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Cao SQ, Jiang TX, Guo YY, Lin R, Lin L. MiR-519d-3p from Placenta-Derived Exosomes Induce Immune Intolerance Regulating Immune Cells, Contributing to the Pathogenesis of Preeclampsia. Immunol Invest 2025; 54:522-543. [PMID: 39819170 DOI: 10.1080/08820139.2025.2450234] [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] [Indexed: 01/19/2025]
Abstract
BACKGROUND MiR-519d-3p, also called specific placenta biomarkers, is a member of the Chromosome 19 miRNA Cluster (C19MC) with the highest concentrations of miRNAs in human placenta and maternal serum. These miRNAs are secreted by fetal trophoblast cells within extracellular vesicles (EVs) and interact with the mother's immune cells, which has been proposed to be crucial for immunological tolerance at the placental-maternal interface. A key mechanism in preeclampsia, a multifactorial, multipath hypertensive pregnancy illness, is an immunological imbalance between the mother and the fetus. METHODS Using Next Generation Sequencing, we determined that the placenta-derived Exosomes (pEXOs) of preeclamptic patients had elevated expression of miR-519. To further develop an in vitro model of trophoblast-immune cell communication, HTR-8/Svneo cells and Jurkat T cells were employed and we utilized experiments such as Western blot (WB), Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR), Cell-Counting-Kit-8 (CCK-8) cell proliferation analysis, cell apoptosis analysis, and other techniques to accomplish research. RESULTS It was discovered that miR-519d-3p in pEXOs promoted Jurkat T cell proliferation, inhibited apoptosis, and induced Jurkat T cell differentiation toward Th17. CONCLUSION MiR-519d-3p in pEXOs disrupts immune tolerance at the maternal-placental interface by encouraging Jurkat T cell proliferation, preventing Jurkat T cell apoptosis, and creating an imbalance in Th17/Treg differentiation. This likely leads to SIRS and unfavorable pregnancy complications like preeclampsia.
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Affiliation(s)
- Si-Qi Cao
- Department of Obstetrics and Gynecology, Shengli Clinical Medical College of Fujian Medical University, Fujian, China
| | - Tu-Xiang Jiang
- Department of Obstetrics and Gynecology, Shengli Clinical Medical College of Fujian Medical University, Fujian, China
| | - Ying-Ying Guo
- Department of Obstetrics and Gynecology, Shengli Clinical Medical College of Fujian Medical University, Fujian, China
| | - Rong Lin
- Department of Obstetrics and Gynecology, Medical Centre of Maternity and Child Health, Shengli Clinical Medical College of Fujian Medical University, Fujian, China
- Fuzhou University Affiliated Provincial Hospital, Fujian, China
| | - Liang Lin
- Department of Obstetrics and Gynecology, Medical Centre of Maternity and Child Health, Shengli Clinical Medical College of Fujian Medical University, Fujian, China
- Fuzhou University Affiliated Provincial Hospital, Fujian, China
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Sadeghzadeh Oskouei B, Asadi Z, Jahanban Esfahlan R. Non-invasive blood tests for earlier diagnosis and treatment of endometriosis. J Reprod Immunol 2025; 169:104521. [PMID: 40121746 DOI: 10.1016/j.jri.2025.104521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 03/03/2025] [Accepted: 03/13/2025] [Indexed: 03/25/2025]
Abstract
Endometriosis is a chronic condition characterized by the presence of endometrial-like tissue outside the uterus, leading to symptoms such as dysmenorrhea and chronic pain. It affects approximately 2-10 % of women of reproductive age and up to 50 % of those experiencing infertility, significantly impacting the healthcare system. Despite its prevalence, endometriosis presents in a variety of forms and phenotypes, partly due to the absence of a non-invasive biomarker for diagnosis. Early detection of endometriosis is crucial for effective management; however, the most dependable diagnostic method currently available is laparoscopy. Many women are reluctant to undergo this surgical procedure, resulting in a substantial number remaining unaware of their condition. This review aims to explore the potential of non-invasive blood tests in developing reliable biomarkers or a combination of biomarkers for the early detection and diagnosis of endometriosis. Innovative therapies such as immunomodulation, stem cell therapy, biosensors, and nanotheranostics present promising avenues for personalized diagnosis and treatment, focusing on genetic, epigenetic, and immunological aspects. The review emphasizes the importance of various biomarkers and the necessity for further research to enhance diagnosis and improve the quality of life for women affected by endometriosis.
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Affiliation(s)
- Behnaz Sadeghzadeh Oskouei
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zoleikha Asadi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rana Jahanban Esfahlan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Panvino F, Paparella R, Pisani F, Tarani F, Ferraguti G, Fiore M, Ardizzone I, Tarani L. Endometriosis in Adolescence: A Narrative Review of the Psychological and Clinical Implications. Diagnostics (Basel) 2025; 15:548. [PMID: 40075795 PMCID: PMC11898908 DOI: 10.3390/diagnostics15050548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 02/19/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
Endometriosis is a chronic, inflammatory condition where endometrial-like tissue grows outside the uterus, affecting around 10% of women of reproductive age. This condition is associated with debilitating symptoms, including dysmenorrhea, dyspareunia, chronic pelvic pain, fatigue, and infertility. Adolescents with endometriosis face unique challenges, as the disease is often misdiagnosed or undiagnosed for an average of 7-10 years due to its complex and multifactorial nature. Consequently, patients frequently suffer from worsening symptoms and significant psychological distress, including anxiety, depression, and social withdrawal. While there is no definitive cure for endometriosis, treatment approaches typically involve hormonal therapies, lifestyle adjustments (such as diet and exercise), and psychological support. Recent studies emphasize the profound impact of endometriosis on the mental health of adolescents, highlighting the need for a more holistic treatment approach that integrates both medical and psychological care. This narrative review explores the psychological and psychosocial effects of endometriosis in adolescents, examining the biological and psychological mechanisms linking the disease to mental health outcomes. It also discusses current therapeutic strategies, such as cognitive behavioral therapy, mindfulness, and peer support, and underscores the importance of early diagnosis and multidisciplinary care to mitigate both the physical and emotional burdens of the condition. This integrated approach is critical in improving the overall well-being and quality of life for adolescents living with endometriosis.
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Affiliation(s)
- Fabiola Panvino
- Department of Human Neuroscience, Sapienza University of Rome, 00185 Rome, Italy; (F.P.)
| | - Roberto Paparella
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (R.P.)
| | - Francesco Pisani
- Department of Human Neuroscience, Sapienza University of Rome, 00185 Rome, Italy; (F.P.)
| | - Francesca Tarani
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (R.P.)
| | - Giampiero Ferraguti
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology (IBBC-CNR), Department of Sensory Organs, Sapienza University of Rome, 00185 Rome, Italy
| | - Ignazio Ardizzone
- Department of Human Neuroscience, Sapienza University of Rome, 00185 Rome, Italy; (F.P.)
| | - Luigi Tarani
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (R.P.)
