels, underscore the need for standardized protocols and rigorous validation methods. Despite these challenges, ongoing research endeavors aim to unravel the complex regulatory roles of C-miRNAs in reproductive biology, with potential implications for clinical practice and therapeutic interventions.
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Affiliation(s)
- Ayan Mukherjee
- Department of Animal Biotechnology, West Bengal University of Animal and Fishery Sciences, Mohanpur, West Bengal, 741252, India.
| | - Arpana Verma
- Department of Biological Sciences, Bose Institute, EN Block, Sector V, Kolkata, West Bengal, 700091, India
| | - Troyee Das
- Department of Biological Sciences, Bose Institute, EN Block, Sector V, Kolkata, West Bengal, 700091, India
| | - Byapti Ghosh
- Department of Biological Sciences, Bose Institute, EN Block, Sector V, Kolkata, West Bengal, 700091, India
| | - Zhumur Ghosh
- Department of Biological Sciences, Bose Institute, EN Block, Sector V, Kolkata, West Bengal, 700091, India.
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Ye L, Dimitriadis E. Endometrial Receptivity-Lessons from "Omics". Biomolecules 2025; 15:106. [PMID: 39858500 PMCID: PMC11764156 DOI: 10.3390/biom15010106] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/03/2025] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
The window of implantation (WOI) is a critical phase of the menstrual cycle during which the endometrial lining becomes receptive and facilitates embryo implantation. Drawing on findings from various branches of "omics", including genomics, epigenomics, transcriptomics, proteomics, lipidomics, metabolomics, and microbiomics, this narrative review aims to (1) discuss mechanistic insights on endometrial receptivity and its implication in infertility; (2) highlight advances in investigations for endometrial receptivity; and (3) discuss novel diagnostic and therapeutic strategies that may improve reproductive outcomes.
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Affiliation(s)
- Louie Ye
- Reproductive Service Unit, The Royal Women’s Hospital, Melbourne, VIC 3052, Australia
- Department of Obstetrics, Gynaecology and Newborn Health, University of Melbourne, Melbourne, VIC 3052, Australia;
| | - Evdokia Dimitriadis
- Department of Obstetrics, Gynaecology and Newborn Health, University of Melbourne, Melbourne, VIC 3052, Australia;
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Lee S, Arffman RK, Komsi EK, Lindgren O, Kemppainen J, Kask K, Saare M, Salumets A, Piltonen TT. Dynamic changes in AI-based analysis of endometrial cellular composition: Analysis of PCOS and RIF endometrium. J Pathol Inform 2024; 15:100364. [PMID: 38445292 PMCID: PMC10914580 DOI: 10.1016/j.jpi.2024.100364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/24/2024] [Accepted: 01/24/2024] [Indexed: 03/07/2024] Open
Abstract
Background The human endometrium undergoes a monthly cycle of tissue growth and degeneration. During the mid-secretory phase, the endometrium establishes an optimal niche for embryo implantation by regulating cellular composition (e.g., epithelial and stromal cells) and differentiation. Impaired endometrial development observed in conditions such as polycystic ovary syndrome (PCOS) and recurrent implantation failure (RIF) contributes to infertility. Surprisingly, despite the importance of the endometrial lining properly developing prior to pregnancy, precise measures of endometrial cellular composition in these two infertility-associated conditions are entirely lacking. Additionally, current methods for measuring the epithelial and stromal area have limitations, including intra- and inter-observer variability and efficiency. Methods We utilized a deep-learning artificial intelligence (AI) model, created on a cloud-based platform and developed in our previous study. The AI model underwent training to segment both areas populated by epithelial and stromal endometrial cells. During the training step, a total of 28.36 mm2 areas were annotated, comprising 2.56 mm2 of epithelium and 24.87 mm2 of stroma. Two experienced pathologists validated the performance of the AI model. 73 endometrial samples from healthy control women were included in the sample set to establish cycle phase-dependent dynamics of the endometrial epithelial-to-stroma ratio from the proliferative (PE) to secretory (SE) phases. In addition, 91 samples from PCOS cases, accounting for the presence or absence of ovulation and representing all menstrual cycle phases, and 29 samples from RIF patients on day 5 after progesterone administration in the hormone replacement treatment cycle were also included and analyzed in terms of cellular composition. Results Our AI model exhibited reliable and reproducible performance in delineating epithelial and stromal compartments, achieving an accuracy of 92.40% and 99.23%, respectively. Moreover, the performance of the AI model was comparable to the pathologists' assessment, with F1 scores exceeding 82% for the epithelium and >96% for the stroma. Next, we compared the endometrial epithelial-to-stromal ratio during the menstrual cycle in women with PCOS and in relation to endometrial receptivity status in RIF patients. The ovulatory PCOS endometrium exhibited epithelial cell proportions similar to those of control and healthy women's samples in every cycle phase, from the PE to the late SE, correlating with progesterone levels (control SE, r2 = 0.64, FDR < 0.001; PCOS SE, r2 = 0.52, FDR < 0.001). The mid-SE endometrium showed the highest epithelial percentage compared to both the early and late SE endometrium in both healthy women and PCOS patients. Anovulatory PCOS cases showed epithelial cellular fractions comparable to those of PCOS cases in the PE (Anovulatory, 14.54%; PCOS PE, 15.56%, p = 1.00). We did not observe significant differences in the epithelial-to-stroma ratio in the hormone-induced endometrium in RIF patients with different receptivity statuses. Conclusion The AI model rapidly and accurately identifies endometrial histology features by calculating areas occupied by epithelial and stromal cells. The AI model demonstrates changes in epithelial cellular proportions according to the menstrual cycle phase and reveals no changes in epithelial cellular proportions based on PCOS and RIF conditions. In conclusion, the AI model can potentially improve endometrial histology assessment by accelerating the analysis of the cellular composition of the tissue and by ensuring maximal objectivity for research and clinical purposes.
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Affiliation(s)
- Seungbaek Lee
- Department of Obstetrics and Gynaecology, Research Unit of Clinical Medicine, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu 90220, Finland
- Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia
| | - Riikka K. Arffman
- Department of Obstetrics and Gynaecology, Research Unit of Clinical Medicine, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu 90220, Finland
| | - Elina K. Komsi
- Department of Obstetrics and Gynaecology, Research Unit of Clinical Medicine, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu 90220, Finland
| | - Outi Lindgren
- Department of Pathology, Oulu University Hospital, Cancer and Translational Medicine Research Unit, University of Oulu, Oulu 90220, Finland
| | - Janette Kemppainen
- Department of Pathology, Oulu University Hospital, Cancer and Translational Medicine Research Unit, University of Oulu, Oulu 90220, Finland
| | - Keiu Kask
- Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia
- Competence Centre on Health Technologies, Tartu 51014, Estonia
| | - Merli Saare
- Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia
- Competence Centre on Health Technologies, Tartu 51014, Estonia
| | - Andres Salumets
- Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia
- Competence Centre on Health Technologies, Tartu 51014, Estonia
- Division of Obstetrics and Gynaecology, Department of Clinical Science, Intervention and Technology, Karolinska Institute and Karolinska University Hospital, Stockholm 14152, Sweden
| | - Terhi T. Piltonen
- Department of Obstetrics and Gynaecology, Research Unit of Clinical Medicine, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu 90220, Finland
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5
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Rezaei M, Moghoofei M. The role of viral infection in implantation failure: direct and indirect effects. Reprod Biol Endocrinol 2024; 22:142. [PMID: 39529140 PMCID: PMC11552308 DOI: 10.1186/s12958-024-01303-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Implantation is the key initial complex stage of pregnancy. Several factors are involved in implantation, but acute and controlled inflammation has been shown to play as a key role. On the other hand, the role of viral infections in directly infecting blastocyst and trophoblast and inducing chronic and uncontrolled inflammation and disrupting microRNAs expression can make this review strongly attractive and practical. We aim to provide an overview of viral infections as the potential etiology of unsuccessful implantation pathophysiology through alteration of the cellular and molecular endometrial microenvironment. Based on our search, this is the first review to discuss the role of inflammation associated with viral infection in implantation failure.
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Affiliation(s)
- Marzieh Rezaei
- Department of Obstetrics and Gynecology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohsen Moghoofei
- Infectious Diseases Research Center, Health Research Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Department of Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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6
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Salmasi S, Heidar MS, Khaksary Mahabady M, Rashidi B, Mirzaei H. MicroRNAs, endometrial receptivity and molecular pathways. Reprod Biol Endocrinol 2024; 22:139. [PMID: 39529197 PMCID: PMC11552404 DOI: 10.1186/s12958-024-01304-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
MicroRNAs (miRNAs) are a type of specific molecules that control the activities of the uterus, such as the process of cellular maturing and evolution. A lot of substances like growth factors, cytokines, and transcription factors play a role in embryo-endometrial interaction. MiRNAs could regulate various these factors by attaching to the 3' UTR of their mRNAs. Moreover, current research show that miRNAs participate in formation of blood vessels in endometrium (miR-206, miR-17-5p, miR-16-5p…), decidualization (miR-154, miR-181, miR-9…), epithelial-mesenchymal transition (miR-30a-3p), immune response (miR-888, miR-376a, miR-300…) embryo attachment (miR-145, miR-27a,451…) and pinopod formation (mir-223-3p, mir-449a, mir-200c). In this study, the focus is on the role of miRNAs in managing the uterus' receptivity to an embryo and its ability to facilitate attachment. More specifically, we are exploring the mechanisms by which miRNAs regulate the presence of specific molecules involved in this crucial physiological process.
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Affiliation(s)
- Soheila Salmasi
- Department of Anatomical Sciences & Cognitive Neuroscience, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Saeed Heidar
- Faculty of life sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mahmood Khaksary Mahabady
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Bahman Rashidi
- Department of Anatomical Sciences & Cognitive Neuroscience, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Xue Y, Zheng H, Xiong Y, Li K. Extracellular vesicles affecting embryo development in vitro: a potential culture medium supplement. Front Pharmacol 2024; 15:1366992. [PMID: 39359245 PMCID: PMC11445000 DOI: 10.3389/fphar.2024.1366992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 09/05/2024] [Indexed: 10/04/2024] Open
Abstract
Extracellular vesicles (EVs) are nanometer-sized lipid bilayer vesicles released by cells, playing a crucial role in mediating cellular communication. This review evaluates the effect of EVs on early embryonic development in vitro by systematically searching the literature across three databases, Embase, PubMed, and Scopus, from inception (Embase, 1947; PubMed, 1996; and Scopus, 2004) to 30 June 2024. A total of 28 studies were considered relevant and included in this review. The EVs included in these investigations have been recovered from a range of sources, including oviduct fluid, follicular fluid, uterine fluid, seminal plasma, embryos, oviduct epithelial cells, endometrial epithelial cells, amniotic cells, and endometrial-derived mesenchymal stem cells collected primarily from mice, rabbits, cattle and pigs. This diversity in EV sources highlights the broad interest and potential applications of EVs in embryo culture systems. These studies have demonstrated that supplementation with EVs derived from physiologically normal biofluids and cells to the embryo culture medium system has positive effects on embryonic development. Conversely, EVs derived from cells under pathological conditions have shown a negative impact. This finding underscores the importance of the source and condition of EVs used in culture media. Further, the addition of EVs as a culture medium supplement holds significant therapeutic potential for optimizing in vitro embryo culture systems. In conclusion, this evaluation offers a thorough assessment of the available data on the role of EVs in embryo culture media and highlights the potential and challenges of using EVs in vitro embryo production.
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Affiliation(s)
- Yamei Xue
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Haixia Zheng
- Institute for Reproductive Health, School of Pharmacy, Hangzhou Medical College, Hangzhou, China
| | - Yuping Xiong
- Institute for Reproductive Health, School of Pharmacy, Hangzhou Medical College, Hangzhou, China
| | - Kun Li
- Institute for Reproductive Health, School of Pharmacy, Hangzhou Medical College, Hangzhou, China
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Yu X, Xu J, Song B, Zhu R, Liu J, Liu YF, Ma YJ. The role of epigenetics in women's reproductive health: the impact of environmental factors. Front Endocrinol (Lausanne) 2024; 15:1399757. [PMID: 39345884 PMCID: PMC11427273 DOI: 10.3389/fendo.2024.1399757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 08/28/2024] [Indexed: 10/01/2024] Open
Abstract
This paper explores the significant role of epigenetics in women's reproductive health, focusing on the impact of environmental factors. It highlights the crucial link between epigenetic modifications-such as DNA methylation and histones post-translational modifications-and reproductive health issues, including infertility and pregnancy complications. The paper reviews the influence of pollutants like PM2.5, heavy metals, and endocrine disruptors on gene expression through epigenetic mechanisms, emphasizing the need for understanding how dietary, lifestyle choices, and exposure to chemicals affect gene expression and reproductive health. Future research directions include deeper investigation into epigenetics in female reproductive health and leveraging gene editing to mitigate epigenetic changes for improving IVF success rates and managing reproductive disorders.
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Affiliation(s)
- Xinru Yu
- College Of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Jiawei Xu
- College Of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine School, Jinan, Shandong, China
| | - Bihan Song
- College Of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine School, Jinan, Shandong, China
| | - Runhe Zhu
- College Of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine School, Jinan, Shandong, China
| | - Jiaxin Liu
- College Of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Yi Fan Liu
- Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Ying Jie Ma
- The First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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9
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Kluz N, Kowalczyk E, Wasilewska M, Gil-Kulik P. Diagnostic Value and Molecular Function of MicroRNAs in Endometrial Diseases: A Systematic Review. Cancers (Basel) 2024; 16:2416. [PMID: 39001478 PMCID: PMC11240806 DOI: 10.3390/cancers16132416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/21/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
The human endometrium experiences significant cyclic morphological and biochemical changes throughout the menstrual cycle to prepare for embryo implantation. These processes are meticulously regulated by ovarian steroids and various locally expressed genes, encompassing inflammatory reactions, apoptosis, cell proliferation, angiogenesis, differentiation (tissue formation), and tissue remodeling. MicroRNAs (miRNAs) have been recognized as crucial regulators of gene expression, with their altered expression being linked to the onset and progression of various disorders, including cancer. This review examines the expression of miRNAs in the endometrium and their potential regulatory roles under pathological conditions such as endometriosis, recurrent implantation failure and endometrial cancer. Given miRNAs' critical role in maintaining gene expression stability, understanding the regulatory mechanisms of endometrial miRNAs and identifying their specific target genes could pave the way for developing preventive and therapeutic strategies targeting specific genes associated with these reproductive disorders.