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Muraoka A, Yokoi A, Yoshida K, Kitagawa M, Bayasula, Murakami M, Miyake N, Sonehara R, Nakamura T, Osuka S, Kajiyama H. Serum-derived small extracellular vesicles as biomarkers for predicting pregnancy and delivery on assisted reproductive technology in patients with endometriosis. Front Endocrinol (Lausanne) 2025; 15:1442684. [PMID: 39897955 PMCID: PMC11782015 DOI: 10.3389/fendo.2024.1442684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 12/18/2024] [Indexed: 02/04/2025] Open
Abstract
Introduction Endometriosis can cause of infertility, and evaluation methods for predicting clinical pregnancy outcomes are desired. Extracellular vesicles (EVs) exist in blood and it contains small non-coding RNAs (ncRNAs) that may reflect disease severity. In this study, we investigated small ncRNAs in serum EVs to identify specific biomarkers for predicting clinical pregnancy. Methods Serum samples were collected from 48 patients who underwent assisted reproductive technology (ART). EVs were successfully isolated from serum samples and characterized using nanoparticle tracking assays, electron microscopy, and western blotting of EV's markers. We performed small RNA sequencing and analyzed microRNA (miRNA) profiles in the infertility patients with and without endometriosis to detect pregnancy-predicting biomarkers. Results Candidate miRNAs in serum EVs were selected by comparing patients without endometriosis who became pregnant (n = 13) with those who did not (n = 21). A total of 241 miRNAs were detected; however, no trends separated the two groups. Next, EVs from patients with endometriosis were analyzed and divided into pregnant (n = 4) and non-pregnant (n = 10) cases. Among the 224 candidate miRNAs, miRNA profiles of pregnant women with endometriosis were separated from those of non-pregnant women by receiver-operating characteristics (ROC) curve analysis (area under the curve [AUC] > 0.8). In patients with endometriosis, serum EVs may be useful for predicting possible pregnancy before infertility treatment. Finally, we used small RNA sequencing of the tissue to demonstrate that pregnancy-predicting miRNAs in serum EVs were produced from endometriosis lesions. Although no predictors were found from miRNAs in serum EVs without endometriosis, miRNAs in serum EVs of patients with endometriosis could provide novel noninvasive biomarkers to predict pregnancy and have potential clinical applicability in ART. Discussion Further studies are required to examine the functional importance of these miRNAs to elucidate the pathological mechanisms of endometriosis and pregnancy.
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Affiliation(s)
- Ayako Muraoka
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akira Yokoi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Nagoya University Institute for Advanced Research, Nagoya, Japan
- Japan Science and Technology Agency (JST), FOREST, Saitama, Japan
| | - Kosuke Yoshida
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Nagoya University Institute for Advanced Research, Nagoya, Japan
| | - Masami Kitagawa
- Bell Research Center for Reproductive Health and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Bayasula
- Bell Research Center for Reproductive Health and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mayuko Murakami
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Natsuki Miyake
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Reina Sonehara
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomoko Nakamura
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Satoko Osuka
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Liao H, Tian W, Yao W, Guo Q, Wang Y, Li J, Qing D, Li Y, Deng T. DBP Exposure Affects Oocyte Fertilization Via Extracellular Vesicles-Derived miR-116-5p in Ovarian Granulosa Cells Through Downregulating FOXO3a Expression. Reprod Sci 2024; 31:3858-3869. [PMID: 38858331 DOI: 10.1007/s43032-024-01559-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: 01/16/2024] [Accepted: 04/12/2024] [Indexed: 06/12/2024]
Abstract
Mono-butyl phthalate (MBP), the metabolite of dibutyl phthalate (DBP), is the most abundant phthalate metabolite found in Chinese women. Extracellular vesicles (EVs) are nanoscale lipid bilayer particles produced by extensive kinds of cells, serving a key role in intercellular communication. Extracellular vesicle miRNAs (EV-miRNAs) in follicular fluid (FF) have been evidenced to be associated with female reproductive health. The objective of this study was to investigate the associations of EV-miRNAs expressed profile with DBP exposure in FF of female participants and expose its potential mechanism in impaired oocyte development. Based on participants' FF MBP concentrations and fertilization status, we compared the miRNA expression between the FF-EVs of group A (high DBP exposure and impaired fertilization) and group B (low DBP exposure and normal fertilization). Compared with group B, miR-1246, miR-3679-5p, miR-423-5p, miR-5585-3p, miR-116-5p, miR-172-5p were upregulated, while miR-34b-3p was downregulated in group A. Target genes of the differently expressed miRNAs were predicted, and the functional analysis was performed. Furthermore, we exposed human ovarian granulosa tumor cell line (KGN) to MBP (4ug/L) to isolate the EVs from the culture medium and validated the expression levels of different miRNAs. We found that MBP exposure was significantly associated with increased levels of miR-116-5p (P = 0.01). In addition, we demonstrated that the most different miRNA, miR-116-5p regulated oocyte fertilization by inhibiting FOXO3a. Our findings suggested that EV-miRNAs in the FF might mediate MBP toxicity in oocytes.
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Affiliation(s)
- Hongmei Liao
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Wenqu Tian
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Wen Yao
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Qingchun Guo
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Yi Wang
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Juan Li
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Danyu Qing
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Yufeng Li
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Taoran Deng
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
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Senousy MA, Shaker OG, Elmaasrawy AH, Ashour AM, Alsufyani SE, Arab HH, Ayeldeen G. Serum lncRNAs TUG1, H19, and NEAT1 and their target miR-29b/SLC3A1 axis as possible biomarkers of preeclampsia: Potential clinical insights. Noncoding RNA Res 2024; 9:995-1008. [PMID: 39026605 PMCID: PMC11254728 DOI: 10.1016/j.ncrna.2024.06.007] [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: 02/15/2024] [Revised: 05/26/2024] [Accepted: 06/07/2024] [Indexed: 07/20/2024] Open
Abstract
To date, the epigenetic signature of preeclampsia (PE) is not completely deciphered. Oxidative stress-responsive long non-coding RNAs (lncRNAs) are deregulated in preeclamptic placenta; however, their circulating profiles and diagnostic abilities are still unexplored. We investigated serum redox-sensitive lncRNAs TUG1, H19, and NEAT1, and their target miR-29b/cystine/neutral/dibasic amino acids transporter solute carrier family 3, member 1 (SLC3A1) as potential non-invasive biomarkers of PE risk, onset, and severity. We recruited 82 patients with PE and 78 healthy pregnant women. We classified PE patients into early-onset (EOPE) and late-onset (LOPE) subgroups at a cut-off 34 gestational weeks and into severe and mild PE subgroups by blood pressure and proteinuria criteria. Bioinformatics analysis was employed to select lncRNAs/microRNA/target gene interactions. Serum H19, NEAT1, and SLC3A1 mRNA expression were reduced, meanwhile miR-29b levels were elevated, whereas there was no significant difference in TUG1 levels between PE patients and healthy pregnancies. Serum H19 levels were lower, whereas miR-29b levels were higher in EOPE versus LOPE. Serum miR-29b and H19 levels were higher in severe versus mild PE. ROC analysis identified serum H19, NEAT1, miR-29b, and SLC3A1 as potential diagnostic markers, with H19 (AUC = 0.818, 95%CI = 0.744-0.894) and miR-29b (AUC = 0.82, 95%CI = 0.755-0.885) were superior discriminators. Only H19 and miR-29b discriminated EOPE and severe PE cases. In multivariate logistic analysis, miR-29b and H19 were associated with EOPE, using maternal age and gestational age as covariates, while miR-29b was associated with severe PE, using maternal age as covariate. Studied markers were correlated with clinical and ultrasound data in the overall PE group. Serum H19 and TUG1 were negatively correlated with albuminuria in EOPE and LOPE, respectively. NEAT1 and SLC3A1 were correlated with ultrasound data in EOPE. Likewise, TUG1, miR-29b, and SLC3A1 showed significant correlations with ultrasound data in LOPE. Conclusively, this study configures SLC3A1 expression as a novel potential serum biomarker of PE and advocates serum H19 and miR-29b as biomarkers of EOPE and miR-29b as a biomarker of PE severity.
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Affiliation(s)
- Mahmoud A. Senousy
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
| | - Olfat G. Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ahmed H.Z. Elmaasrawy
- Department of Obstetrics and Gynecology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Ahmed M. Ashour
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al Qura University, P.O. Box 13578, Makkah, 21955, Saudi Arabia
| | - Shuruq E. Alsufyani
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia
| | - Hany H. Arab
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia
| | - Ghada Ayeldeen
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
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Wagner M, Hicks C, El-Omar E, Combes V, El-Assaad F. The Critical Role of Host and Bacterial Extracellular Vesicles in Endometriosis. Biomedicines 2024; 12:2585. [PMID: 39595151 PMCID: PMC11591939 DOI: 10.3390/biomedicines12112585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 10/29/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
Endometriosis is a chronic, inflammatory, oestrogen-dependent disorder that is defined by the presence of endometrium-like tissue in the extra-uterine environment. It is estimated to affect approximately 10% of women of reproductive age, and the cause is still largely unknown. The heterogenous nature and complex pathophysiology of the disease results in diagnostic and therapeutic challenges. This review examines the emerging role of host extracellular vesicles (EVs) in endometriosis development and progression, with a particular focus on bacterial extracellular vesicles (BEVs). EVs are nano-sized membrane-bound particles that can transport bioactive molecules such as nucleic acids, proteins, and lipids, and therefore play an essential role in intercellular communication. Due to their unique cargo composition, EVs can play a dual role, both in the disease pathogenesis and as biomarkers. Both host and bacterial EVs (HEVs and BEVs) have been implicated in endometriosis, by modulating inflammatory responses, angiogenesis, tissue remodelling, and cellular proliferation within the peritoneal microenvironment. Understanding the intricate mechanisms underlying EVs in endometriosis pathophysiology and modulation of the lesion microenvironment may lead to novel diagnostic tools and therapeutic targets. Future research should focus on uncovering the specific cargo, the inter-kingdom cell-to-cell interactions, and the anti-inflammatory and anti-microbial mechanisms of both HEVs and BEVs in endometriosis in the hope of discovering translational findings that could improve the diagnosis and treatment of the disease.
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Affiliation(s)
- Michaela Wagner
- Microbiome Research Centre, St George and Sutherland Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia; (M.W.); (C.H.); (E.E.-O.)
| | - Chloe Hicks
- Microbiome Research Centre, St George and Sutherland Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia; (M.W.); (C.H.); (E.E.-O.)
| | - Emad El-Omar
- Microbiome Research Centre, St George and Sutherland Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia; (M.W.); (C.H.); (E.E.-O.)
| | - Valery Combes
- Malaria and Microvesicles Research Group, School of Life Science, Faculty of Science, University of Technology Sydney, Ultimo, Sydney, NSW 2007, Australia;
| | - Fatima El-Assaad
- Microbiome Research Centre, St George and Sutherland Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia; (M.W.); (C.H.); (E.E.-O.)
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Lai Y, Fu Z, Gao Y, Ma N, Li L. Hypoxia-inducible factors (HIFs) in early pregnancy: implications for miscarriage†. Biol Reprod 2024; 111:987-999. [PMID: 39325972 DOI: 10.1093/biolre/ioae139] [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: 05/09/2024] [Revised: 09/07/2024] [Accepted: 09/25/2024] [Indexed: 09/28/2024] Open
Abstract
Miscarriage poses a significant threat to both maternal and fetal health. Its etiology remains unknown, and there are no established effective identification or prevention strategies. A low-oxygen environment in early pregnancy is a physiological necessity for embryonic and placental growth. Hypoxia-inducible factors are a family of classic hypoxia signaling molecules whose expression level may fluctuate abnormally because of an imbalance in oxygen levels. Its unusual fluctuations initiate multiple signaling pathways at the maternal womb. Hypoxia-inducible factors are a family of classic hypoxia-signaling molecules and immune tolerance. Notably, aberrant regulation of these processes may lead to miscarriage. This review aims to clarify how the hypoxia-inducible factor-1α mediates the aberrant regulation of biological processes, including autophagy, metabolic reprogramming, et al., and how these effects impact trophoblasts and other cells at the maternal-fetal interface. These findings provide new insights into potential therapeutic and preventive strategies for miscarriage.
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Affiliation(s)
- Yuxuan Lai
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Zhiyu Fu
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Yaxin Gao
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Environment and Population Health, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Ning Ma
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Environment and Population Health, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Lu Li
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Environment and Population Health, School of Public Health, Hebei Medical University, Shijiazhuang, China
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9
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Iorio R, Petricca S, Di Emidio G, Falone S, Tatone C. Mitochondrial Extracellular Vesicles (mitoEVs): Emerging mediators of cell-to-cell communication in health, aging and age-related diseases. Ageing Res Rev 2024; 101:102522. [PMID: 39369800 DOI: 10.1016/j.arr.2024.102522] [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: 07/03/2024] [Revised: 08/17/2024] [Accepted: 09/23/2024] [Indexed: 10/08/2024]
Abstract
Mitochondria are metabolic and signalling hubs that integrate a plethora of interconnected processes to maintain cell homeostasis. They are also dormant mediators of inflammation and cell death, and with aging damages affecting mitochondria gradually accumulate, resulting in the manifestation of age-associated disorders. In addition to coordinate multiple intracellular functions, mitochondria mediate intercellular and inter-organ cross talk in different physiological and stress conditions. To fulfil this task, mitochondrial signalling has evolved distinct and complex conventional and unconventional routes of horizontal/vertical mitochondrial transfer. In this regard, great interest has been focused on the ability of extracellular vesicles (EVs), such as exosomes and microvesicles, to carry selected mitochondrial cargoes to target cells, in response to internal and external cues. Over the past years, the field of mitochondrial EVs (mitoEVs) has grown exponentially, revealing unexpected heterogeneity of these structures associated with an ever-expanding mitochondrial function, though the full extent of the underlying mechanisms is far from being elucidated. Therefore, emerging subsets of EVs encompass exophers, migrasomes, mitophers, mitovesicles, and mitolysosomes that can act locally or over long-distances to restore mitochondrial homeostasis and cell functionality, or to amplify disease. This review provides a comprehensive overview of our current understanding of the biology and trafficking of MitoEVs in different physiological and pathological conditions. Additionally, a specific focus on the role of mitoEVs in aging and the onset and progression of different age-related diseases is discussed.
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Affiliation(s)
- Roberto Iorio
- Dept. of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, L'Aquila 67100, Italy.
| | - Sabrina Petricca
- Dept. of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, L'Aquila 67100, Italy
| | - Giovanna Di Emidio
- Dept. of Life, Health and Environmental Sciences, University of L'Aquila, Via Vetoio, L'Aquila 67100, Italy
| | - Stefano Falone
- Dept. of Life, Health and Environmental Sciences, University of L'Aquila, Via Vetoio, L'Aquila 67100, Italy
| | - Carla Tatone
- Dept. of Life, Health and Environmental Sciences, University of L'Aquila, Via Vetoio, L'Aquila 67100, Italy
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Parvin A, Erabi G, Mohammadpour D, Maleki-Kakelar H, Sadeghpour S, Pashaei MR, Taheri-Anganeh M, Ghasemnejad-Berenji H. Infertility: Focus on the therapeutic potential of extracellular vesicles. Reprod Biol 2024; 24:100925. [PMID: 39018753 DOI: 10.1016/j.repbio.2024.100925] [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: 03/30/2024] [Revised: 05/28/2024] [Accepted: 07/05/2024] [Indexed: 07/19/2024]
Abstract
Infertility is a well-known problem that arises from a variety of reproductive diseases. Until now, researchers have tried various methods to restore fertility, including medication specific to the cause, hormone treatments, surgical removals, and assisted reproductive technologies. While these methods do produce results, they do not consistently lead to fertility restoration in every instance. The use of exosome therapy has significant potential in treating infertility in patients. This is because exosomes, microvesicles, and apoptotic bodies, which are different types of vesicles, play a crucial role in transferring bioactive molecules that aid in cell-to-cell communication. Reproductive fluids can transport a variety of molecular cargos, such as miRNAs, mRNAs, proteins, lipids, and DNA molecules. The percentage of these cargos in the fluids can be linked to their physiological and pathological status. EVs are involved in several physiological and pathological processes and offer interesting non-cellular therapeutic possibilities to treat infertility. EVs (extracellular vesicles) transplantation has been shown in many studies to be a key part of regenerating different parts of the reproductive system, including the production of oocytes and the start of sperm production. Nevertheless, the existing evidence necessitates testifying to the effectiveness of injecting EVs in resolving reproductive problems among humans. This review focuses on the current literature about infertility issues in both females and males, specifically examining the potential treatments involving extracellular vesicles (EVs).