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Affiliation(s)
- Natalia Kluz
- Department of Clinical Genetics, Medical University of Lublin, 11 Radziwillowska Str., 20-080 Lublin, Poland;
| | - Emilia Kowalczyk
- Department of Clinical Genetics, Medical University of Lublin, 11 Radziwillowska Str., 20-080 Lublin, Poland;
| | - Małgorzata Wasilewska
- Department of Physical Chemistry, Institute of Chemical Sciences, Maria Curie-Sklodowska University, Maria Curie-Sklodowska Sq. 3, 20-031 Lublin, Poland;
| | - Paulina Gil-Kulik
- Department of Clinical Genetics, Medical University of Lublin, 11 Radziwillowska Str., 20-080 Lublin, Poland;
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He Y, Ju Y, Lei H, Dong J, Jin N, Lu J, Chen S, Wang X. MiR-135a-5p regulates window of implantation by suppressing pinopodes development and decidualization of endometrial stromal cells. J Assist Reprod Genet 2024; 41:1645-1659. [PMID: 38512656 PMCID: PMC11224217 DOI: 10.1007/s10815-024-03088-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/07/2024] [Indexed: 03/23/2024] Open
Abstract
PURPOSE The window of implantation (WOI) is a brief period during which the endometrium is receptive to embryo implantation. This study investigated the relationship between miR-135a-5p and endometrial receptivity. METHODS Peripheral blood was collected on the day of ovulation and the 5th day after ovulation for high-throughput sequencing from women who achieved clinical pregnancy through natural cycle frozen embryo transfer. RT-qPCR assessed miR-135a-5p expression in the endometrium tissue or cells during the mouse implantation window or decidualization. Scanning electron microscopy was utilized to observe pinopode morphology and quantity in mice overexpressing miR-135a-5p during the WOI. Human endometrial stromal cells (HESC) and artificial induction of mouse uterine decidualization were used to explore whether miR-135a-5p overexpression inhibits decidualization by regulating HOXA10 and BMPR2. Furthermore, the impact of miR-135a-5p on HESC proliferation and HTR8/SVneo invasion was explored. RESULTS A total of 54 women were enrolled in the study. bioinformatics analysis and animal models demonstrated that miR-135a-5p was significantly downregulated during the WOI, and its high expression can lead to abnormal pregnancy outcomes. Overexpression of miR-135a-5p resulted in the absence of pinopode in mouse endometrial tissue during the WOI. High miR-135a-5p levels were found to potentially inhibit endometrial tissue decidualization by downregulating HOXA10 and BMPR2 expression. Finally, CEBPD was identified as a potential regulator of miR-135a-5p, which would explain the decreased miR-135a-5p expression during the WOI. CONCLUSION MiR-135a-5p expression is significantly downregulated during the WOI. High miR-135a-5p levels suppress pinopode development and endometrial tissue decidualization through HOXA10 and BMPR2, contributing to inadequate endometrial receptivity.
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Affiliation(s)
- Yunan He
- Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, No.1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China
- Clinical Research Center for Reproductive Medicine and Gynecological Endocrine Diseases of Shaanxi Province, Xi'an, Shaanxi, China
| | - Ying Ju
- Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, No.1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China
- Clinical Research Center for Reproductive Medicine and Gynecological Endocrine Diseases of Shaanxi Province, Xi'an, Shaanxi, China
| | - Hui Lei
- Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, No.1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China
- Clinical Research Center for Reproductive Medicine and Gynecological Endocrine Diseases of Shaanxi Province, Xi'an, Shaanxi, China
| | - Jie Dong
- Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, No.1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China
- Clinical Research Center for Reproductive Medicine and Gynecological Endocrine Diseases of Shaanxi Province, Xi'an, Shaanxi, China
| | - Ni Jin
- Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, No.1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China
- Clinical Research Center for Reproductive Medicine and Gynecological Endocrine Diseases of Shaanxi Province, Xi'an, Shaanxi, China
| | - Jie Lu
- Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, No.1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China
- Clinical Research Center for Reproductive Medicine and Gynecological Endocrine Diseases of Shaanxi Province, Xi'an, Shaanxi, China
| | - Shuqiang Chen
- Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, No.1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China.
- Clinical Research Center for Reproductive Medicine and Gynecological Endocrine Diseases of Shaanxi Province, Xi'an, Shaanxi, China.
| | - Xiaohong Wang
- Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, No.1 Xinsi Road, Baqiao District, Xi'an, Shaanxi, China.
- Clinical Research Center for Reproductive Medicine and Gynecological Endocrine Diseases of Shaanxi Province, Xi'an, Shaanxi, China.
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11
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Rokhsartalab Azar P, Maleki Aghdam M, Karimi S, Haghtalab A, Sadeghpour S, Mellatyar H, Taheri-Anganeh M, Ghasemnejad-Berenji H. Uterine fluid microRNAs in repeated implantation failure. Clin Chim Acta 2024; 558:119678. [PMID: 38641194 DOI: 10.1016/j.cca.2024.119678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 04/13/2024] [Accepted: 04/15/2024] [Indexed: 04/21/2024]
Abstract
Recurrent implantation failure (RIF) is a significant obstacle in assisted reproductive procedures, primarily because of compromised receptivity. As such, there is a need for a dependable and accurate clinical test to evaluate endometrial receptiveness, particularly during embryo transfer. MicroRNAs (miRNAs) have diverse functions in the processes of implantation and pregnancy. Dysregulation of miRNAs results in reproductive diseases such as recurrent implantation failure (RIF). The endometrium secretes several microRNAs (miRNAs) during the implantation period, which could potentially indicate whether the endometrium is suitable for in vitro fertilization (IVF). The goal of this review is to examine endometrial miRNAs as noninvasive biomarkers that successfully predict endometrium receptivity in RIF.
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Affiliation(s)
| | - Mahdi Maleki Aghdam
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Sarmad Karimi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Arian Haghtalab
- School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Sonia Sadeghpour
- Department of Obstetrics and Gynecology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran; Reproductive Health Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Hojat Ghasemnejad-Berenji
- Reproductive Health Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
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12
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Shen L, Zeng H, Fu Y, Ma W, Guo X, Luo G, Hua R, Wang X, Shi X, Wu B, Luo C, Quan S. Specific plasma microRNA profiles could be potential non-invasive biomarkers for biochemical pregnancy loss following embryo transfer. BMC Pregnancy Childbirth 2024; 24:351. [PMID: 38720272 PMCID: PMC11080217 DOI: 10.1186/s12884-024-06488-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 04/07/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Plasma microRNAs act as biomarkers for predicting and diagnosing diseases. Reliable non-invasive biomarkers for biochemical pregnancy loss have not been established. We aim to analyze the dynamic microRNA profiles during the peri-implantation period and investigate if plasma microRNAs could be non-invasive biomarkers predicting BPL. METHODS In this study, we collected plasma samples from patients undergoing embryo transfer (ET) on ET day (ET0), 11 days after ET (ET11), and 14 days after ET (ET14). Patients were divided into the NP (negative pregnancy), BPL (biochemical pregnancy loss), and CP (clinical pregnancy) groups according to serum hCG levels at day11~14 and ultrasound at day28~35 following ET. MicroRNA profiles at different time-points were detected by miRNA-sequencing. We analyzed plasma microRNA signatures for BPL at the peri-implantation stage, we characterized the dynamic microRNA changes during the implantation period, constructed a microRNA co-expression network, and established predictive models for BPL. Finally, the sequencing results were confirmed by Taqman RT-qPCR. RESULTS BPL patients have distinct plasma microRNA profiles compared to CP patients at multiple time-points during the peri-implantation period. Machine learning models revealed that plasma microRNAs could predict BPL. RT-qPCR confirmed that miR-181a-2-3p, miR-9-5p, miR-150-3p, miR-150-5p, and miR-98-5p, miR-363-3p were significantly differentially expressed between patients with different reproductive outcomes. CONCLUSION Our study highlights the non-invasive value of plasma microRNAs in predicting BPL.
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Affiliation(s)
- Lang Shen
- Reproductive Center of Gynecology and Obstetrics Department, NanFang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Hong Zeng
- Reproductive Center of Gynecology and Obstetrics Department, NanFang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Reproductive Medicine Center, Foshan Maternal and Child Health Care Hospital, Southern Medical University, Foshan, 528000, China
| | - Yu Fu
- Reproductive Center of Gynecology and Obstetrics Department, NanFang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Wenmin Ma
- Department of Reproductive Medicine Center, Foshan Maternal and Child Health Care Hospital, Southern Medical University, Foshan, 528000, China
| | - Xiaoling Guo
- Department of Reproductive Medicine Center, Foshan Maternal and Child Health Care Hospital, Southern Medical University, Foshan, 528000, China
| | - Guoqun Luo
- Department of Reproductive Medicine Center, Foshan Maternal and Child Health Care Hospital, Southern Medical University, Foshan, 528000, China
| | - Rui Hua
- Reproductive Center of Gynecology and Obstetrics Department, NanFang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaocong Wang
- Reproductive Center of Gynecology and Obstetrics Department, NanFang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiao Shi
- Reproductive Center of Gynecology and Obstetrics Department, NanFang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Biao Wu
- Reproductive Center of Gynecology and Obstetrics Department, NanFang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Chen Luo
- Reproductive Center of Gynecology and Obstetrics Department, NanFang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Song Quan
- Reproductive Center of Gynecology and Obstetrics Department, NanFang Hospital, Southern Medical University, Guangzhou, 510515, China.
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13
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Chettiar V, Patel A, Chettiar SS, Jhala DD. Meta-analysis of endometrial transcriptome data reveals novel molecular targets for recurrent implantation failure. J Assist Reprod Genet 2024; 41:1417-1431. [PMID: 38456991 PMCID: PMC11143096 DOI: 10.1007/s10815-024-03077-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 02/27/2024] [Indexed: 03/09/2024] Open
Abstract
PURPOSE Gene expression analysis of the endometrium has been shown to be a useful approach for identifying the molecular signatures and pathways involved in recurrent implantation failure (RIF). Nevertheless, individual studies have limitations in terms of study design, methodology and analysis to detect minor changes in expression levels or identify novel gene signatures associated with RIF. METHOD To overcome this, we conducted an in silico meta-analysis of nine studies, the systematic collection and integration of gene expression data, utilizing rigorous selection criteria and statistical techniques to ensure the robustness of our findings. RESULTS Our meta-analysis successfully unveiled a meta-signature of 49 genes closely associated with RIF. Of these genes, 38 were upregulated and 11 downregulated in RIF patients' endometrium and believed to participate in key processes like cell differentiation, communication, and adhesion. GADD45A, IGF2, and LIF, known for their roles in implantation, were identified, along with lesser-studied genes like OPRK1, PSIP1, SMCHD1, and SOD2 related to female infertility. Many of these genes are involved in MAPK and PI3K-Akt pathways, indicating their role in inflammation. We also investigated to look for key miRNAs regulating these 49 dysregulated mRNAs as potential diagnostic biomarkers. Along with this, we went to associate protein-protein interactions of 49 genes, and we could recognize one cluster consisting of 11 genes (consisted of 22 nodes and 11 edges) with the highest score (p = 0.001). Finally, we validated some of the genes by qRT-PCR in our samples. CONCLUSION In summary, the meta-signature genes hold promise for improving RIF patient identification and facilitating the development of personalized treatment strategies, illuminating the multifaceted nature of this complex condition.
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Affiliation(s)
- Venkatlaxmi Chettiar
- Department of Life Sciences, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
| | - Alpesh Patel
- GeneXplore Diagnostics and Research Centre PVT. LTD., Ahmedabad, Gujarat, India
| | | | - Devendrasinh D Jhala
- Department of Zoology, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India.
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14
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Fathi M, Omrani MA, Kadkhoda S, Ghahghaei-Nezamabadi A, Ghafouri-Fard S. Impact of miRNAs in the pathoetiology of recurrent implantation failure. Mol Cell Probes 2024; 74:101955. [PMID: 38479679 DOI: 10.1016/j.mcp.2024.101955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/05/2024] [Accepted: 03/10/2024] [Indexed: 04/02/2024]
Abstract
Recurrent implantation failure (RIF) is a condition with a multifactorial basis. Recent research has focused on the role of genetic factors in the pathophysiology of RIF. Of particular note, miRNAs have been found to contribute to the pathogenesis of RIF. Several miRNA polymorphisms have been investigated in this context. Moreover, dysregulation of expression of a number of miRNAs, including miR-374a-5p, miR-145-5p, miR-30b-5p, miR-196b-5p, miR-22, miR-181 and miR-145 has been found in RIF. This review concentrates on the role of miRNAs in RIF to help in identification of the molecular basis for this condition and design of more effective methods for management of RIF, especially in a personalized manner that relies on the expression profiles of miRNAs in the peripheral blood or endometrium.
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Affiliation(s)
- Mohadeseh Fathi
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Omrani
- Urology and Nephrology Research Center (UNRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sepideh Kadkhoda
- Urology and Nephrology Research Center (UNRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Akram Ghahghaei-Nezamabadi
- Department of Obstetrics and Gynecology, Arash Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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15
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Zhang Y, Sun X, Li Z, Han X, Wang W, Xu P, Liu Y, Xue Y, Wang Z, Xu S, Wang X, Li G, Tian Y, Zhao Q. Interactions between miRNAs and the Wnt/β-catenin signaling pathway in endometriosis. Biomed Pharmacother 2024; 171:116182. [PMID: 38262146 DOI: 10.1016/j.biopha.2024.116182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 01/25/2024] Open
Abstract
Endometriosis is a disease characterized by the ectopic growth of endometrial tissue (glands and stroma) outside the confines of the uterus and often involves vital organs such as the intestines and urinary system. Endometriosis is considered a refractory disease owing to its enigmatic etiology, propensity for recurrence following conservative or surgical interventions, and the absence of radical treatment and long-term management. In recent years, the incidence of endometriosis has gradually increased, rendering it a pressing concern among women of childbearing age. A more profound understanding of its pathogenesis can significantly improve prognosis. Recent research endeavors have spotlighted the molecular mechanisms by which microRNAs (miRNAs) regulate the occurrence and progression of endometriosis. Many miRNAs have been reported to be aberrantly expressed in the affected tissues of both patients and animal models. These miRNAs actively participate in the regulation of inflammatory reactions, cellular proliferation, angiogenesis, and tissue remodeling. Their capacity to modulate crucial signaling pathways, such as the Wnt/β-catenin signaling pathway, reinforces their potential utility as diagnostic markers or therapeutic agents for endometriosis. In this review, we provide the latest insights into the role of miRNAs that interact with the Wnt/β-catenin pathway to regulate the biological behaviors of endometriosis cells and disease-related symptoms, such as pain and infertility. We hope that this review will provide novel insights and promising targets for innovative therapies addressing endometriosis.