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Affiliation(s)
- Ali Parvin
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Gisou Erabi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Donna Mohammadpour
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Hadi Maleki-Kakelar
- Solid Tumor Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Sonia Sadeghpour
- Reproductive Health Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran; Department of Obstetrics & Gynecology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohammad Reza Pashaei
- Department of Internal Medicine, School of Medicine, 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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11
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Franko R, de Almeida Monteiro Melo Ferraz M. Exploring the potential of in vitro extracellular vesicle generation in reproductive biology. JOURNAL OF EXTRACELLULAR BIOLOGY 2024; 3:e70007. [PMID: 39238549 PMCID: PMC11375532 DOI: 10.1002/jex2.70007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 07/11/2024] [Accepted: 08/15/2024] [Indexed: 09/07/2024]
Abstract
The interest in the growing field of extracellular vesicle (EV) research highlights their significance in intercellular signalling and the selective transfer of biological information between donor and recipient cells. EV studies have provided valuable insights into intercellular communication mechanisms, signal identification and their involvement in disease states, offering potential avenues for manipulating pathological conditions, detecting biomarkers and developing drug-delivery systems. While our understanding of EV functions in reproductive tissues has significantly progressed, exploring their potential as biomarkers for infertility, therapeutic interventions and enhancements in assisted reproductive technologies remains to be investigated. This knowledge gap stems partly from the difficulties associated with large-scale EV production relevant to clinical applications. Most existing studies on EV production rely on conventional 2D cell culture systems, characterized by suboptimal EV yields and a failure to replicate in vivo conditions. This results in the generation of EVs that differ from their in vivo counterparts. Hence, this review firstly delves into the importance of EVs in reproduction to then expand on current techniques for in vitro EV production, specifically examining diverse methods of culture and the potential of bioengineering technologies to establish innovative systems for enhanced EV production.
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Affiliation(s)
- Roksan Franko
- Clinic of Ruminants, Faculty of Veterinary Medicine Ludwig-Maximilians-Universität München Oberschleißheim Germany
- Gene Center Ludwig-Maximilians-Universität München Munich Germany
| | - Marcia de Almeida Monteiro Melo Ferraz
- Clinic of Ruminants, Faculty of Veterinary Medicine Ludwig-Maximilians-Universität München Oberschleißheim Germany
- Gene Center Ludwig-Maximilians-Universität München Munich Germany
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12
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Duval C, Wyse BA, Tsang BK, Librach CL. Extracellular vesicles and their content in the context of polycystic ovarian syndrome and endometriosis: a review. J Ovarian Res 2024; 17:160. [PMID: 39103867 DOI: 10.1186/s13048-024-01480-7] [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: 04/30/2024] [Accepted: 07/18/2024] [Indexed: 08/07/2024] Open
Abstract
Extracellular vesicles (EVs), particles enriched in bioactive molecules like proteins, nucleic acids, and lipids, are crucial mediators of intercellular communication and play key roles in various physiological and pathological processes. EVs have been shown to be involved in ovarian follicular function and to be altered in two prevalent gynecological disorders; polycystic ovarian syndrome (PCOS) and endometriosis.Ovarian follicles are complex microenvironments where folliculogenesis takes place with well-orchestrated interactions between granulosa cells, oocytes, and their surrounding stromal cells. Recent research unveiled the presence of EVs, including exosomes and microvesicles, in the follicular fluid (FFEVs), which constitutes part of the developing oocyte's microenvironment. In the context of PCOS, a multifaceted endocrine, reproductive, and metabolic disorder, studies have explored the dysregulation of these FFEVs and their cargo. Nine PCOS studies were included in this review and two miRNAs were commonly reported in two different studies, miR-379 and miR-200, both known to play a role in female reproduction. Studies have also demonstrated the potential use of EVs as diagnostic tools and treatment options.Endometriosis, another prevalent gynecological disorder characterized by ectopic growth of endometrial-like tissue, has also been linked to aberrant EV signaling. EVs in the peritoneal fluid of women with endometriosis carry molecules that modulate the immune response and promote the establishment and maintenance of endometriosis lesions. EVs derived from endometriosis lesions, serum and peritoneal fluid obtained from patients with endometriosis showed no commonly reported biomolecules between the eleven reviewed studies. Importantly, circulating EVs have been shown to be potential biomarkers, also reflecting the severity of the pathology.Understanding the interplay of EVs within human ovarian follicles may provide valuable insights into the pathophysiology of both PCOS and endometriosis. Targeting EV-mediated communication may open avenues for novel diagnostic and therapeutic approaches for these common gynecological disorders. More research is essential to unravel the mechanisms underlying EV involvement in folliculogenesis and its dysregulation in PCOS and endometriosis, ultimately leading to more effective and personalized interventions.
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Affiliation(s)
- Cyntia Duval
- CReATe Fertility Center, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | | | - Benjamin K Tsang
- Inflammation and Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Departments of Obstetrics and Gynecology & Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Clifford L Librach
- CReATe Fertility Center, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
- Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada
- Sunnybrook Research Institute, Toronto, ON, Canada
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13
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Shekarchi AA, Hosseini L, Kamrani A, Alipourfard I, Soltani-Zangbar MS, Akbari M, Roshangar L, Aghebati-Maleki L, Chakari-Khiavi F, Chakari-Khiavi A, Motlagh Asghari K, Danaii S, Pourlak T, Ahmadian Heris J, Yousefi M. Evaluation of changes in exhausted T lymphocytes and miRNAs expression in the different trimesters of pregnancy in pregnant women. Mol Biol Rep 2024; 51:442. [PMID: 38520563 DOI: 10.1007/s11033-024-09370-3] [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: 08/09/2023] [Accepted: 02/20/2024] [Indexed: 03/25/2024]
Abstract
BACKGROUND Throughout the three trimesters of a typical pregnancy, we looked at changes in the expression of miRNAs and exhausted T lymphocytes for this study. METHODS AND RESULTS Fifty healthy subjects were included in this study. The frequency of exhausted T lymphocytes was measured in isolated PBMCs using flow cytometry. PD-1, TIM-3, and related miRNAs gene expression were assessed using qRT-PCR. The analyses revealed a significant decline in PD-1 and Tim-3 expression in PBMCs from RPL women (p = 0.0003 and p = 0.001, respectively). In addition, PD-1 and TIM-3 expression increased significantly in the 2nd trimester compared with the 1st trimester of healthy pregnant women (p < 0.0001 and p = 0.0002, respectively). PD-1 and TIM-3 expression was down-regulated in the 3rd trimester compared with the 1st and 2nd trimesters. In the present study, we demonstrated that TIM-3+/CD4+, TIM-3+/CD8+, PD-1+/CD4+, and PD-1+/CD8 + exhausted T lymphocytes increased in the circulation of women in the 2nd trimester compared to the 1st and 3rd trimester. In the 3rd trimester, the expression of miR-16-5p increased significantly (p < 0.0001). miR-125a-3p expression was down and upregulated in 2nd (p < 0.0001) and 3rd (p = 0.0007) trimesters compared to 1st trimester, respectively. This study showed a significant elevation of miR-15a-5p in 3rd trimester compared to 1st trimester of pregnant women (p = 0.0002). CONCLUSIONS Expression pattern of PD-1 and TIM3 in exhausted T lymphocytes is different not only between normal pregnant and RPL women but also in different trimesters of pregnancy. So, our results showed the role of these markers in the modulation lymphocytes activity in different stages of pregnancy.