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Affiliation(s)
- Yu Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Xueyu Sun
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China; Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China
| | - Zhongkang Li
- Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China
| | - Xianhong Han
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Wenjun Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Penglin Xu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Yangyang Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Yuna Xue
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Zhe Wang
- Department of Basic Medicine, Chengde Medical College, Chengde, Hebei 067000, PR China
| | - Shuling Xu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Xueying Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Gailing Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Yanpeng Tian
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
| | - Qian Zhao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
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16
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Zahir M, Tavakoli B, Zaki-Dizaji M, Hantoushzadeh S, Majidi Zolbin M. Non-coding RNAs in Recurrent implantation failure. Clin Chim Acta 2024; 553:117731. [PMID: 38128815 DOI: 10.1016/j.cca.2023.117731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/17/2023] [Accepted: 12/18/2023] [Indexed: 12/23/2023]
Abstract
Recurrent implantation failure (RIF), defined as the inability to achieve conception following multiple consecutive in-vitro fertilization (IVF) attempts, represents a complex and multifaceted challenge in reproductive medicine. The emerging role of non-coding RNAs in RIF etiopathogenesis has only gained prominence over the last decade, illustrating a new dimension to our understanding of the intricate network underlying RIF. Successful embryo implantation demands a harmonious synchronization between an adequately decidualized endometrium, a competent blastocyst, and effective maternal-embryonic interactions. Emerging evidence has clarified the involvement of a sophisticated network of non-coding RNAs, including microRNAs, circular RNAs, and long non-coding RNAs, in orchestrating these pivotal processes. Disconcerted expression of these molecules can disrupt the delicate equilibrium required for implantation, amplifying the risk of RIF. This comprehensive review presents an in-depth investigation of the complex role played by non-coding RNAs in the pathogenesis of RIF. Furthermore, it underscores the vast potential of non-coding RNAs as diagnostic biomarkers and therapeutic targets, with the ultimate goal of enhancing implantation success rates in IVF cycles. As ongoing research continues to unravel the intercalated web of molecular interactions, exploiting the power of non-coding RNAs may offer promising avenues for mitigating the challenges posed by RIF and improving the outcomes of assisted reproduction.
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Affiliation(s)
- Mazyar Zahir
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahareh Tavakoli
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Biology, Maragheh University, Maragheh, Iran
| | - Majid Zaki-Dizaji
- Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
| | - Sedigheh Hantoushzadeh
- Vali-E-Asr Reproductive Health Research Center, Family Health Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Masoumeh Majidi Zolbin
- Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
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17
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Soczewski E, Murrieta-Coxca JM, Miranda L, Fuentes-Zacarías P, Gutiérrez-Samudio R, Grasso E, Marti M, PérezLeirós C, Morales-Prieto D, Markert UR, Ramhorst R. miRNAs associated with endoplasmic reticulum stress and unfolded protein response during decidualization. Reprod Biomed Online 2023; 47:103289. [PMID: 37657301 DOI: 10.1016/j.rbmo.2023.103289] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/29/2023] [Accepted: 07/17/2023] [Indexed: 09/03/2023]
Abstract
RESEARCH QUESTION Do microRNAs (miRNAs) play a role in regulating endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) in decidualized cells and endometrium associated with reproductive failures? DESIGN Endometrial stromal cell line St-T1b was decidualized in vitro with 8-Br-cAMP over 5 days, or treated with the ERS inducer thapsigargin. Expression of ERS sensors, UPR markers and potential miRNA regulators was analysed by quantitative PCR. Endometrial biopsies from patients with recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) were investigated for the location of miRNA expression. RESULTS Decidualization of St-T1b cells resulted in increased expression of ERS sensors including ATF6α, PERK and IRE1α, and the UPR marker, CHOP. TXNIP, which serves as a link between the ERS pathway and inflammation, as well as inflammasome NLRP3 and interleukin 1β expression increased in decidualized cells. An in-silico analysis identified miR-17-5p, miR-21-5p and miR-193b-3p as miRNAs potentially involved in regulation of the ERS/UPR pathways and inflammation associated with embryo implantation. Their expression decreased significantly (P ≤ 0.0391) in non-decidualized cells in the presence of thapsigargin. Finally, expression of the selected miRNAs was localized by in-situ hybridization in stromal and glandular epithelial cells in endometrial samples from patients with RPL and RIF. Expression in stroma cells from patients with RPL was lower in comparison with stroma cells from patients with RIF. CONCLUSIONS Decidualization in St-T1b cells is accompanied by ERS/UPR processes, associated with an inflammatory response that is potentially influenced by miR-17-5p, miR-21-5p and miR-193b-3p. These miRNAs are expressed differentially in stromal cells from patients with RPL and RIF, indicating an alteration in regulation of the ERS/UPR pathways.
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Affiliation(s)
- Elizabeth Soczewski
- CONICET, Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales IQUIBICEN, Buenos Aires, Argentina
| | | | - Lucas Miranda
- CONICET, Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales IQUIBICEN, Buenos Aires, Argentina
| | | | | | - Esteban Grasso
- CONICET, Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales IQUIBICEN, Buenos Aires, Argentina
| | - Marcelo Marti
- CONICET, Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales IQUIBICEN, Buenos Aires, Argentina
| | - Claudia PérezLeirós
- CONICET, Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales IQUIBICEN, Buenos Aires, Argentina
| | | | - Udo R Markert
- Placenta Lab, Department of Obstetrics, Jena University Hospital, Jena, Germany.
| | - Rosanna Ramhorst
- CONICET, Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales IQUIBICEN, Buenos Aires, Argentina
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18
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Brennan E, Butler AE, Drage DS, Sathyapalan T, Atkin SL. Serum polychlorinated biphenyl levels and circulating miRNAs in non-obese women with and without polycystic ovary syndrome. Front Endocrinol (Lausanne) 2023; 14:1233484. [PMID: 37790603 PMCID: PMC10544902 DOI: 10.3389/fendo.2023.1233484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 08/24/2023] [Indexed: 10/05/2023] Open
Abstract
Introduction Polychlorinated biphenyls (PCBs), organic lipophilic pollutants that accumulate through diet and increase with age, have been associated with polycystic ovary syndrome (PCOS) and shown to affect microRNA (miRNA) expression. This work aimed to determine if PCBs were associated with circulating miRNAs and whether there were any correlations with serum PCB/miRNA levels and hormonal changes. Methods 29 non-obese PCOS and 29 healthy control women, with similar age and body mass index (BMI), had their serum miRNAs measured together with 7 indicator PCBs (PCB28, PCB52, PCB101, PCB118, PCB138, PCB153, PCB180) using high resolution gas chromatography coupled with high resolution mass spectrometry. Results In the combined study cohort, four miRNAs (hsa-miR-139-5p, hsa-miR-424-5p, hsa-miR-195-5p, hsa-miR-335-5p) correlated with PCBs, but none correlated with metabolic parameters. hsa-miR-335-5p correlated with FSH. When stratified, 25 miRNAs correlated with PCBs in controls compared to only one (hsa-miR-193a-5p) in PCOS; none of these miRNAs correlated with the metabolic parameters of BMI, insulin resistance, or inflammation (C-reactive protein, CRP). However, of these 25 miRNAs in controls, hsa-miR-26a-5p, hsa-miR-193a-5p, hsa-miR-2110 and hsa-miR-195-5p positively correlated with luteinizing hormone (LH), hsa-miR-99b-5p and hsa-miR-146b-5p correlated with estradiol, hsa-miR-193a-5p correlated with progesterone, hsa-miR-195-5p correlated with follicle stimulating hormone (FSH), and hsa-miR-139-5p and hsa-miR-146b-5p negatively correlated with anti-müllerian hormone (AMH) (all p<0.05). hsa-miR-193a-5p in PCOS cases correlated with estradiol. Conclusion In this cohort of women, with no difference in age and BMI, and with similar PCB levels, the miRNAs correlating to PCBs associated with menstrual cycle factors in healthy menstruating controls versus the anovulatory PCOS subjects. The PCB-associated miRNAs did not correlate with non-reproductive hormonal and metabolic parameters. This suggests that PCB effects on miRNAs may result in changes to the hypothalamo-ovarian axis that may thus affect fertility.
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Affiliation(s)
- Edwina Brennan
- School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain, Busaiteen, Bahrain
| | - Alexandra E. Butler
- School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain, Busaiteen, Bahrain
| | - Daniel S. Drage
- School of Geography, Earth and Environmental Sciences, University of Birmingham, Birmingham, United Kingdom
- Queensland Alliance for Environmental Health Sciences, The University of Queensland, Brisbane, QLD, Australia
| | | | - Stephen L. Atkin
- School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain, Busaiteen, Bahrain
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19
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Parraga-Leo A, Sebastian-Leon P, Devesa-Peiro A, Marti-Garcia D, Pellicer N, Remohi J, Dominguez F, Diaz-Gimeno P. Deciphering a shared transcriptomic regulation and the relative contribution of each regulator type through endometrial gene expression signatures. Reprod Biol Endocrinol 2023; 21:84. [PMID: 37700285 PMCID: PMC10496172 DOI: 10.1186/s12958-023-01131-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 08/22/2023] [Indexed: 09/14/2023] Open
Abstract
BACKGORUND While various endometrial biomarkers have been characterized at the transcriptomic and functional level, there is generally a poor overlap among studies, making it unclear to what extent their upstream regulators (e.g., ovarian hormones, transcription factors (TFs) and microRNAs (miRNAs)) realistically contribute to menstrual cycle progression and function. Unmasking the intricacies of the molecular interactions in the endometrium from a novel systemic point of view will help gain a more accurate perspective of endometrial regulation and a better explanation the molecular etiology of endometrial-factor infertility. METHODS An in-silico analysis was carried out to identify which regulators consistently target the gene biomarkers proposed in studies related to endometrial progression and implantation failure (19 gene lists/signatures were included). The roles of these regulators, and of genes related to progesterone and estrogens, were then analysed in transcriptomic datasets compiled from samples collected throughout the menstrual cycle (n = 129), and the expression of selected TFs were prospectively validated in an independent cohort of healthy participants (n = 19). RESULTS A total of 3,608 distinct genes from the 19 gene lists were associated with endometrial progression and implantation failure. The lists' regulation was significantly favoured by TFs (89% (17/19) of gene lists) and progesterone (47% (8 /19) of gene lists), rather than miRNAs (5% (1/19) of gene lists) or estrogen (0% (0/19) of gene lists), respectively (FDR < 0.05). Exceptionally, two gene lists that were previously associated with implantation failure and unexplained infertility were less hormone-dependent, but primarily regulated by estrogen. Although endometrial progression genes were mainly targeted by hormones rather than non-hormonal contributors (odds ratio = 91.94, FDR < 0.05), we identified 311 TFs and 595 miRNAs not previously associated with ovarian hormones. We highlight CTCF, GATA6, hsa-miR-15a-5p, hsa-miR-218-5p, hsa-miR-107, hsa-miR-103a-3p, and hsa-miR-128-3p, as overlapping novel master regulators of endometrial function. The gene expression changes of selected regulators throughout the menstrual cycle (FDR < 0.05), dually validated in-silico and through endometrial biopsies, corroborated their potential regulatory roles in the endometrium. CONCLUSIONS This study revealed novel hormonal and non-hormonal regulators and their relative contributions to endometrial progression and pathology, providing new leads for the potential causes of endometrial-factor infertility.
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Affiliation(s)
- Antonio Parraga-Leo
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Valencia, Spain
- Department of Pediatrics, Obstetrics and Gynaecology, Universidad de Valencia, Av. Blasco Ibáñez 15, 46010, Valencia, Valencia, Spain
| | - Patricia Sebastian-Leon
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Valencia, Spain
| | - Almudena Devesa-Peiro
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Valencia, Spain
- Department of Pediatrics, Obstetrics and Gynaecology, Universidad de Valencia, Av. Blasco Ibáñez 15, 46010, Valencia, Valencia, Spain
| | - Diana Marti-Garcia
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Valencia, Spain
- Department of Pediatrics, Obstetrics and Gynaecology, Universidad de Valencia, Av. Blasco Ibáñez 15, 46010, Valencia, Valencia, Spain
| | - Nuria Pellicer
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Valencia, Spain
- IVIRMA Global Research Alliance, IVIRMA Valencia, Plaza de La Policia Local 3, 46015, Valencia, Spain
| | - Jose Remohi
- Department of Pediatrics, Obstetrics and Gynaecology, Universidad de Valencia, Av. Blasco Ibáñez 15, 46010, Valencia, Valencia, Spain
- IVIRMA Global Research Alliance, IVIRMA Valencia, Plaza de La Policia Local 3, 46015, Valencia, Spain
| | - Francisco Dominguez
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Valencia, Spain
| | - Patricia Diaz-Gimeno
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Av. Fernando Abril Martorell 106, Torre A, Planta 1ª, 46026, Valencia, Valencia, Spain.
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Dong J, Wang L, Xing Y, Qian J, He X, Wu J, Zhou J, Hai L, Wang J, Yang H, Huang J, Gou X, Ju Y, Wang X, He Y, Su D, Kong L, Liang B, Wang X. Dynamic peripheral blood microRNA expression landscape during the peri-implantation stage in women with successful pregnancy achieved by single frozen-thawed blastocyst transfer. Hum Reprod Open 2023; 2023:hoad034. [PMID: 37700872 PMCID: PMC10493182 DOI: 10.1093/hropen/hoad034] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 08/07/2023] [Indexed: 09/14/2023] Open
Abstract
STUDY QUESTION What are the dynamic expression features of plasma microRNAs (miRNAs) during the peri-implantation period in women with successful pregnancy via single frozen-thawed blastocyst transfer? SUMMARY ANSWER There is a significant change in the plasma miRNA expression profile before and after blastocyst transfer, during the window of implantation. WHAT IS KNOWN ALREADY The expression of miRNAs in peripheral blood has indicative functions during the peri-implantation period. Nevertheless, the dynamic expression profile of circulating miRNAs during the peri-implantation stage in women with a successful pregnancy has not been studied. STUDY DESIGN SIZE DURATION Seventy-six women treated for infertility with a single frozen-thawed blastocyst transfer in a natural cycle were included in this study. Among them, 57 women had implantation success and a live birth, while 19 patients experienced implantation failure. Peripheral blood samples were collected at five different time points throughout the peri-implantation period, including D0 (ovulation day), D3, D5, D7, and D9 in this cycle of embryo transfer. The plasma miRNAs in women with blastocyst transfer were isolated, sequenced, and analyzed. PARTICIPANTS/MATERIALS SETTING METHODS Peripheral blood samples were collected in EDTA tubes and stored at -80°C until further use. miRNAs were isolated from blood, cDNA libraries were constructed, and the resulting sequences were mapped to the human genome. The plasma miRNAs were initially analyzed in a screening cohort (n = 34) with successful pregnancy. Trajectory analysis, including a global test and pairwise comparisons, was performed to detect dynamic differentially expressed (DE) miRNAs. Fuzzy c-means clustering was conducted for all dynamic DE miRNAs. The correlation between DE miRNAs and clinical characteristics of patients was investigated using a linear mixed model. Target genes of the miRNAs were predicted, and functional annotation analysis was performed. The expression of DE miRNAs was also identified in a validation set consisting of women with successful (n = 23) and unsuccessful (n = 19) pregnancies. MAIN RESULTS AND THE ROLE OF CHANCE Following small RNA sequencing, a total of 2656 miRNAs were determined as valid read values. After trajectory analysis, 26 DE miRNAs (false discovery rate < 0.05) were identified by the global test, while pairwise comparisons in addition identified 20 DE miRNAs. A total of seven distinct clusters representing different temporal patterns of miRNA expression were discovered. Nineteen DE miRNAs were further identified to be associated with at least one clinical trait. Endometrium thickness and progesterone level showed a correlation with multiple DE miRNAs (including two of the same miRNAs, hsa-miR-1-3p and hsa-miR-6741-3p). Moreover, the 19 DE miRNAs were predicted to have 403 gene targets, and there were 51 (12.7%) predicted genes likely involved in both decidualization and embryo implantation. Functional annotation for predicted targets of those clinically related DE miRNAs suggested the involvement of vascular endothelial growth factor and Wnt signaling pathways, as well as responses to hormones, immune responses, and cell adhesion-related signaling pathways during the peri-implantation stage. LARGE SCALE DATA The raw miRNA sequence data reported in this article have been deposited in the Genome Sequence Archive (GSA-Human: HRA005227) and are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human/browse/HRA005227. LIMITATIONS REASONS FOR CAUTION Although the RNA sequencing results revealed the global dynamic changes of miRNA expression, further experiments examining the clinical significance of the identified DE miRNAs in embryo implantation outcome and the relevant regulatory mechanisms involved are warranted. WIDER IMPLICATIONS OF THE FINDINGS Understanding the dynamic landscape of the miRNA transcriptome could shed light on the physiological mechanisms involved from ovulation to the post-implantation stage, as well as identifying biomarkers that characterize stage-related biological process. STUDY FUNDING/COMPETING INTERESTS The study was funded by the Major clinical research project of Tangdu Hospital (2021LCYJ004) and the Discipline Platform Improvement Plan of Tangdu Hospital (2020XKPT003). The funders had no influence on the study design, data collection, and analysis, decision to publish, or preparation of the article. There are no conflicts of interest to declare.
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Affiliation(s)
- Jie Dong
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Lu Wang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Yanru Xing
- Research Department, Basecare Medical Device Co, Suzhou, China
| | - Jun Qian
- Research Department, Basecare Medical Device Co, Suzhou, China
| | - Xiao He
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Jing Wu
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Juan Zhou
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Li Hai
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Jun Wang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Hongya Yang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Jianlei Huang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Xingqing Gou
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Ying Ju
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Xiyi Wang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Yunan He
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Danjie Su
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
| | - Lingyin Kong
- Research Department, Basecare Medical Device Co, Suzhou, China
| | - Bo Liang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaohong Wang
- Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi Province, China
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Piergentili R, Gullo G, Basile G, Gulia C, Porrello A, Cucinella G, Marinelli E, Zaami S. Circulating miRNAs as a Tool for Early Diagnosis of Endometrial Cancer-Implications for the Fertility-Sparing Process: Clinical, Biological, and Legal Aspects. Int J Mol Sci 2023; 24:11356. [PMID: 37511115 PMCID: PMC10379073 DOI: 10.3390/ijms241411356] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/04/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
This review article explores the possibility of developing an integrated approach to the management of the different needs of endometrial cancer (EC) patients seeking to become pregnant. Life preservation of the woman, health preservation of the baby, a precocious and-as much as possible-minimally invasive characterization of the health and fertility parameters of the patient, together with the concerns regarding the obstetric, neonatal, and adult health risks of the children conceived via assisted reproductive techniques (ART) are all essential aspects of the problem to be taken into consideration, yet the possibility to harmonize such needs through a concerted and integrated approach is still very challenging. This review aims to illustrate the main features of EC and how it affects the normal physiology of pre-menopausal women. We also focus on the prospect of a miR-based, molecular evaluation of patient health status, including both EC early diagnosis and staging and, similarly, the receptivity of the woman, discussing the possible evaluation of both aspects using a single specific panel of circulating miRs in the patient, thus allowing a relatively fast, non-invasive testing with a significantly reduced margin of error. Finally, the ethical and legal/regulatory aspects of such innovative techniques require not only a risk-benefit analysis; respect for patient autonomy and equitable health care access allocation are fundamental issues as well.
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Affiliation(s)
- Roberto Piergentili
- Istituto di Biologia e Patologia Molecolari del CNR (IBPM-CNR), 00185 Rome, Italy
| | - Giuseppe Gullo
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, IVF UNIT, University of Palermo, 90146 Palermo, Italy
| | | | - Caterina Gulia
- Dipartimento di Urologia, Ospedale della Misericordia, 58100 Grosseto, Italy
| | - Alessandro Porrello
- Lineberger Comprehensive Cancer Center & RNA Discovery Center, University of North Carolina at Chapel Hill, 450 West Drive, Chapel Hill, NC 27599, USA
| | - Gaspare Cucinella
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, IVF UNIT, University of Palermo, 90146 Palermo, Italy
| | - Enrico Marinelli
- Department of Medico-Surgical Sciences and Biotechnologies, "Sapienza" University of Rome, 00161 Rome, Italy
| | - Simona Zaami
- Department of Anatomical, Histological, Forensic and Orthopedic Sciences, "Sapienza" University of Rome, 00161 Rome, Italy
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22
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Dong F, Liu Y, Yan W, Meng Q, Song X, Cheng B, Yao R. Netrin-4: Focus on Its Role in Axon Guidance, Tissue Stability, Angiogenesis and Tumors. Cell Mol Neurobiol 2023; 43:1663-1683. [PMID: 36350538 PMCID: PMC11412186 DOI: 10.1007/s10571-022-01279-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/26/2022] [Indexed: 11/11/2022]
Abstract
Netrin-4, a member of the Netrins family, is an important secreted protein that plays a role in axonal outgrowth and migration orientation. It was initially described that Netrin-4 had a high correlation with the laminin β-chain and promoted the growth of neurites in cultured olfactory bulb explants. Subsequently, it was discovered that Netrin-4 is involved in regulating various physiological processes, including angiogenesis, the occurrence and metastasis of various tumors, and the development of the kidney and alveoli. This paper reviews the current research on Netrin-4 since its discovery and provides a theoretical basis for further research on the biological characteristics of Netrin-4. Effects of Netrin-4. Netrin-4 regulates axon guidance, angiogenesis and the development of various tumors.
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Affiliation(s)
- Fuxing Dong
- Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu Province, People's Republic of China
- Public Experimental Research Center, Xuzhou Medical University, Xuzhou, 221004, Jiangsu Province, People's Republic of China
| | - Yaping Liu
- Laboratory of National Experimental Teaching and Demonstration Center of Basic Medicine, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu Province, People's Republic of China
| | - Weixing Yan
- Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu Province, People's Republic of China
| | - Qiqi Meng
- Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu Province, People's Republic of China
| | - Xueli Song
- Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu Province, People's Republic of China
| | - Bing Cheng
- Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu Province, People's Republic of China
| | - Ruiqin Yao
- Department of Cell Biology and Neurobiology, Xuzhou Key Laboratory of Neurobiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu Province, People's Republic of China.
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23
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Azizi E, Mofarahe ZS, Naji M. MicroRNAs, small regulatory elements with significant effects on human implantation: a review. J Assist Reprod Genet 2023; 40:697-717. [PMID: 36723761 PMCID: PMC10224887 DOI: 10.1007/s10815-023-02735-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 01/23/2023] [Indexed: 02/02/2023] Open
Abstract
Embryo implantation is a critical process for achieving a successful pregnancy and live birth. The proper implantation must have a synchronized interaction between blastocyst and a receptive endometrium. Many genes are involved in the modulation of precise molecular events during implantation. MicroRNAs (miRNAs) have been extensively reported as gene regulatory molecules on post-transcriptional levels involved in various biological processes such as gametogenesis, embryogenesis, and the quality of sperm, oocyte, and embryos. A plethora of evidence has demonstrated critical roles for miRNAs in regulating genes involved in the implantation process; hence, dysregulation of miRNAs could be associated with significant impairments in implantation, such as recurrent implantation failure. In addition to the indispensable role of miRNAs in the intracellular control of gene expression, they can also be secreted into extracellular fluid and circulation. Therefore, miRNAs in body fluids and blood may be exploited as non-invasive diagnostic biomarkers for different pathological and physiological conditions. Recently, several studies have focused on the discovery of miRNAs function in the implantation process by appraising miRNAs and their target genes in human embryos, endometrial tissue, and cell culture models. Moreover, it was revealed that there could be a significant association between endometrial receptivity or implantation status and the expression of miRNAs in human body fluids, reinforcing their role as non-invasive biomarkers. In the current work, we reviewed the studies concerning the role of intracellular and extracellular miRNAs in human implantation and the influence of their dysregulation on implantation disorders.
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Affiliation(s)
- Elham Azizi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Shams Mofarahe
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Naji
- Urology and Nephrology Research Center (UNRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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24
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Saadeldin IM, Tanga BM, Bang S, Seo C, Maigoro AY, Kang H, Cha D, Yun SH, Kim SI, Lee S, Cho J. Isolation, characterization, proteome, miRNAome, and the embryotrophic effects of chicken egg yolk nanovesicles (vitellovesicles). Sci Rep 2023; 13:4204. [PMID: 36918605 PMCID: PMC10014936 DOI: 10.1038/s41598-023-31012-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 03/06/2023] [Indexed: 03/16/2023] Open
Abstract
Egg yolk constitutes about a third of the structure of the chicken egg however, the molecular structure and physiological effects of egg yolk-derived lipid membranous vesicles are not clearly understood. In this study, for the first record, the egg yolk nanovesicles (vitellovesicles, VVs) were isolated, characterized, and used as a supplement for porcine embryo culture. Yolks of ten freshly oviposited eggs were filtered and ultracentrifuged at 100,000 × g for 3 h to obtain a pellet. Cryogenic transmission electron microscopy and nanoparticle tracking analysis of the pellet revealed bilipid membranous vesicles. Protein contents of the pellet were analyzed using tandem mass spectrometry and the miRNA content was also profiled through BGISEQ-500 sequencer. VVs were supplemented with the in vitro culture medium of day-7 hatched parthenogenetic blastocysts. After 2 days of blastocyst culture, the embryonic cell count was increased in VVs supplemented embryos in comparison to the non-supplemented embryos. TUNEL assay showed that apoptotic cells were increased in control groups when compared with the VVs supplemented group. Reduced glutathione was increased by 2.5 folds in the VVs supplemented group while reactive oxygen species were increased by 5.3 folds in control groups. Quantitative PCR analysis showed that VVs significantly increased the expression of lipid metabolism-associated genes (monoglyceride lipase and lipase E), anti-apoptotic gene (BCL2), and superoxide dismutase, while significantly reducing apoptotic gene (BAX). Culturing embryos on Matrigel basement membrane matrix indicated that VVs significantly enhanced embryo attachment and embryonic stem cell outgrowths compared to the non-supplemented group. This considers the first report to characterize the molecular bioactive cargo contents of egg yolk nanovesicles to show their embryotrophic effect on mammalian embryos. This effect might be attributed to the protein and miRNA cargo contents of VVs. VVs can be used for the formulation of in vitro culture medium for mammalian embryos including humans.
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Affiliation(s)
- Islam M Saadeldin
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, 99, Daehak-Ro, Daejeon, 34134, Republic of Korea.
- Research Institute of Veterinary Medicine, Chungnam National University, Daejeon, 34134, Republic of Korea.
| | - Bereket Molla Tanga
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, 99, Daehak-Ro, Daejeon, 34134, Republic of Korea
| | - Seonggyu Bang
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, 99, Daehak-Ro, Daejeon, 34134, Republic of Korea
| | - Chaerim Seo
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, 99, Daehak-Ro, Daejeon, 34134, Republic of Korea
| | - Abdulkadir Y Maigoro
- Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Heejae Kang
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, 99, Daehak-Ro, Daejeon, 34134, Republic of Korea
| | - Dabin Cha
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, 99, Daehak-Ro, Daejeon, 34134, Republic of Korea
| | - Sung Ho Yun
- Korea Basic Science Institute (KBSI), Ochang, 28119, Republic of Korea
| | - Seung Il Kim
- Korea Basic Science Institute (KBSI), Ochang, 28119, Republic of Korea
| | - Sanghoon Lee
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, 99, Daehak-Ro, Daejeon, 34134, Republic of Korea
| | - Jongki Cho
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, 99, Daehak-Ro, Daejeon, 34134, Republic of Korea.
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25
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Machtinger R, Racowsky C, Baccarelli AA, Bollati V, Orvieto R, Hauser R, Barnett-Itzhaki Z. Recombinant human chorionic gonadotropin and gonadotropin-releasing hormone agonist differently affect the profile of extracellular vesicle microRNAs in human follicular fluid. J Assist Reprod Genet 2023; 40:527-536. [PMID: 36609942 PMCID: PMC10033801 DOI: 10.1007/s10815-022-02703-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 12/19/2022] [Indexed: 01/08/2023] Open
Abstract
PURPOSE To compare the expression profile of extracellular vesicle microRNAs (EV-miRNAs) derived from follicular fluid after a trigger with recombinant human chorionic gonadotropin (r-hCG) or with a gonadotropin-releasing hormone GnRH agonist (GnRH-a) for final oocyte maturation. METHODS A retrospective analysis of a prospective cohort. Women undergoing in vitro fertilization at a tertiary university-affiliated hospital were recruited between 2014 and 2016. EV-miRNAs were extracted from the follicular fluid of a single follicle, and their expression was assessed using TaqMan Open Array®. Genes regulated by EV-miRNAs were analyzed using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources, Kyoto-Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO). RESULTS Eighty-two women were included in the r-hCG trigger group and 9 in the GnRH-a group. Of 754 EV-miRNAs screened, 135 were detected in at least 50% of the samples and expressed in both groups and were further analyzed. After adjusting for multiple testing, 41 EV-miRNAs whose expression levels significantly differed between the two trigger groups were identified. Bioinformatics analysis of the genes regulated by these EV-miRNAs showed distinct pathways between the two triggers, including TGF-beta signaling, cell cycle, and Wnt signaling pathways. Most of these pathways regulate cascades associated with apoptosis, embryo development, implantation, decidualization, and placental development. CONCLUSIONS Trigger with GnRH-a or r-hCG leads to distinct EV-miRNAs expression profiles and to downstream biological effects in ovarian follicles. These findings may provide an insight for the increased apoptosis and the lower implantation rates following GnRH-a trigger vs. r-hCG in cases lacking intensive luteal phase support.