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Affiliation(s)
- Ali Akbar Shekarchi
- Department of Pathology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Hosseini
- Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Kamrani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Iraj Alipourfard
- Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland
| | - Mohammad Sadegh Soltani-Zangbar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Roshangar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Aref Chakari-Khiavi
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Kimia Motlagh Asghari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahla Danaii
- Gynecology Department, Eastern Azerbaijan ACECR ART center, Eastern Azerbaijan branch of ACECR, Tabriz, Iran
| | - Tannaz Pourlak
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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14
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Ji J, Wang H, Yuan M, Li J, Song X, Lin K. Exosomes from ectopic endometrial stromal cells promote M2 macrophage polarization by delivering miR-146a-5p. Int Immunopharmacol 2024; 128:111573. [PMID: 38278065 DOI: 10.1016/j.intimp.2024.111573] [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: 08/19/2023] [Revised: 01/10/2024] [Accepted: 01/18/2024] [Indexed: 01/28/2024]
Abstract
BACKGROUND Ectopic endometrial stromal cells (ESCs) and M2 macrophages co-exist in the lesions of endometriosis and participate in the occurrence and progression of endometriosis. However, the interaction between ectopic ESCs and M2-type macrophage polarization is poorly understood. This study aims to investigate the effect of exosomes released from ectopic ESCs on M2 macrophage polarization and the potential mechanism. METHODS Human THP-1 monocytic cells induced macrophage differentiation (M0) and M2 polarization. Ectopic ESCs and their exosomes were used to stimulate M2 macrophages. M2 macrophage polarization was examined by detecting CD163 and ARG1 expression. Exosomal microRNAs were analyzed by small-RNA sequencing. RESULTS Our in vitro results suggest that exosomes of ectopic ESCs promoted M2 macrophage polarization. Meanwhile, The miR-146a-5p level was highly increased in ectopic ESCs and their exosomes and promoted the role of exosomes in M2 macrophage polarization. As a target, TRAF6 overexpression inhibits the function of miR-146a-5p mimic on M2 macrophage polarization. In the rat model, exosomes from ectopic ESCs contribute to the development of endometriosis. CONCLUSIONS It was suggested that exosomes derived from ectopic ESCs promote the M2 macrophage polarization by delivering miR-146a-5p targeting TRAF6 in the pathological process of endometriosis.
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Affiliation(s)
- Jiaqi Ji
- Hangzhou Normal University Division of Health Sciences, Yuhangtang Road 2318, Hangzhou, Zhejiang 311121, PR China
| | - Huihua Wang
- Department of Gynecology, the First People's Hospital of Tongxiang, Jiaochang Road 1918, Tongxiang, Zhejiang 314500, PR China
| | - Ming Yuan
- Hangzhou Normal University Division of Health Sciences, Yuhangtang Road 2318, Hangzhou, Zhejiang 311121, PR China
| | - Jin Li
- Department of Gynecology, Women's Hospital of Hangzhou Normal University, Kunpeng Road 369, Hangzhou, Zhejiang 310000, PR China
| | - Xiaohong Song
- Department of Gynecology, Women's Hospital of Hangzhou Normal University, Kunpeng Road 369, Hangzhou, Zhejiang 310000, PR China
| | - Kaiqing Lin
- Department of Gynecology and Obstetrics, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, PR China.
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15
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Dehghan Z, Rezaee D, Noori E, Pilehchi T, Saberi F, Taheri Z, Darya G, Mehdinejadiani S. Exosomes as modulators of embryo implantation. Mol Biol Rep 2024; 51:284. [PMID: 38324178 DOI: 10.1007/s11033-024-09282-2] [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: 12/12/2023] [Accepted: 01/23/2024] [Indexed: 02/08/2024]
Abstract
Exosomes, known as extracellular vehicles (EVs), are found in biological fluids. They have the capability to carry and transfer signaling molecules, such as nucleic acids and proteins, facilitating intercellular communication and regulating the gene expression profile in target cells. EVs have the potential to be used as biomarkers in diagnosis, prognosis and also as feasible therapeutic targets. The available evidence suggests that exosomes play critical roles in the reproductive system, particularly during implantation, which is widely recognized as a crucial step in early pregnancy. A proper molecular dialogue between a high-quality embryo and a receptive endometrium is essential for the establishment of a normal pregnancy. This review focuses on the key role of exosomes originated from various sources, including the embryo, seminal fluid, and uterus fluid, based on the available evidence. It explores their potential applications as a novel approach in assisted reproductive technologies (ART).
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Affiliation(s)
- Zeinab Dehghan
- Department of Comparative Biomedical Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Delsuz Rezaee
- School of Allied Medical Sciences, Ilam University of Medical Sciences, Ilam, Iran
| | - Effat Noori
- Department of Biotechnology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Tayyebeh Pilehchi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Saberi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Taheri
- Department of Biology and Biotechnology, Pavia University, Pavia, Italy
| | - Gholamhossein Darya
- Department of Comparative Biomedical Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shayesteh Mehdinejadiani
- Department of Reproductive Biology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
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16
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Izadpanah M, Yalameha B, Sani MZ, Cheragh PK, Mahdipour M, Rezabakhsh A, Rahbarghazi R. Exosomes as Theranostic Agents in Reproduction System. Adv Biol (Weinh) 2024; 8:e2300258. [PMID: 37955866 DOI: 10.1002/adbi.202300258] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 10/06/2023] [Indexed: 11/14/2023]
Abstract
Exosomes (Exos), belonging to extracellular vesicles, are cell-derived nano-sized vesicles with the potential to carry different kinds of biological molecules. Many studies have proved the impacts of exosomal cargo on several biological processes in female and male reproductive systems. It is also hypothesized that changes in exosomal cargo are integral to the promotion of certain pathological conditions, thus Exos can be used as valid biomarkers for the diagnosis of infertility and other abnormal conditions. Here, efforts are made to collect some recent data related to the physiological significance of Exos in the reproductive system, and their potential therapeutic effects. It is anticipated that the current review article will lay the groundwork for elucidating the source and mechanisms by which Exos control the reproductive system additionally supplying fresh methods and concepts for the detection and treatment of disorders associated with fertility for future studies.
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Affiliation(s)
- Melika Izadpanah
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Banafsheh Yalameha
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Zamani Sani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mahdi Mahdipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aysa Rezabakhsh
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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17
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Utkarsh K, Srivastava N, Papayannakos C, Nayyar A, Khan A, Haque S. Breaking the silence: The role of extracellular vesicles in unraveling the diagnosis and treatment of endometriosis. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2023; 4:599-614. [PMID: 39697806 PMCID: PMC11648450 DOI: 10.20517/evcna.2023.43] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 11/04/2023] [Accepted: 11/27/2023] [Indexed: 12/20/2024]
Abstract
Cell-to-cell communication is believed to be facilitated by membrane-bound vesicles called extracellular vesicles (EVs), which are released by cells. Protein, lipids, and nucleic acids are major cargo of EVs and are transported in these vesicles. Depending on the parent and recipient cell types, they can affect a wide variety of biological processes in the tissues to which they are delivered. EVs are essential for embryo implantation and endometriosis, and they are located in the uterine cavities of different species, where they promote blastocyst and endometrial preparation for implantation. This review focuses on what is currently understood regarding pathologic and diagnostic characteristics, and the potential therapeutic value of EVs in the context of endometriosis, where they can be used for drug delivery and targeted therapy due to their ability to carry bioactive molecules to specific cells or tissues. The findings of this review highlight the potential for a wide range of clinical applications that involve endometrial EVs in the areas of treatment, such as surgical and pharmacological, diagnostic biomarker development, and drug delivery systems, all with the ultimate goal of improving pregnancy success rates.