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Affiliation(s)
- R Machtinger
- Department of Obstetrics and Gynecology, Division of IVF, Sheba Medical Center, Ramat Gan 5262000, Israel.
- Sackler School of Medicine, Tel-Aviv University, 6997801, Tel Aviv, Israel.
| | - C Racowsky
- Department of Obstetrics, Gynecology and Reproductive Medicine, Hospital Foch, Suresnes, France
| | - A A Baccarelli
- Laboratory of Precision Environmental Biosciences, Department of Environmental Health Sciences, Columbia Mailman School of Public Health, New York, NY, 10032, USA
| | - V Bollati
- EPIGET Lab, Department of Clinical Sciences and Community Health, Università Degli Studi Di Milano, 20122, Milan, Italy
- Occupational Health Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy
| | - R Orvieto
- Department of Obstetrics and Gynecology, Division of IVF, Sheba Medical Center, Ramat Gan 5262000, Israel
| | - R Hauser
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Z Barnett-Itzhaki
- Public Health Services, Ministry of Health, 9446724, Jerusalem, Israel
- Faculty of Engineering, Ruppin Academic Center, 4025000, Emek Hefer, Israel
- Ruppin Research Group in Environmental and Social Sustainability, Ruppin Academic Center, 4025000, Emek Hefer, Israel
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Eivazi S, Tanhaye Kalate Sabz F, Amiri S, Zandieh Z, Bakhtiyari M, Rashidi M, Aflatoonian R, Mehraein F, Amjadi F. MiRNAs secreted by human blastocysts could be potential gene expression regulators during implantation. Mol Biol Rep 2023; 50:1375-1383. [PMID: 36469260 DOI: 10.1007/s11033-022-08121-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 11/14/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Micro RNAs (miRNAs) are small non-coding RNAs known as essential regulators of cell-cell communication. Recent studies have revealed that miRNAs are secreted by a blastocyst in culture media. We hypothesized that endometrial epithelial cells take up embryo-derived miRNAs as well as other soluble factors and regulate their receptivity-related gene expression. METHODS AND RESULTS Blastocyst culture media (BCM) were collected from the individually cultured embryos, while human endometrial epithelial cells (HEECs) were collected from healthy fertile volunteers. To evaluate the effect of BCM on the endometrial receptivity gene expression, HEECs were co-cultured with implanted BCM, non-implanted BCM, and a control culture medium. After determining altered gene expression in the HEECs, the miRNAs-related genes through bioinformatics databases were identified and evaluated in the BCM. Co-culture of primary HEECs with BCM significantly stimulated the expression levels of VEGFA, HBEGF, HOXA10, and LIF in the implanted group compared with non-implanted and control groups. The fold changes of miR-195 significantly diminished in the implanted BCM group compared with the non-implanted BCM group. Reduced fold changes of miR-29b, 145 and increased miR-223 were also observed in the implanted BCM group compared with the non-implanted ones. CONCLUSION miRNAs could function as potential gene expression regulators during implantation. These molecules are secreted by human blastocyst, taken up by endometrial epithelial cells, and cause a change in the endometrial function. We found that BCMs can be effective in implantation process by stimulating related receptivity gene expression.
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Affiliation(s)
- Sadegh Eivazi
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, 1168743514, Iran
| | - Fatemeh Tanhaye Kalate Sabz
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, 1168743514, Iran
- Department of Anatomical Sciences and Pathology, School of Medicine, North Khorasan University of Medical Sciences, bojnurd, Iran
| | - Sadegh Amiri
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, 1168743514, Iran
| | - Zahra Zandieh
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, 1168743514, Iran
- Shahid Akbar Abadi Clinical Research Development Unit (SHACRDU), School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Mehrdad Bakhtiyari
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, 1168743514, Iran
| | - Mandana Rashidi
- Shahid Akbar Abadi Clinical Research Development Unit (SHACRDU), School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Reza Aflatoonian
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Fereshteh Mehraein
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, 1168743514, Iran.
| | - Fatemehsadat Amjadi
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, 1168743514, Iran.
- Shahid Akbar Abadi Clinical Research Development Unit (SHACRDU), School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
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Yaghoobi A, Nazerian Y, Meymand AZ, Ansari A, Nazerian A, Niknejad H. Hypoxia-sensitive miRNA regulation via CRISPR/dCas9 loaded in hybrid exosomes: A novel strategy to improve embryo implantation and prevent placental insufficiency during pregnancy. Front Cell Dev Biol 2023; 10:1082657. [PMID: 36704201 PMCID: PMC9871368 DOI: 10.3389/fcell.2022.1082657] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 12/21/2022] [Indexed: 01/12/2023] Open
Abstract
Assisted reproductive techniques as a new regenerative medicine approach have significantly contributed to solving infertility problems that affect approximately 15% of couples worldwide. However, the success rate of an in vitro fertilization (IVF) cycle remains only about 20%-30%, and 75% of these losses are due to implantation failure (the crucial rate-limiting step of gestation). Implantation failure and abnormal placenta formation are mainly caused by defective adhesion, invasion, and angiogenesis. Placental insufficiency endangers both the mother's and the fetus's health. Therefore, we suggested a novel treatment strategy to improve endometrial receptivity and implantation success rate. In this strategy, regulating mir-30d expression as an upstream transcriptomic modifier of the embryo implantation results in modified expression of the involved genes in embryonic adhesion, invasion, and angiogenesis and consequently impedes implantation failure. For this purpose, "scaffold/matrix attachment regions (S/MARs)" are employed as non-viral episomal vectors, transfecting into trophoblasts by exosome-liposome hybrid carriers. These vectors comprise CRISPR/dCas9 with a guide RNA to exclusively induce miR-30d gene expression in hypoxic stress conditions. In order to avoid concerns about the fetus's genetic manipulation, our vector would be transfected specifically into the trophoblast layer of the blastocyst via binding to trophoblast Erb-B4 receptors without entering the inner cell mass. Additionally, S/MAR episomal vectors do not integrate with the original cell DNA. As an on/off regulatory switch, a hypoxia-sensitive promoter (HRE) is localized upstream of dCas9. The miR-30d expression increases before and during the implantation and placental insufficiency conditions and is extinguished after hypoxia elimination. This hypothesis emphasizes that improving the adhesion, invasion, and angiogenesis in the uterine microenvironment during pregnancy will result in increased implantation success and reduced placental insufficiency, as a new insight in translational medicine.
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Affiliation(s)
- Alireza Yaghoobi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Nazerian
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arman Zeinaddini Meymand
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Ansari
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran,*Correspondence: Hassan Niknejad,
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Yahaya TO, Bashar DM, Oladele EO, Umar J, Anyebe D, Izuafa A. Epigenetics in the etiology and management of infertility. World J Med Genet 2022; 10:7-21. [DOI: 10.5496/wjmg.v10.i2.7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 06/28/2022] [Accepted: 10/12/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Epigenetic disruptions have been implicated in some cases of infertility and can serve as therapeutic targets. However, the involvement of epigenetics in infertility has not received adequate attention.
AIM This study aimed to determine the epigenetic basis of infertility in order to enhance public knowledge.
METHODS Relevant articles on the subject were collected from PubMed, RCA, Google Scholar, SpringerLink, and Scopus. The articles were pooled together and duplicates were removed using Endnote software.
RESULTS Available information shows that epigenetic mechanisms, mainly DNA methylation, histone modification, and microRNA interference are necessary for normal gametogenesis and embryogenesis. As a result, epigenetic disruptions in genes that control gametogenesis and embryogenesis, such as DDX3X, ADH4, AZF, PLAG1, D1RAS3, CYGB, MEST, JMJD1A, KCNQ1, IGF2, H19, and MTHFR may result in infertility. Aberrant DNA methylation during genomic imprinting and parental epigenetic mark erasures, in particular, may affect the DNA epigenomes of sperm and oocytes, resulting in reproductive abnormalities. Histone epigenetic dysregulation during oocyte development and histone-protamine replacement in the sperm may also cause reproductive abnormalities. Furthermore, overexpression or repression of certain microRNAs embedded in the ovary, testis, embryo, as well as granulosa cells and oocytes may impair reproduction. Male infertility is characterized by spermatogenesis failure, which includes oligozoospermia, asthenozoospermia, and teratozoospermia, while female infertility is characterized by polycystic ovary syndrome. Some epigenetic modifications can be reversed by deactivating the regulatory enzymes, implying that epigenetic reprogramming could help treat infertility in some cases. For some disorders, epigenetic drugs are available, but none have been formulated for infertility.
CONCLUSION Some cases of infertility have an epigenetic etiology and can be treated by reversing the same epigenetic mechanism that caused it. As a result, medical practitioners are urged to come up with epigenetic treatments for infertility that have an epigenetic cause.
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Affiliation(s)
| | - Danlami M Bashar
- Department of Microbiology, Federal University Birnin Kebbi, Kebbi State 23401, Nigeria
| | - Esther O Oladele
- Biology Unit, Distance Learning Institute, University of Lagos, Lagos State 23401, Nigeria
| | - Ja'afar Umar
- Department of Biological Sciences, Federal University Birnin Kebbi, Kebbi State 23401, Nigeria
| | - Daniel Anyebe
- Department of Biochemistry and Molecular Biology, Federal University Birnin Kebbi, Kebbi State 23401, Nigeria
| | - Abdulrazaq Izuafa
- Department of Biological Sciences, Federal University Birnin Kebbi, Kebbi State 23401, Nigeria
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Goharitaban S, Abedelahi A, Hamdi K, Khazaei M, Esmaeilivand M, Niknafs B. Role of endometrial microRNAs in repeated implantation failure (mini-review). Front Cell Dev Biol 2022; 10:936173. [PMID: 36060804 PMCID: PMC9437697 DOI: 10.3389/fcell.2022.936173] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 07/12/2022] [Indexed: 11/28/2022] Open
Abstract
MicroRNAs (miRNAs) play various roles in the implantation and pregnancy process. Abnormal regulation of miRNAs leads to reproductive disorders such as repeated implantation failure (RIF). During the window of implantation, different miRNAs are released from the endometrium, which can potentially reflect the status of the endometrium for in vitro fertilization (IVF). The focus of this review is to determine whether endometrial miRNAs may be utilized as noninvasive biomarkers to predict the ability of endometrium to implant and provide live birth during IVF cycles. The levels of certain miRNAs in the endometrium have been linked to implantation potential and pregnancy outcomes in previous studies. Endometrial miRNAs could be employed as non-invasive biomarkers in the assisted reproductive technology (ART) cycle to determine the optimal time for implantation. Few human studies have evaluated the association between ART outcomes and endometrial miRNAs in RIF patients. This review may pave the way for more miRNA transcriptomic studies on human endometrium and introduce a specific miRNA profile as a multivariable prediction model for choosing the optimal time in the IVF cycle.
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Affiliation(s)
- Sepide Goharitaban
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Ali Abedelahi
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Kobra Hamdi
- Womens Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mozafar Khazaei
- Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoumeh Esmaeilivand
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behrooz Niknafs
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- *Correspondence: Behrooz Niknafs, , 0000-0003-4438-1880
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Cao Z, Xu B, Wu Y, Luan K, Du X. A comprehensive analysis of miRNA/isomiRs profile of hydrosalpinx patients with interventional ultrasound sclerotherapy. PLoS One 2022; 17:e0268328. [PMID: 35969523 PMCID: PMC9377599 DOI: 10.1371/journal.pone.0268328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 04/28/2022] [Indexed: 11/18/2022] Open
Abstract
Hydrosalpinx is a chronic inflammatory condition with high recurrence rate, and it is reported among female population having fallopian tubal factor infertility. Previously, we have reported that interventional ultrasound sclerotherapy improves endometrial receptivity and pregnancy rate with negligible adverse effects in patients suffering from hydrosalpinx. During present investigation, we have used next generation sequencing (NGS) to characterize the isomiR profiles from the endometrium of patients suffering from hydrosalpinx before and after interventional ultrasound sclerotherapy. Our results indicated that miRNA arm shift and switch remained unaffected when compared in patients before and after interventional ultrasound sclerotherapy. We observed that isomiRs with trimming at 3’ and isomiRs with canonical sequences were lower in post-treatment than in pre-treatment group. Gene ontology (GO) annotation and KEGG pathway analysis revealed that the expression of mature mir-30 was significantly lower in the pre-treatment as compared to post treatment group while the expression of mir-30 isomiR was 4.26-fold higher in pre-treatment when compared with the post-treatment group. These different expression patterns of mir-30 mature miRNA and mir-30 isomiRs in two groups are affecting the physiological function of the endometrium. Our results suggested that differential isomiR distribution in hydrosalpinx patients before and after treatment plays an important role in hydrosalpinx incidence and can help in designing novel strategy for the treatment of hydrosalpinx in female population.
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Affiliation(s)
- Zhengyi Cao
- Reproductive Medicine Center, Hefei, Anhui, P.R. China
| | - Bo Xu
- Division of Life Sciences and Medicine, Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Yan Wu
- Reproductive Medicine Center, Hefei, Anhui, P.R. China
| | - Kang Luan
- Reproductive Medicine Center, Hefei, Anhui, P.R. China
| | - Xin Du
- Reproductive Medicine Center, Hefei, Anhui, P.R. China
- * E-mail:
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Babian S, Salehpour S, Nazari L, Ghorbanmehr N. The expression level of mir-21-3p in platelet-rich plasma: A potential effective factor and predictive biomarker in recurrent implantation failure. Mol Reprod Dev 2022; 89:498-505. [PMID: 35892150 DOI: 10.1002/mrd.23636] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 06/16/2022] [Accepted: 07/17/2022] [Indexed: 11/08/2022]
Abstract
Recurrent implantation failure (RIF) is the most important complication associated with in vitro fertilization (IVF). Despite the good quality of the transferred embryo, the success rate is rather disappointing. Therefore, predictive biomarkers for implantation are critical to making decisions about transferring high-quality embryos or cryopreserving them for cycles with a higher chance of implantation. Recently, intrauterine infusion of autologous platelet-rich plasma (PRP) has been proposed to increase the endometrial receptivity in RIF patients. PRP is rich in both growth factors and microRNAs (miRNAs). We investigated the possible association of mir-21-3p, mir-21-5p, mir-494-3p, mir-145-5p, and insulin-like growth factor-I (IGF-I) levels in PRP and platelet-poor plasma (PPP) samples with the pregnancy outcomes in RIF patients. The miRNA expression level and IGF-I concentration were assessed using real-time PCR and chemiluminescence methods respectively. Mir-21-3p was upregulated in PRP samples of the pregnant group in comparison to the nonpregnant group. There was no difference in the expression of mir-21-3p in PPP samples of these groups. The concentration of IGF-I was higher in PRP and PPP samples of the nonpregnant in comparison to the pregnant group. Receiver-operating characteristic curve analysis showed that mir-21-3p can be a valuable biomarker for the prediction of pregnancy chance in RIF patients treated with PRP.