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Affiliation(s)
- Kumar Utkarsh
- Department of Microbiology and Biotechnology, Shoolini University, Solan, Himachal Pradesh 173229, India
| | - Namita Srivastava
- Department of Microbiology and Biotechnology, Shoolini University, Solan, Himachal Pradesh 173229, India
| | - Christopher Papayannakos
- Department of Pediatrics, Institute of Molecular Medicine, Feinstein Institute for Medical Research, Northwell Health, 350 Community Drive, Manhasset, New York, NY 11030, USA
| | - Ashima Nayyar
- Department of Neurology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA
| | - Azhar Khan
- Department of Microbiology and Biotechnology, Shoolini University, Solan, Himachal Pradesh 173229, India
| | - Shabirul Haque
- Department of Autoimmune Diseases, Institute of Molecular Medicine, Feinstein Institute for Medical Research, Northwell Health, 350 Community Drive, Manhasset, New York, NY 11030, USA
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18
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Niafar M, Samaie V, Soltani-Zangbar MS, Motavalli R, Dolati S, Danaii S, Mehdizadeh A, Yousefi M. The association of Treg and Th17 cells development factors and anti-TPO autoantibodies in patients with recurrent pregnancy loss. BMC Res Notes 2023; 16:302. [PMID: 37907956 PMCID: PMC10619307 DOI: 10.1186/s13104-023-06579-6] [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: 10/17/2022] [Accepted: 10/18/2023] [Indexed: 11/02/2023] Open
Abstract
OBJECTIVES Thyroid autoimmunity is considered as the most prevalent autoimmune condition in women in fertility age. There are different clinical evidences indicating the association between thyroid autoimmunity and increased risk of RPL. This study aimed to analyze the association of Tregs and Th17 cells development factors and anti-thyroid peroxidase (anti-TPO) antibodies in RPL patients. Healthy controls (n = 36), TPO + controls (n = 25) and TPO + RPL (n = 32) participated in this study. After blood sampling, the frequency of Th17 and Tregs was evaluated using flow cytometry. Real-time PCR and ELISA was used to assess the status of Tregs and Th17 related transcription factors and cytokines in mRNA and protein level, respectively. RESULTS TPO + RPL group showed a higher Th17 frequency compared to healthy controls and TPO + controls groups (p = 0.0002 and p = 0.04, respectively). Additionally, mRNA expression levels of RORγT and IL-17 were significantly higher in TPO + RPL compared to healthy controls and TPO + controls groups. In contrast, Foxp3 and TGFβ expression was lower in TPO + RPL. ELISA findings also indicated a significantly higher IL-17 and lower TGFβ secretion in TPO + RPL compared to healthy controls and TPO + controls. Thyroid autoimmunity should intensely be controlled specially in patients with RPL history.
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Affiliation(s)
- Mitra Niafar
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vajihe Samaie
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Sadegh Soltani-Zangbar
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Roza Motavalli
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Molecular Medicine, Faculty of Advanced Medical sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanam Dolati
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahla Danaii
- Gynecology Departments, ACECR ART Center, Eastern Azerbaijan Branch of ACECR, Eastern, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Department of Immunology, Faculty of medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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19
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Biglari N, Mehdizadeh A, Vafaei Mastanabad M, Gharaeikhezri MH, Gol Mohammad Pour Afrakoti L, Pourbala H, Yousefi M, Soltani-Zangbar MS. Application of mesenchymal stem cells (MSCs) in neurodegenerative disorders: History, findings, and prospective challenges. Pathol Res Pract 2023; 247:154541. [PMID: 37245265 DOI: 10.1016/j.prp.2023.154541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 05/30/2023]
Abstract
Over the past few decades, the application of mesenchymal stem cells has captured the attention of researchers and practitioners worldwide. These cells can be obtained from practically every tissue in the body and are used to treat a broad variety of conditions, most notably neurological diseases such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Studies are still being conducted, and the results of these studies have led to the identification of several different molecular pathways involved in the neuroglial speciation process. These molecular systems are closely regulated and interconnected due to the coordinated efforts of many components that make up the machinery responsible for cell signaling. Within the scope of this study, we compared and contrasted the numerous mesenchymal cell sources and their cellular features. These many sources of mesenchymal cells included adipocyte cells, fetal umbilical cord tissue, and bone marrow. In addition, we investigated whether these cells can potentially treat and modify neurodegenerative illnesses.
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Affiliation(s)
- Negin Biglari
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahsa Vafaei Mastanabad
- Neurosurgery Department, Faculty of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | | | - Hooman Pourbala
- Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Sadegh Soltani-Zangbar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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20
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Pourakbari R, Parhizkar F, Soltani-Zangbar MS, Samadi P, Zamani M, Aghebati-Maleki L, Motavalli R, Mahmoodpoor A, Jadidi-Niaragh F, Yousefi B, Kafil HS, Hojjat-Farsangi M, Danaii S, Yousefi M. Preeclampsia-Derived Exosomes Imbalance the Activity of Th17 and Treg in PBMCs from Healthy Pregnant Women. Reprod Sci 2023; 30:1186-1197. [PMID: 36155892 DOI: 10.1007/s43032-022-01059-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 08/04/2022] [Indexed: 10/14/2022]
Abstract
The disturbance of maternofetal immune tolerance is identified as one of the important issues in the pathology of preeclampsia (PE). PE exosomes are believed to possess significant roles in immune abnormalities. In this study, to assess the possible effects of PE exosomes in the pathophysiology of preeclampsia patients, exosomes were isolated from the serum of PE patients and incubated with peripheral blood mononuclear cells (PBMCs) of healthy pregnant women. Also, exosomes from healthy pregnant women were utilized as the control. Th17/Treg ratio in PE and healthy pregnant women and the effects of PE exosomes on expression level of Th17 and Treg transcription factors, as well as their related cytokines in PBMCs of healthy pregnant women, were evaluated. A significant decrease in Treg cell number and increase in Th17 cells and Th17/Treg ratio were observed in PE patients. Following PE-exosome intervention, a significant increase in mRNA expression level of RORγt, IL-17, IL-23, IL-1β, and IL-6, and significant decrease in IL-10 and TGFβ were evident. On the other hand, no significant difference in FoxP3 level was detected. Additionally, increased IL-6, IL-17, IL-23, and IL-1β levels and decreased IL-10 level in the supernatant of cultured PBMCs from healthy pregnant women following PE-exosome intervention were exhibited. However, TGF-β level did not change significantly. Based on our findings, PE exosomes are able to alter the activity of Th17 and Treg cells as well as their related gene expression and cytokine profiles. These findings support the probable role of PE exosomes in PE pathogenesis.
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Affiliation(s)
- Ramin Pourakbari
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Forough Parhizkar
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Parisa Samadi
- Hematology Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | | | - Roza Motavalli
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ata Mahmoodpoor
- Anesthesiology Research Team, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Bahman Yousefi
- Molecular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Samadi Kafil
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hojjat-Farsangi
- Department of Oncology-Pathology, Immune and Gene Therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institute, Stockholm, Sweden
| | - Shahla Danaii
- Gynecology Department, ACECR ART Centre, Eastern Azerbaijan Branch of ACECR, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran.
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21
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Juárez-Barber E, Segura-Benítez M, Carbajo-García MC, Bas-Rivas A, Faus A, Vidal C, Giles J, Labarta E, Pellicer A, Cervelló I, Ferrero H. Extracellular vesicles secreted by adenomyosis endometrial organoids contain miRNAs involved in embryo implantation and pregnancy. Reprod Biomed Online 2023; 46:470-481. [PMID: 36697316 DOI: 10.1016/j.rbmo.2022.12.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/02/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
RESEARCH QUESTION Do extracellular vesicles secreted by the endometrium of women with adenomyosis contain miRNAs involved in adenomyosis-related infertility? DESIGN A descriptive study using organoids from eutopic endometrium of women with adenomyosis (n = 4) generated and differentiated to secretory and gestational phases, in which miRNA cargo from extracellular vesicles secreted by these differentiated organoids in each phase was analysed by next-generation sequencing. miRNAs in secretory-extracellular vesicles and gestational-extracellular vesicles were selected based on the counts per million. miRNAs target genes in each phase were obtained from miRNet and gene ontology was used for enrichment analysis. RESULTS miRNA sequencing identified 80 miRNAs in secretory-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-24-3p, hsa-miR-26a-5p, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-miR-200c-3p and hsa-miR-423a-5p, related to adenomyosis pathogenesis and implantation failure. Further, 60 miRNAs were identified in gestational-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-26a-5p, hsa-miR-30a-5p, hsa-miR-30c-5p, hsa-miR-222-3p and hsa-miR-423a-5p were associated with preeclampsia and miscarriage. Among the target genes of these miRNAs, PTEN, MDM4, PLAGL2 and CELF1, whose downregulation (P = 0.0003, P < 0.0001, P = 0.0002 and P = 0.0003, respectively) contributes to adenomyosis pathogenesis, and impaired early embryo development, leading to implantation failure and miscarriage, are highlihghted. Further, functional enrichment analyses of the target genes revealed their involvement in cell differentiation, proliferation, apoptosis, cell cycle regulation and response to extracellular stimuli. CONCLUSIONS Eutopic endometrium in secretory and gestational phase from women with adenomyosis releases extracellular vesicles containing miRNAs involved in adenomyosis progression, impaired embryo implantation and pregnancy complications.
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Affiliation(s)
- Elena Juárez-Barber
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
| | - Marina Segura-Benítez
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, 46010 Valencia, Spain
| | - María Cristina Carbajo-García
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, 46010 Valencia, Spain
| | - Alba Bas-Rivas
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
| | - Amparo Faus
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
| | - Carmen Vidal
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; IVI-RMA Valencia, 46015 Valencia, Spain
| | - Juan Giles
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; IVI-RMA Valencia, 46015 Valencia, Spain
| | - Elena Labarta
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; IVI-RMA Valencia, 46015 Valencia, Spain
| | - Antonio Pellicer
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain; IVI-RMA Rome, 00197 Rome, Italy
| | - Irene Cervelló
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain
| | - Hortensia Ferrero
- Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain.
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22
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Parhizkar F, Kiani A, Darzi S, Motavalli R, Noori Dolama F, Yousefzadeh Y, Aghebati-Maleki L, Pia H, Abdollahi-Fard S, Mardi A, Danaii S, Ahmadian Heris J, Yousefi M, Soltani-Zangbar MS. The evaluation of CD39, CD73, and HIF-1 α expression besides their related miRNAs in PBMCs of women with recurrent pregnancy loss. J Reprod Immunol 2023; 156:103820. [PMID: 36758470 DOI: 10.1016/j.jri.2023.103820] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 12/24/2022] [Accepted: 01/28/2023] [Indexed: 02/01/2023]
Abstract
The molecular mechanisms involved in the pathogenesis of recurrent pregnancy loss (RPL) are not completely recognized. The present study aimed to assess the molecules associated with ATP catabolism and hypoxia besides their related miRNAs in patients with RPL. The frequency of Th17 and Treg cells in PBMCs of RPL women and healthy pregnant women were evaluated with Flow cytometry. The expression levels of CD39, CD73, and Hypoxia-inducible factor-alpha (HIF-1α), miR-18a, miR-30a, and miR-206 in PBMCs of two groups were measured with real-time PCR and western blotting. Then, serum levels of IGF-1, TGF-β, and HIF-1α were measured by ELISA. Our results indicated a higher (p = 0.0002) and lower (p < 0.0001) frequency of Th17 and Treg lymphocytes in RPL women, respectively. The expression level of CD39 decreased in PBMCs of RPL women whereas the level of CD73 and HIF-α increased (p = 0.0010, 0.0023, 0.0006 respectively). The results of CD39 and CD37 were also confirmed by protein analysis (p = 0.0047, 0.0364 respectively). Almost, the same results for CD39 and CD73 expression at mRNA and protein levels were observed in isolated Treg cells. Moreover, we found the higher expression of miR-206 and miRNA-30a (p = 0.0038, 0.0123), but the lower expression of miRNA-18a (p = 0.0101) in RPL. The concentration level of IGF-1, and TGF-β reduced (p = 0.0017, 0.0065 respectively) while the level of HIF-α elevated (p = 0.0235) in serum samples of RPL. In conclusion, we observed the dysregulation of molecules that are involved in ATP catabolism and hypoxia, including CD39, CD73, and HIF-1a which is related to miR-18a, miR-30a, and miR-206 change in RPL women. It may be potentially used for RPL prognosis by more comprehensive future studies.
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Affiliation(s)
- Forough Parhizkar
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirhossein Kiani
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapour University of Medical Sciences, Ahvaz, Iran
| | - Satinik Darzi
- Department of Obstetrics and Gynecology, Abnormal Uterine Bleeding Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Roza Motavalli
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Molecular Medicine, Faculty of Advanced Medical sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Yousef Yousefzadeh
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Helen Pia
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Amirhossein Mardi
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahla Danaii
- Gynecology Department, Eastern Azerbaijan ACECR ART center, Eastern Azerbaijan branch of ACECR, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammad Sadegh Soltani-Zangbar
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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23
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Chen C, Zhang Z, Gu X, Sheng X, Xiao L, Wang X. Exosomes: New regulators of reproductive development. Mater Today Bio 2023; 19:100608. [PMID: 36969697 PMCID: PMC10034510 DOI: 10.1016/j.mtbio.2023.100608] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/12/2023] [Accepted: 03/07/2023] [Indexed: 03/13/2023] Open
Abstract
Exosomes are a subtype of extracellular vesicles (EVs) with a size range between 30 and 150 nm, which can be released by the majority of cell types and circulate in body fluid. They function as a long-distance cell-to-cell communication mechanism that modulates the gene expression profile and fate of target cells. Increasing evidence has indicated exosomes' central role in regulating various complex reproductive processes. However, to our knowledge, a review that focally and vividly describes the role of exosomes in reproductive development is still lacking. This review highlights our knowledge about the contribution of exosomes to early mammalian reproduction, such as gametogenesis, fertilization, early embryonic development, implantation, placentation and pregnancy. The discussion is primarily drawn from literature pertaining to the mammalian lineage with emphasis on the roles of exosomes in human reproduction and laboratory and livestock models.
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24
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Scheck S, Paterson ESJ, Henry CE. A promising future for endometriosis diagnosis and therapy: extracellular vesicles - a systematic review. Reprod Biol Endocrinol 2022; 20:174. [PMID: 36544197 PMCID: PMC9768904 DOI: 10.1186/s12958-022-01040-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 11/19/2022] [Indexed: 12/24/2022] Open
Abstract
Endometriosis is a chronic, inflammatory gynaecological disease that can have severe negative impacts on quality of life and fertility, placing burden on patients and the healthcare system. Due to the heterogeneous nature of endometriosis, and the lack of correlation between symptom and surgical disease severity, diagnosis and treatment remain a significant clinical challenge. Extracellular vesicles (EVs) are biologically active particles containing molecular cargo involved in intercellular communication, that can be exploited for diagnostic and therapeutic purposes.We systematically reviewed studies exploring EVs and their role in endometriosis, specifically addressing diagnostic and therapeutic potential and current understanding of pathophysiology. Five databases (Pubmed, Embase, Medline, Web of Science, Google Scholar) were searched for keywords 'endometriosis' and either 'extracellular vesicles' or 'exosomes'.There were 28 studies included in the review. Endometrium derived EVs contribute to the development of endometriosis. EVs derived from endometriosis lesions contribute to angiogenesis, immunomodulation and fibrosis. Such EVs can be detected in blood, with early data demonstrating utility in diagnosis and recurrence detection. EV isolation techniques varied between studies and only eight of twenty-eight studies fully characterised EVs according to current recommended standards. Reporting/type of endometriosis was limited across studies. Varied patient population, type of sample and isolation techniques created bias and difficulty in comparing studies.EVs hold promise for improving care for symptomatic patients who have never had surgery, as well as those with recurrent symptoms after previous surgery. We encourage further EV research in endometriosis with the inclusion of rigorous reporting of both the patient population and technical methodology used, with the ultimate goal of achieving clinical utility for diagnosis, prognosis and eventually treatment.