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Affiliation(s)
- Scarlet Babian
- Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran
| | - Saghar Salehpour
- Department of Obstetrics and Gynecology, Preventative Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leila Nazari
- Department of Obstetrics and Gynecology, Preventative Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nassim Ghorbanmehr
- Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran
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Abstract
PURPOSE OF REVIEW To succinctly review the basic mechanisms of implantation and luteal phase endometrial differentiation, the etiologies of impaired endometrial function and receptivity, and the current methods that exist to evaluate and treat impaired endometrial receptivity. RECENT FINDINGS Human embryo implantation requires bidirectional communication between blastocyst and a receptive endometrium. Etiologies of impaired endometrial receptivity are varied. Some of these include delayed endometrial maturation, structural abnormalities, inflammation, and progesterone resistance. Current methods to evaluate endometrial receptivity include ultrasonography, hysteroscopy, and endometrial biopsy. Treatments are limited, but include operative hysteroscopy, treatment of endometriosis, and personalized timing of embryo transfer. SUMMARY Although some mechanisms of impaired endometrial receptivity are well understood, treatment options remain limited. Future efforts should be directed towards developing interventions targeted towards the known mediators of impaired endometrial receptivity.
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Shekibi M, Heng S, Nie G. MicroRNAs in the Regulation of Endometrial Receptivity for Embryo Implantation. Int J Mol Sci 2022; 23:ijms23116210. [PMID: 35682889 PMCID: PMC9181585 DOI: 10.3390/ijms23116210] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/13/2022] [Accepted: 05/28/2022] [Indexed: 12/13/2022] Open
Abstract
Development of endometrial receptivity is crucial for successful embryo implantation and pregnancy initiation. Understanding the molecular regulation underpinning endometrial transformation to a receptive state is key to improving implantation rates in fertility treatments such as IVF. With microRNAs (miRNAs) increasingly recognized as important gene regulators, recent studies have investigated the role of miRNAs in the endometrium. Studies on miRNAs in endometrial disorders such as endometriosis and endometrial cancer have been reviewed previously. In this minireview, we aim to provide an up-to-date knowledge of miRNAs in the regulation of endometrial receptivity. Since endometrial remodelling differs considerably between species, we firstly summarised the key events of the endometrial cycle in humans and mice and then reviewed the miRNAs identified so far in these two species with likely functional significance in receptivity establishment. To date, 29 miRNAs have been reported in humans and 15 miRNAs in mice within various compartments of the endometrium that may potentially modulate receptivity; miRNAs regulating the Wnt signalling and those from the let-7, miR-23, miR-30, miR-200 and miR-183 families are found in both species. Future studies are warranted to investigate miRNAs as biomarkers and/or therapeutic targets to detect/improve endometrial receptivity in human fertility treatment.
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Zhang L, Zhou C, Jiang X, Huang S, Li Y, Su T, Wang G, Zhou Y, Liu M, Xu D. Circ0001470 Acts as a miR-140-3p Sponge to Facilitate the Progression of Embryonic Development through Regulating PTGFR Expression. Cells 2022; 11:cells11111746. [PMID: 35681442 PMCID: PMC9179393 DOI: 10.3390/cells11111746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/20/2022] [Accepted: 05/22/2022] [Indexed: 12/10/2022] Open
Abstract
Embryonic implantation and development are vital in early pregnancy and assisted reproduction. Circular RNAs (circRNAs) are involved in the two physiological processes and thus regulate animal reproduction. However, their specific regulatory functions and mechanisms remain unclear. Here, a novel circ0001470, originating from the porcine GRN gene, differentially expressed on day 18 versus day 32 of gestation in Meishan and Yorkshire pigs was screened. The circularization characteristic of circ0001470 was identified based on divergent primer amplification, Sanger sequencing, RNase digestion, and RNA nuclear-cytoplasmic fractionation. Functionally, circ0001470 can promote cell proliferation and cycle progression of endometrial epithelial cells (EECs) and also inhibit apoptosis of EECs using CCK-8 assays and flow cytometry analyses. Mechanistically, bioinformatics database prediction, luciferase screening, RNA immunoprecipitation (RIP), RNA-pull down, and FISH co-localization experiments revealed that the circ0001470 acted as a competing endogenous RNA (ceRNA) through sponging miR-140-3p to regulate downstream PTGFR expression. Moreover, in vivo assays revealed that mmu_circGRN promoted embryonic development by affecting the expression of PTGFR, which can activate the MAPK reproduction pathway and facilitate pregnancy maintenance. This study enriched our understanding of circRNAs in embryo implantation and development by deciding the fate of EECs.
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Affiliation(s)
- Long Zhang
- Colleges of Animal Science & Technology, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (C.Z.); (X.J.); (S.H.); (Y.L.); (T.S.); (G.W.); (Y.Z.); (M.L.)
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
| | - Changfan Zhou
- Colleges of Animal Science & Technology, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (C.Z.); (X.J.); (S.H.); (Y.L.); (T.S.); (G.W.); (Y.Z.); (M.L.)
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
| | - Xiaoyu Jiang
- Colleges of Animal Science & Technology, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (C.Z.); (X.J.); (S.H.); (Y.L.); (T.S.); (G.W.); (Y.Z.); (M.L.)
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
| | - Shuntao Huang
- Colleges of Animal Science & Technology, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (C.Z.); (X.J.); (S.H.); (Y.L.); (T.S.); (G.W.); (Y.Z.); (M.L.)
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
| | - Yiheng Li
- Colleges of Animal Science & Technology, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (C.Z.); (X.J.); (S.H.); (Y.L.); (T.S.); (G.W.); (Y.Z.); (M.L.)
| | - Tao Su
- Colleges of Animal Science & Technology, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (C.Z.); (X.J.); (S.H.); (Y.L.); (T.S.); (G.W.); (Y.Z.); (M.L.)
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
| | - Guowei Wang
- Colleges of Animal Science & Technology, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (C.Z.); (X.J.); (S.H.); (Y.L.); (T.S.); (G.W.); (Y.Z.); (M.L.)
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
| | - You Zhou
- Colleges of Animal Science & Technology, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (C.Z.); (X.J.); (S.H.); (Y.L.); (T.S.); (G.W.); (Y.Z.); (M.L.)
| | - Min Liu
- Colleges of Animal Science & Technology, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (C.Z.); (X.J.); (S.H.); (Y.L.); (T.S.); (G.W.); (Y.Z.); (M.L.)
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
| | - Dequan Xu
- Colleges of Animal Science & Technology, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (C.Z.); (X.J.); (S.H.); (Y.L.); (T.S.); (G.W.); (Y.Z.); (M.L.)
- Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, China
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China
- Correspondence:
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Chen CW, Huang RL, Do AQ, Wang HC, Lee YX, Wang CW, Hsieh CC, Tzeng CR, Hu YM, Chen CH, Weng YC, Su PH, Chen LY, Lai HC. Genome-wide analysis of cervical secretions obtained during embryo transfer reveals the association between deoxyribonucleic acid methylation and pregnancy outcomes. F&S SCIENCE 2022; 3:74-83. [PMID: 35559997 DOI: 10.1016/j.xfss.2021.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To study whether the methylation status of cervical secretions can reflect the ability of the endometrium to allow embryo implantation. DESIGN Case-control study. SETTING In vitro fertilization centers. PATIENT(S) Women undergoing embryo transfer cycles, in which at least 1 good-quality embryo was transferred. INTERVENTION(S) Collection of cervical secretions during the procedure of embryo transfer. MAIN OUTCOME MEASURE(S) Methylation profiles of cervical secretions in relation to pregnancy outcomes. RESULT(S) Genome-wide methylation profiles differ between cervical secretions from pregnancy and nonpregnancy cycles. Clustering analysis on the basis of the top 2,000 differentially methylated probes of cervical secretions from 28 pregnancy and 29 nonpregnancy cycles correctly categorized 86.0% of the samples in terms of conceptional status, which was verified in selected genes by quantitative methylation-specific polymerase chain reaction and validated in another independent sample set. The combination of selected genes was estimated to predict pregnancy outcomes with a maximal area under the receiver operating characteristic curve of 0.83. CONCLUSION(S) The methylation profiles of cervical secretions were associated with pregnancy outcomes in embryo transfer cycles. Although not clinically useful at present, deoxyribonucleic acid methylation in cervical secretions may shed new light on the less invasive assessment of endometrial receptivity.
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Affiliation(s)
| | - Rui-Lan Huang
- Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan; Translational Epigenetic Center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan; Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Anh Q Do
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Obstetrics and Gynecology, Hai Phong University of Medicine and Pharmacy, Hai Phong, Vietnam; International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hui-Chen Wang
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yi-Xuan Lee
- Translational Epigenetic Center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan; Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Taipei Fertility Center, Taipei, Taiwan
| | | | | | | | | | - Chi-Huang Chen
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yu-Chun Weng
- Translational Epigenetic Center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Po-Hsuan Su
- Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan; Translational Epigenetic Center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Lin-Yu Chen
- Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan; Translational Epigenetic Center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Hung-Cheng Lai
- Department of Obstetrics and Gynecology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan; Translational Epigenetic Center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan; Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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Zhong J, Liu J, Zheng Y, Xie X, He Q, Zhong W, Wu Q. miR-938 rs2505901 T>C polymorphism increases Hirschsprung disease risk: a case-control study of Chinese children. Per Med 2021; 18:551-558. [PMID: 34761964 DOI: 10.2217/pme-2021-0001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: To explore the association between miR-938 rs2505901 T>C polymorphism and Hirschsprung disease (HSCR) risk in Chinese children. Materials & Methods: We conducted a case-control study in a Chinese population with 1381 cases and 1457 controls. The associated correlation strengths were assessed by adjusted odds ratios (AORs) and 95% CIs. Results: The results revealed that the rs2505901 TC and rs2505901 TC/CC genotype were related to an increased HSCR risk compared to the risk contributed by the rs2505901 TT genotype. A stratification analysis showed that the rs2505901 TC/CC genotype promoted the progression of HSCR more significantly in patients with the short-segment HSCR subtype. Conclusion: Our study indicated that miR-938 rs2505901 T>C polymorphism is significantly associated with HSCR risk in Chinese children. This result needs to be confirmed with well-designed studies.
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Affiliation(s)
- Jun Zhong
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women & Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Jiabin Liu
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women & Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Yi Zheng
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women & Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Xiaoli Xie
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women & Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Qiuming He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women & Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Wei Zhong
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women & Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Qiang Wu
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women & Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
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Orazov M, Silantieva E, Orekhov R. THE CAPACITY OF PHYSICAL THERAPY FOR REPEATED IMPLANTATION FAILURES IN IVF PROGRAMS: A LITERATURE REVIEW. REPRODUCTIVE MEDICINE 2021. [DOI: 10.37800/rm.3.2021.27-34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Relevance: Studies of the etiology and pathogenesis of implantation failures, both repeated and primary, as well as the possibilities of therapy today carry many contraversions. However, in recent years, numerous studies have demonstrated the high effectiveness of various physiotherapy methods in improving reproductive outcomes, including therapy and overcoming repeated implantation failures in in-vitro fertilization programs.
The purpose of the study was to study the capacity of physical therapy for repeated implantation failures in in-vitro fertilization programs.
Materials and Methods: The capacity of physical therapy for repeated implantation failures in in-vitro fertilization programs were studied through the search and analysis of the scientific sources for 1995-2021, available in the Scopus and Pubmed databases, using the keywords “in-vitro fertilization,” “repeated implantation failure,” “assisted reproductive technology,” and «physiotherapy.»
Results: Electrical impulse therapy has established itself as the most studied method in the treatment of disorders of endometrial receptivity with proven efficacy. Physical methods of exposure can improve reproductive outcomes through a beneficial effect on the angiogenesis and architectonics of the endometrium, improving its receptivity, and normalizing physiology. Further detailed study of the etiology, pathogenetic mechanisms, as well as the effectiveness of overcoming repeated implantation failures by various methods is needed to develop treatment protocols.
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Xie Y, Liu G, Zang X, Hu Q, Zhou C, Li Y, Liu D, Hong L. Differential Expression Pattern of Goat Uterine Fluids Extracellular Vesicles miRNAs during Peri-Implantation. Cells 2021; 10:cells10092308. [PMID: 34571957 PMCID: PMC8470123 DOI: 10.3390/cells10092308] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/29/2021] [Accepted: 08/31/2021] [Indexed: 12/22/2022] Open
Abstract
Early pregnancy failure occurs when a mature embryo attaches to an unreceptive endometrium. During the formation of a receptive endometrium, extracellular vesicles (EVs) of the uterine fluids (UFs) deliver regulatory molecules such as small RNAs to mediate intrauterine communication between the embryo and the endometrium. However, profiling of small RNAs in goat UFs’ EVs during pregnancy recognition (day 16) has not been carried out. In this study, EVs were isolated from UFs on day 16 of the estrous cycle or gestation. They were isolated by Optiprep™ Density G radient (ODG) and verified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. Immunostaining demonstrated that CD63 was present both in the endometrial epithelium and glandular epithelium, and stain intensity was greater in the pregnant endometrium compared to the non-pregnant endometrium. Small RNA sequencing revealed that UFs’ EVs contained numerous sRNA families and a total of 106 differentially expressed miRNAs (DEMs). Additionally, 1867 target genes of the DEMs were obtained, and miRNA–mRNA interaction networks were constructed. GO and KEGG analysis showed that miRNAs were significantly associated with the formation of a receptive endometrium and embryo implantation. In addition, the fluorescence in situ hybridization assay (FISH) showed that chi-miR-451-5p was mainly expressed in stromal cells of the endometrium and a higher level was detected in the endometrial luminal epithelium in pregnant states. Moreover, the dual-luciferase reporter assay showed that chi-miR-451-5p directly binds to PSMB8 and may play an important role in the formation of a receptive endometrium and embryo implantation. In conclusion, these results reveal that UFs’ EVs contain various small RNAs that may be vital in the formation of a receptive endometrium and embryo implantation.
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Affiliation(s)
- Yanshe Xie
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.X.); (G.L.); (X.Z.); (Q.H.); (C.Z.); (Y.L.)
- National Local Joint Engineering Research Center of Livestock and Poutry, South China Agricultural University, Guangzhou 510642, China
| | - Guangbin Liu
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.X.); (G.L.); (X.Z.); (Q.H.); (C.Z.); (Y.L.)
- National Local Joint Engineering Research Center of Livestock and Poutry, South China Agricultural University, Guangzhou 510642, China
| | - Xupeng Zang
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.X.); (G.L.); (X.Z.); (Q.H.); (C.Z.); (Y.L.)
- National Local Joint Engineering Research Center of Livestock and Poutry, South China Agricultural University, Guangzhou 510642, China
| | - Qun Hu
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.X.); (G.L.); (X.Z.); (Q.H.); (C.Z.); (Y.L.)
- National Local Joint Engineering Research Center of Livestock and Poutry, South China Agricultural University, Guangzhou 510642, China
| | - Chen Zhou
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.X.); (G.L.); (X.Z.); (Q.H.); (C.Z.); (Y.L.)
- National Local Joint Engineering Research Center of Livestock and Poutry, South China Agricultural University, Guangzhou 510642, China
| | - Yaokun Li
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.X.); (G.L.); (X.Z.); (Q.H.); (C.Z.); (Y.L.)
- National Local Joint Engineering Research Center of Livestock and Poutry, South China Agricultural University, Guangzhou 510642, China
| | - Dewu Liu
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.X.); (G.L.); (X.Z.); (Q.H.); (C.Z.); (Y.L.)
- National Local Joint Engineering Research Center of Livestock and Poutry, South China Agricultural University, Guangzhou 510642, China
- Correspondence: (D.L.); (L.H.)
| | - Linjun Hong
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (Y.X.); (G.L.); (X.Z.); (Q.H.); (C.Z.); (Y.L.)
- National Local Joint Engineering Research Center of Livestock and Poutry, South China Agricultural University, Guangzhou 510642, China
- Correspondence: (D.L.); (L.H.)
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Verma RK, Soni UK, Chadchan SB, Maurya VK, Soni M, Sarkar S, Pratap JV, Jha RK. miR-149-PARP-2 Signaling Regulates E-cadherin and N-cadherin Expression in the Murine Model of Endometrium Receptivity. Reprod Sci 2021; 29:975-992. [PMID: 34460092 DOI: 10.1007/s43032-021-00710-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 07/30/2021] [Indexed: 10/20/2022]
Abstract
Cadherins play an essential role in the attachment of the blastocyst to the endometrium, a process known as endometrial receptivity. Loss of E-cadherin expression is essential during the process, while the expression level of the other cadherin, N-cadherin, has been reported to be altered in cases of infertility. Both E-cadherin and N-cadherin can be regulated by members of the PARP family. Specifically, PARP-2, which is under the epigenetic control of miR-149, has been observed to promote E-cadherin expression in other human cells. We investigated the roles of E-cadherin and N-cadherin in endometrial receptivity using mouse models for normal endometrial receptivity, pseudopregnancy, and LPS-induced endometrial receptivity failure. E-cadherin and phosphorylated E-cadherin were predominantly expressed during pre-receptive stages as well as in the implantation site of the receptive stage, which were observed reduced during the later stages of implantation in both implantation and non-implantation regions, while N-cadherin was detected only at pre-receptive stages. E-cadherin and N-cadherin were also seen in the uterus during pseudopregnancy, showing a downregulation trend during receptive and post-receptive stages. LPS-induced failed endometrial receptivity showed upregulation of E-cadherin and downregulation of N-cadherin. The E-cadherin expression promoter, GSK-3, was lost and its suppressor, SLUG was upregulated during normal course of endometrial receptivity in mouse model, while GSK-3 was increased during LPS-induced failed embryo implantation. In an in vitro model of embryo implantation, E-cadherin expression is promoted by PARP-2 and regulated by miR-149 epigenetically in human endometrium epithelial cells. In conclusion, E-cadherin is predominantly expressed during pre-receptive stage and promoted by PARP-2, which is regulated by miR-149 in the endometrial epithelial cells.
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Affiliation(s)
- Raj Kumar Verma
- Female Reproductive Biology Laboratory, Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
| | - Upendra Kumar Soni
- Female Reproductive Biology Laboratory, Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
| | - Sangappa Basanna Chadchan
- Female Reproductive Biology Laboratory, Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
| | - Vineet Kumar Maurya
- Female Reproductive Biology Laboratory, Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
| | - Mohini Soni
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
| | - Sudarsan Sarkar
- Female Reproductive Biology Laboratory, Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India
| | - J Venkatesh Pratap
- Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India
| | - Rajesh Kumar Jha
- Female Reproductive Biology Laboratory, Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India. .,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India.
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Zhou T, Ni T, Li Y, Zhang Q, Yan J, Chen ZJ. circFAM120A participates in repeated implantation failure by regulating decidualization via the miR-29/ABHD5 axis. FASEB J 2021; 35:e21872. [PMID: 34449947 DOI: 10.1096/fj.202002298rr] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 08/03/2021] [Accepted: 08/09/2021] [Indexed: 11/11/2022]
Abstract
Repeated implantation failure (RIF) is a major problem that limits the pregnancy rate associated with assisted reproductive technology. However, the pathogenesis of RIF is still unknown. Recently, the expression levels of circular RNAs (circRNAs) were profiled in the endometrial tissues of patients with RIF. However, the exact role of circRNAs in RIF remains unclear. In our study, we found that circFAM120A levels were significantly down-regulated in the endometrium at the window of implantation in RIF patients compared with non-RIF controls. The suppression of circFAM120A expression inhibited decidualization in human endometrial stromal cells (hESCs). Furthermore, RNA-seq analysis after circFAM120A knockdown revealed ABHD5 as a potential downstream target gene of circFAM120A. As expected, down-regulating ABHD5 in hESCs also inhibited decidualization. Using the starBase and TargetScan databases, we predicted that miR-29 may interact with ABHD5, based on nucleotide sequence matching. Luciferase reporter assay showed that miR-29 bound to the 3' UTR of ABHD5 at the predicted complementary sites. Moreover, miR-29 mimics efficiently reduced ABHD5 expression levels and suppressed the decidualization process, whereas a miR-29 inhibitor partly rescued ABHD5 mRNA expression level and decidualization reduced by the knockdown of circFAM120A. Therefore, circFAM120A modulated decidualization in RIF through the miR-29/ABHD5 axis.
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Affiliation(s)
- Tingting Zhou
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Tianxiang Ni
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Yan Li
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Qian Zhang
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Junhao Yan
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Zi-Jiang Chen
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
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Kolanska K, Bendifallah S, Canlorbe G, Mekinian A, Touboul C, Aractingi S, Chabbert-Buffet N, Daraï E. Role of miRNAs in Normal Endometrium and in Endometrial Disorders: Comprehensive Review. J Clin Med 2021; 10:jcm10163457. [PMID: 34441754 PMCID: PMC8396961 DOI: 10.3390/jcm10163457] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/15/2021] [Accepted: 07/29/2021] [Indexed: 12/12/2022] Open
Abstract
The molecular responses to hormonal stimuli in the endometrium are modulated at the transcriptional and post-transcriptional stages. Any imbalance in cellular and molecular endometrial homeostasis may lead to gynecological disorders. MicroRNAs (miRNAs) are involved in a wide variety of physiological mechanisms and their expression patterns in the endometrium are currently attracting a lot of interest. miRNA regulation could be hormone dependent. Conversely, miRNAs could regulate the action of sexual hormones. Modifications to miRNA expression in pathological situations could either be a cause or a result of the existing pathology. The complexity of miRNA actions and the diversity of signaling pathways controlled by numerous miRNAs require rigorous analysis and findings need to be interpreted with caution. Alteration of miRNA expression in women with endometriosis has been reported. Thus, a potential diagnostic test supported by a specific miRNA signature could contribute to early diagnosis and a change in the therapeutic paradigm. Similarly, specific miRNA profile signatures are expected for RIF and endometrial cancer, with direct implications for associated therapies for RIF and adjuvant therapies for endometrial cancer. Advances in targeted therapies based on the regulation of miRNA expression are under evaluation.
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Affiliation(s)
- Kamila Kolanska
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
- Correspondence:
| | - Sofiane Bendifallah
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
| | - Geoffroy Canlorbe
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Service de Chirurgie et Cancérologie Gynécologique et Mammaire, Hôpitaux Universitaires Pitié-Salpêtrière, Charles-Foix, Sorbonne Université, 47/83, Boulevard de l’Hôpital, 75013 Paris, France
| | - Arsène Mekinian
- Service de Médecine Interne, Hôpital Saint Antoine, AP-HP, 184 Rue du Faubourg Saint Antoine, Sorbonne Université, 75012 Paris, France;
| | - Cyril Touboul
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
| | - Selim Aractingi
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Faculté de Médecine Paris 5 Descartes, 12 Rue de l’Ecole de Médecine, 75006 Paris, France
| | - Nathalie Chabbert-Buffet
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
| | - Emile Daraï
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
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Chen P, Li T, Guo Y, Jia L, Wang Y, Fang C. Construction of Circulating MicroRNAs-Based Non-invasive Prediction Models of Recurrent Implantation Failure by Network Analysis. Front Genet 2021; 12:712150. [PMID: 34367263 PMCID: PMC8344057 DOI: 10.3389/fgene.2021.712150] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 06/18/2021] [Indexed: 01/11/2023] Open
Abstract
Background Recurrent implantation failure (RIF) is an obstacle in the process of assisted reproductive technology (ART). At present, there is limited research on its pathogenesis, diagnosis, and treatment methods. Methods and Results In this study, a series of analytical tools were used to analyze differences in miRNAs, mRNAs, and lncRNAs in the endometrium of patients in a RIF group and a control group. Then the competing endogenous RNA (ceRNA) network was built to describe the relationship between gene regulation in the endometrium of the RIF group. Based on the results of the logistic regression of co-expression miRNAs between serum and endometrial samples, we built a predictive model based on circulating miRNAs. Conclusion The stability and non-invasiveness of the circular miRNA prediction model provided a new method for diagnosis in RIF patients.
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Affiliation(s)
- Peigen Chen
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tingting Li
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yingchun Guo
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lei Jia
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yanfang Wang
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Cong Fang
- Reproductive Medicine Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Heng S, Samarajeewa N, Aberkane A, Essahib W, Van de Velde H, Scelwyn M, Hull ML, Vollenhoven B, Rombauts LJ, Nie G. Podocalyxin inhibits human embryo implantation in vitro and luminal podocalyxin in putative receptive endometrium is associated with implantation failure in fertility treatment. Fertil Steril 2021; 116:1391-1401. [PMID: 34272065 DOI: 10.1016/j.fertnstert.2021.06.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 06/10/2021] [Accepted: 06/15/2021] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To study whether endometrial epithelial podocalyxin (PCX) inhibits implantation of human embryos in vitro and in patients undergoing in vitro fertilization (IVF). DESIGN We have recently identified PCX as a key negative regulator of endometrial epithelial receptivity. Podocalyxin is expressed in all epithelial cells in the nonreceptive endometrium, but is selectively downregulated in the luminal epithelium (LE) for receptivity. In the current study, we first investigated whether high levels of PCX in Ishikawa monolayer inhibit attachment and/or penetration of human blastocysts in in vitro models. We then examined PCX by immunohistochemistry in putative receptive endometrial tissues biopsied from 81 IVF patients who underwent frozen embryo transfer in the next natural cycle and retrospectively analyzed the association between PCX staining in LE and clinical pregnancy as a proxy of successful implantation. SETTING RMIT University, Australia; Vrije Universiteit Brussel, Belgium. PATIENT(S) In vitro fertilization patients undergoing frozen/thawed embryo transfer. INTERVENTION(S) N/A. MAIN OUTCOME MEASURE(S) Endometrial epithelial PCX inhibits implantation of human embryos in vitro and in IVF patients. RESULT(S) High levels of PCX in Ishikawa monolayer significantly inhibited blastocyst attachment and penetration. Among the 81 putative receptive tissues, 73% were negative, but 27% were heterogeneously positive for PCX in LE. The clinical pregnancy rate was 53% in those with a PCX-negative LE but only 18% in those with a PCX-positive LE. If LE was positive for PCX, the odds ratio of no clinical pregnancy was 4.95 (95% Confidence interval, 1.48-14.63). CONCLUSION(S) Podocalyxin inhibits embryo implantation. Assessment of PCX may aid the evaluation and optimization of endometrial receptivity in fertility treatment.
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Affiliation(s)
- Sophea Heng
- School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology University, Victoria, Australia
| | - Nirukshi Samarajeewa
- School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology University, Victoria, Australia
| | - Asma Aberkane
- Research Group of Reproduction and Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Wafaa Essahib
- Research Group of Reproduction and Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Hilde Van de Velde
- Research Group of Reproduction and Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - M Louise Hull
- Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia
| | - Beverley Vollenhoven
- Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia; Womens and Newborn Programme, Monash Health, Clayton, Victoria, Australia
| | - Luk J Rombauts
- Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia; Womens and Newborn Programme, Monash Health, Clayton, Victoria, Australia
| | - Guiying Nie
- School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology University, Victoria, Australia; Hudson Institute of Medical Research, Clayton, Victoria, Australia.
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Milesi MM, Lorenz V, Durando M, Rossetti MF, Varayoud J. Glyphosate Herbicide: Reproductive Outcomes and Multigenerational Effects. Front Endocrinol (Lausanne) 2021; 12:672532. [PMID: 34305812 PMCID: PMC8293380 DOI: 10.3389/fendo.2021.672532] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 06/14/2021] [Indexed: 12/20/2022] Open
Abstract
Glyphosate base herbicides (GBHs) are the most widely applied pesticides in the world and are mainly used in association with GBH-tolerant crop varieties. Indiscriminate and negligent use of GBHs has promoted the emergence of glyphosate resistant weeds, and consequently the rise in the use of these herbicides. Glyphosate, the active ingredient of all GBHs, is combined with other chemicals known as co-formulants that enhance the herbicide action. Nowadays, the safety of glyphosate and its formulations remain to be a controversial issue, as evidence is not conclusive whether the adverse effects are caused by GBH or glyphosate, and little is known about the contribution of co-formulants to the toxicity of herbicides. Currently, alarmingly increased levels of glyphosate have been detected in different environmental matrixes and in foodstuff, becoming an issue of social concern. Some in vitro and in vivo studies have shown that glyphosate and its formulations exhibit estrogen-like properties, and growing evidence has indicated they may disrupt normal endocrine function, with adverse consequences for reproductive health. Moreover, multigenerational effects have been reported and epigenetic mechanisms have been proved to be involved in the alterations induced by the herbicide. In this review, we provide an overview of: i) the routes and levels of human exposure to GBHs, ii) the potential estrogenic effects of glyphosate and GBHs in cell culture and animal models, iii) their long-term effects on female fertility and mechanisms of action, and iv) the consequences on health of successive generations.
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Affiliation(s)
- María Mercedes Milesi
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
- Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL), Santa Fe, Argentina
| | - Virginia Lorenz
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
| | - Milena Durando
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
- Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL), Santa Fe, Argentina
| | - María Florencia Rossetti
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
- Departamento de Bioquímica Clínica y Cuantitativa, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL), Santa Fe, Argentina
| | - Jorgelina Varayoud
- Instituto de Salud y Ambiente del Litoral (ISAL), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina
- Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL), Santa Fe, Argentina
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Nazarian H, Novin MG, Khaleghi S, Habibi B. Small non-coding RNAs in embryonic pre-implantation. Curr Mol Med 2021; 22:287-299. [PMID: 34042034 DOI: 10.2174/1566524021666210526162917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 04/02/2021] [Accepted: 04/03/2021] [Indexed: 11/22/2022]
Abstract
Failure of embryo implantation has been introduced as an important limiting parameter in early assisted reproduction and pregnancy. The embryo-maternal interactions, endometrial receptivity, and detections of implantation consist of the embryo viability. For regulating the implantation, multiple molecules may be consisted, however, their specific regulatory mechanisms still stand unclear. MicroRNAs (miRNAs) have been highly concerned due to their important effect on human embryo implantation. MicroRNA (miRNA), which acts as the transcriptional regulator of gene expression, is consisted in embryo implantation. Scholars determined that miRNAs cannot affect the cells and release by cells in the extracellular environment considering facilitating intercellular communication, multiple packaging forms, and preparing indicative data in the case of pathological and physiological conditions. The detection of extracellular miRNAs provided new information in cases of implantation studies. For embryo-maternal communication, MiRNAs offered novel approaches. In addition, in assisted reproduction, for embryo choice and prediction of endometrial receptivity, they can act as non-invasive biomarkers and can enhance the accuracy in the process of reducing the mechanical damage for the tissue.
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Affiliation(s)
- Hamid Nazarian
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marefat Ghaffari Novin
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Khaleghi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bahare Habibi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Ahmadi M, Pashangzadeh S, Moraghebi M, Sabetian S, Shekari M, Eini F, Salehi E, Mousavi P. Construction of circRNA-miRNA-mRNA network in the pathogenesis of recurrent implantation failure using integrated bioinformatics study. J Cell Mol Med 2021; 26:1853-1864. [PMID: 33960101 PMCID: PMC8918409 DOI: 10.1111/jcmm.16586] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 04/10/2021] [Accepted: 04/13/2021] [Indexed: 12/20/2022] Open
Abstract
This research attempted to elucidate the molecular components are involved in the pathogenesis of recurrent implantation failure (RIF). We initially identified that 386 mRNAs, 144 miRNAs and 2548 circRNAs were differentially expressed (DE) in RIF and then investigated the genetic cause of the observed abnormal expression by constructing a circRNA‐miRNA‐mRNA network considering the competing endogenous RNA theory. We further analysed the upstream transcription factors and related kinases of DEmRNAs (DEMs) and demonstrated that SUZ12, AR, TP63, NANOG, and TCF3 were the top five TFs binding to these DEMs. Besides, protein‐protein interaction analysis disclosed that ACTB, CXCL10, PTGS2, CXCL12, GNG4, AGT, CXCL11, SST, PENK, and FOXM1 were the top 10 hub genes in the acquired network. Finally, we performed the functional enrichment analysis and found that arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), pathways in cancer, TNF signalling pathway and steroid hormone biosynthesis were the potentially disrupted pathways in RIF patients. Optimistically, our findings may deepen our apprehensions about the underlying molecular and biological causes of RIF and provide vital clues for future laboratory and clinical experiments that will ultimately bring a better outcome for patients with RIF.
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Affiliation(s)
- Mohsen Ahmadi
- Student Research Committee, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.,Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.,Division of Medical Genetics, Booali Medical Diagnostic Laboratory, Qom, Iran
| | - Salar Pashangzadeh
- Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High-Risk Behaviors, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahta Moraghebi
- Student Research Committee, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Soudabeh Sabetian
- Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Shekari
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Fatemeh Eini
- Fertility and Infertility Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Ensieh Salehi
- Fertility and Infertility Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Pegah Mousavi
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.,Fertility and Infertility Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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Ruiz-Alonso M, Valbuena D, Gomez C, Cuzzi J, Simon C. Endometrial Receptivity Analysis (ERA): data versus opinions. Hum Reprod Open 2021; 2021:hoab011. [PMID: 33880420 PMCID: PMC8045472 DOI: 10.1093/hropen/hoab011] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Indexed: 12/14/2022] Open
Abstract
This article summarises and contextualises the accumulated basic and clinical data on the ERA test and addresses specific comments and opinions presented by the opponent as part of an invited debate. Progress in medicine depends on new technologies and concepts that translate to practice to solve long-standing problems. In a key example, combining RNA sequencing data (transcriptomics) with artificial intelligence (AI) led to a clinical revolution in personalising disease diagnosis and fostered the concept of precision medicine. The reproductive field is no exception. Translation of endometrial transcriptomics to the clinic yielded an objective definition of the limited time period during which the maternal endometrium is receptive to an embryo, known as the window of implantation (WOI). The WOI is induced by the presence of exogenous and/or endogenous progesterone (P) after proper oestradiol (E2) priming. The window lasts 30-36 hours and, depending on the patient, occurs between LH + 6 and LH + 9 in natural cycles or between P + 4 and P + 7 in hormonal replacement therapy (HRT) cycles. In approximately 30% of IVF cycles in which embryo transfer is performed blindly, the WOI is displaced and embryo-endometrial synchrony is not achieved. Extending this application of endometrial transcriptomics, the endometrial receptivity analysis (ERA) test couples next-generation sequencing (NGS) to a computational predictor to identify transcriptomic signatures for each endometrial stage: proliferative (PRO), pre-receptive (PRE), receptive (R) and post-receptive (POST). In this way, personalised embryo transfer (pET) may be possible by synchronising embryo transfer with each patient's WOI. Data are the only way to confront arguments sustained in opinions and/or misleading concepts; it is up to the reader to make their own conclusions regarding its clinical utility.
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Affiliation(s)
- Maria Ruiz-Alonso
- Igenomix Foundation-INCLIVA, Valencia, Spain
- Igenomix SL, Valencia, Spain
| | - Diana Valbuena
- Igenomix Foundation-INCLIVA, Valencia, Spain
- Igenomix SL, Valencia, Spain
| | | | | | - Carlos Simon
- Igenomix Foundation-INCLIVA, Valencia, Spain
- Department of Pediatrics, Obstetrics & Gynecology, University of
Valencia, Valencia, Spain
- Department of Obstetrics and Gynecology, BIMDC, Harvard
University, Boston, MA, USA
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Wang Z, Liu Y, Liu J, Kong N, Jiang Y, Jiang R, Zhen X, Zhou J, Li C, Sun H, Yan G. ATF3 deficiency impairs the proliferative-secretory phase transition and decidualization in RIF patients. Cell Death Dis 2021; 12:387. [PMID: 33846304 PMCID: PMC8041902 DOI: 10.1038/s41419-021-03679-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 12/20/2022]
Abstract
Decidualization is a complex process involving cellular proliferation and differentiation of the endometrial stroma and is required to establish and support pregnancy. Dysregulated decidualization has been reported to be a critical cause of recurrent implantation failure (RIF). In this study, we found that Activating transcription factor 3 (ATF3) expression was significantly downregulated in the endometrium of RIF patients. Knockdown of ATF3 in human endometrium stromal cells (hESCs) hampers decidualization, while overexpression could trigger the expression of decidual marker genes, and ameliorate the decidualization of hESCs from RIF patients. Mechanistically, ATF3 promotes decidualization by upregulating FOXO1 via suppressing miR-135b expression. In addition, the endometrium of RIF patients was hyperproliferative, while overexpression of ATF3 inhibited the proliferation of hESCs through CDKN1A. These data demonstrate the critical roles of endometrial ATF3 in regulating decidualization and proliferation, and dysregulation of ATF3 in the endometrium may be a novel cause of RIF and therefore represent a potential therapeutic target for RIF.
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Affiliation(s)
- Zhilong Wang
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 210008, Nanjing, People's Republic of China
| | - Yang Liu
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 210008, Nanjing, People's Republic of China
| | - Jingyu Liu
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 210008, Nanjing, People's Republic of China
| | - Na Kong
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 210008, Nanjing, People's Republic of China
| | - Yue Jiang
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 210008, Nanjing, People's Republic of China
| | - Ruiwei Jiang
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 210008, Nanjing, People's Republic of China
| | - Xin Zhen
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 210008, Nanjing, People's Republic of China
| | - Jidong Zhou
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 210008, Nanjing, People's Republic of China
| | - Chaojun Li
- Nanjing University Medical School, 210008, Nanjing, People's Republic of China
| | - Haixiang Sun
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 210008, Nanjing, People's Republic of China.
| | - Guijun Yan
- Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 210008, Nanjing, People's Republic of China.
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Liu C, Li L, Wang M, Shui S, Yao H, Sui C, Zhang H. Endometrial extracellular vesicles of recurrent implantation failure patients inhibit the proliferation, migration, and invasion of HTR8/SVneo cells. J Assist Reprod Genet 2021; 38:825-833. [PMID: 33521905 PMCID: PMC8079592 DOI: 10.1007/s10815-021-02093-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 01/27/2021] [Indexed: 01/03/2023] Open
Abstract
PURPOSE Endometrial extracellular vesicles are essential in regulating trophoblasts' function. This study aims to investigate whether endometrial extracellular vesicles (EVs) from recurrent implantation failure (RIF) patients inhibit the proliferation, invasion, and migration of HTR8/SVneo cells. METHODS Eighteen RIF patients and thirteen fertile women were recruited for endometria collection. Endometrial cells isolated from the endometria were cultured and modulated by hormones, and the conditioned medium was used for EV isolation. EVs secreted by the endometrial cells of RIF patients (RIF-EVs) or fertile women (FER-EVs) were determined by Western blotting, nanoparticle tracking analysis, and transmission electron microscopy. Fluorescence-labeled EVs were used to visualize internalization by HTR8/SVneo cells. RIF-EVs and FER-EVs were co-cultured with HTR8/SVneo cells. Cell Counting Kit-8, transwell invasion, and wound closure assays were performed to determine cellular proliferation, invasion, and migration, respectively, in different treatments. RESULTS RIF-EVs and FER-EVs were bilayer membrane vesicles, ranging from 100 to 150 nm in size, that expressed the classic EV markers Alix and CD9. RIF-EVs and FER-EVs were internalized by HTR8/SVneo cells within 2 h. The proliferation rate in the FER-EV group was significantly higher than that in the RIF-EV group at 20 μg/mL. Moreover, the invasion and migration capacity of trophoblast cells were decreased in the RIF-EV group relative to the FER-EV group at 20 μg/mL. CONCLUSION Endometrial EVs from RIF patients inhibited the functions of trophoblasts by decreasing their proliferation, migration, and invasive capacity. Such dysregulations induced by RIF-EVs may provide novel insights for better understanding the pathogenesis of implantation failure.
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Affiliation(s)
- Chang Liu
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095#, Wuhan, 430030, People's Republic of China
| | - Linshuang Li
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095#, Wuhan, 430030, People's Republic of China
| | - Meng Wang
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095#, Wuhan, 430030, People's Republic of China
| | - Shike Shui
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095#, Wuhan, 430030, People's Republic of China
| | - Haixia Yao
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095#, Wuhan, 430030, People's Republic of China
| | - Cong Sui
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095#, Wuhan, 430030, People's Republic of China
| | - Hanwang Zhang
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095#, Wuhan, 430030, People's Republic of China.
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Zang X, Zhou C, Wang W, Gan J, Li Y, Liu D, Liu G, Hong L. Differential MicroRNA Expression Involved in Endometrial Receptivity of Goats. Biomolecules 2021; 11:biom11030472. [PMID: 33810054 PMCID: PMC8004627 DOI: 10.3390/biom11030472] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/08/2021] [Accepted: 03/18/2021] [Indexed: 12/13/2022] Open
Abstract
Endometrial receptivity represents one of the leading factors affecting the successful implantation of embryos during early pregnancy. However, the mechanism of microRNAs (miRNAs) to establish goat endometrial receptivity remains unclear. This study was intended to identify potential miRNAs and regulatory mechanisms associated with establishing endometrial receptivity through integrating bioinformatics analysis and experimental verification. MiRNA expression profiles were obtained by high-throughput sequencing, resulting in the detection of 33 differentially expressed miRNAs (DEMs), followed by their validation through quantitative RT-PCR. Furthermore, 10 potential transcription factors (TFs) and 1316 target genes of these DEMs were obtained, and the TF–miRNA and miRNA–mRNA interaction networks were constructed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that these miRNAs were significantly linked to establishing endometrial receptivity. Moreover, the fluorescence in situ hybridization (FISH) analysis, dual-luciferase report assay, and immunohistochemistry (IHC) analysis corroborated that chi-miR-483 could directly bind to deltex E3 ubiquitin ligase 3L (DTX3L) to reduce its expression level. In conclusion, our findings contribute to a better understanding of molecular mechanisms regulating the endometrial receptivity of goats, and they provide a reference for improving embryo implantation efficiency.
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Affiliation(s)
- Xupeng Zang
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (X.Z.); (C.Z.); (W.W.); (J.G.); (Y.L.); (D.L.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Chen Zhou
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (X.Z.); (C.Z.); (W.W.); (J.G.); (Y.L.); (D.L.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Wenjing Wang
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (X.Z.); (C.Z.); (W.W.); (J.G.); (Y.L.); (D.L.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Jianyu Gan
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (X.Z.); (C.Z.); (W.W.); (J.G.); (Y.L.); (D.L.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Yaokun Li
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (X.Z.); (C.Z.); (W.W.); (J.G.); (Y.L.); (D.L.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Dewu Liu
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (X.Z.); (C.Z.); (W.W.); (J.G.); (Y.L.); (D.L.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
| | - Guangbin Liu
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (X.Z.); (C.Z.); (W.W.); (J.G.); (Y.L.); (D.L.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
- Correspondence: (G.L.); (L.H.); Tel.: +86-02085281859 (L.H.)
| | - Linjun Hong
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China; (X.Z.); (C.Z.); (W.W.); (J.G.); (Y.L.); (D.L.)
- Lingnan Guangdong Laboratory of Modern Agriculture, Guangzhou 510642, China
- Correspondence: (G.L.); (L.H.); Tel.: +86-02085281859 (L.H.)
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