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Affiliation(s)
- Simon Scheck
- Department of Obstetrics, Gynaecology and Women's Health, University of Otago, Wellington, New Zealand
- Department of Obstetrics and Gynaecology, Wellington Hospital, Capital and Coast District Health Board, Wellington, New Zealand
| | - Emily S J Paterson
- Department of Obstetrics, Gynaecology and Women's Health, University of Otago, Wellington, New Zealand
| | - Claire E Henry
- Department of Obstetrics, Gynaecology and Women's Health, University of Otago, Wellington, New Zealand.
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25
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Yousefzadeh Y, Soltani-Zangbar MS, Kalafi L, Tarbiat A, Shahmohammadi Farid S, Aghebati-Maleki L, Parhizkar F, Danaii S, Taghavi S, Jadidi-Niaragh F, Samadi Kafil H, Mahmoodpoor A, Ahmadian Heris J, Hojjat-Farsangi M, Yousefi M. Evaluation of CD39, CD73, HIF-1α, and their related miRNAs expression in decidua of preeclampsia cases compared to healthy pregnant women. Mol Biol Rep 2022; 49:10183-10193. [PMID: 36048381 DOI: 10.1007/s11033-022-07887-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 08/18/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND The Preeclampsia (PE) molecular mechanisms are not fully revealed and different biological processes are involved in the pathogenesis of PE. We aimed to evaluate adenosine and hypoxia-related signaling molecules in PE patients in the current study. METHODS Decidua tissue and peripheral blood samples were taken from 25 healthy pregnant and 25 PE women at delivery time. CD39, CD73, and Hypoxia-inducible factor-alpha (HIF-α) were evaluated in mRNA and protein level using real-time PCR and western blotting techniques, respectively. Also, miR-30a, miR-206, and miR-18a expression were evaluated by real-time PCR. At last, secretion levels of IGF and TGF-β in the taken serum of blood samples were measured by ELISA. RESULTS Our results revealed that Expression of CD39 is decreased in PE cases versus healthy controls at mRNA and protein levels (p = 0.0003 for both). CD73 and HIF-α showed an increased level of expression in PE patients at RNA and protein status (p = 0.0157 and p < 0.0001 for protein evaluation of CD73 and HIF-α, respectively). The miRNA-30a (p = 0.0037) and miR-206 (p = 0.0113) showed elevated expression in the decidua of the PE group. The concentration of secreted IGF-1 (p = 0.0002) and TGF-β (p = 0.0101) in serum samples of PE cases compared to the healthy group were decreased. CONCLUSION In conclusion, our results showed that aberrant expression of molecules that are involved in ATP catabolism and the hypoxic conditions is observed in PE cases and involved in their hypertension and inflammation could be served as PE prognosis by more confirming in comprehensive future studies. miR-206 and miR-30a play a role by regulating CD39 and CD73 as molecules that are involved in ATP catabolism as well as regulating the production of IGF-1 in the process of hypertension, which is the main feature in patients with preeclampsia. On the other hand, decreased level of miR-18a lead to upregulation of HIF-1a, and the consequence condition of hypoxia increases hypertension and inflammation in these patients.
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Affiliation(s)
- Yousef Yousefzadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, PO Box: 516-6615573, Tabriz, Iran
| | - Mohammad Sadegh Soltani-Zangbar
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, PO Box: 516-6615573, Tabriz, Iran
| | - Ladan Kalafi
- Gynecology Department, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Tarbiat
- Department of Cardiology, Medical Faculty, Urmia University of Medical Sciences, Urmia, Iran
| | - Sima Shahmohammadi Farid
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, PO Box: 516-6615573, Tabriz, Iran
| | | | - Forough Parhizkar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahla Danaii
- Gynecology Department, Eastern Azerbaijan ACECR ART Center, Eastern Azerbaijan Branch of ACECR, Tabriz, Iran
| | - Simin Taghavi
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, PO Box: 516-6615573, Tabriz, Iran
| | - Hossein Samadi Kafil
- Drug Applied Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ata Mahmoodpoor
- Department of Anesthesiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hojjat-Farsangi
- Department of Oncology-Pathology, Immune and Gene Therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institute, Stockholm, Sweden
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, PO Box: 516-6615573, Tabriz, Iran.
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26
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Omidvar MH, Soltani-Zangbar MS, Zamani M, Motavalli R, Jafarpoor M, Dolati S, Ahmadi M, Mehdizadeh A, Khabbazi A, Hajialilo M, Yousefi M. The effect of osteoporotic and non-osteoporotic individuals' T cell-derived exosomes on osteoblast cells' bone remodeling related genes expression and alkaline phosphatase activity. BMC Res Notes 2022; 15:272. [PMID: 35941659 PMCID: PMC9358836 DOI: 10.1186/s13104-022-06139-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/30/2022] [Indexed: 12/03/2022] Open
Abstract
Objectives Osteoporosis is a common skeletal disorder attributed to age and is defined as a systematic degradation of bone mass and the microarchitecture leading to bone fractures. Exosomes have been reported in almost all biological fluids and during the failure of bone remodeling. 20 ml of blood samples were obtained from osteoporotic and non-osteoporotic postmenopausal women. After the isolation of peripheral blood mononuclear cells (PBMCs), T cells were separated via the magnetic-activated cell sorting (MACS) technique. Exosomes were driven from T cells of non-osteoporotic and osteoporotic volunteers. Subsequently, normal osteoblasts were treated with obtained T cell exosomes to assess osteoblastic function and gene expression. Results Runx2, type I collagen, osteopontin, and osteocalcin expression decreased in osteoblasts treated by osteoporotic T cell exosomes. In contrast, an increased expression of the mentioned genes was observed following non-osteoporotic T cell exosome treatment. Additionally, osteoblast alkaline phosphatase (ALP) activity treated with non-osteoporotic T cell exosomes increased. However, this activity decreased in another group. Our data demonstrated that T cell exosomes obtained from osteoporotic and non-osteoporotic individuals could alter the osteoblastic function and gene expression by affecting the genes essential for bone remodeling. Supplementary Information The online version contains supplementary material available at 10.1186/s13104-022-06139-4.
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Affiliation(s)
- Mohammad Hasan Omidvar
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Sadegh Soltani-Zangbar
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Roza Motavalli
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Jafarpoor
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanam Dolati
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Khabbazi
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehrzad Hajialilo
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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27
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Kowalczyk A, Wrzecińska M, Czerniawska-Piątkowska E, Kupczyński R. Exosomes - Spectacular role in reproduction. Biomed Pharmacother 2022; 148:112752. [PMID: 35220028 DOI: 10.1016/j.biopha.2022.112752] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 11/28/2022] Open
Abstract
Exosomes are nano-sized structures that are found in semen, epididymal -fluid, endometrium, as well as in follicular fluid. They are responsible for transporting bioactive cargo- proteins, lipids, and nucleic acids. Exosomes have been proven to influence processes in both female and male reproductive systems, including gametogenesis, acrosomal reaction, sperm capacitation, and embryo implantation in the endometrium. Exosomes are made of the same particles as the cells they come from and are secreted by normal and pathological cells. Therefore, exosomes can reflect the physiological state of cells. Moreover, due to the transportation of biomolecules, they participate in intercellular communication and can be used as biomarkers of many diseases, including ovarian, endometrial and prostate cancer. Identification of exosomes as biomarkers could contribute to a better understanding of genital dysfunction and fertility disorders.
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Affiliation(s)
- Alicja Kowalczyk
- Department of Environment Hygiene and Animal Welfare, Wrocław University of Environmental and Life Sciences, Chełmońskiego 38C, Wrocław, Poland.
| | - Marcjanna Wrzecińska
- Department of Ruminant Science, West Pomeranian University of Technology, ul. Klemensa Janickiego 29, 71-270 Szczecin, Poland.
| | - Ewa Czerniawska-Piątkowska
- Department of Ruminant Science, West Pomeranian University of Technology, ul. Klemensa Janickiego 29, 71-270 Szczecin, Poland.
| | - Robert Kupczyński
- Department of Environment Hygiene and Animal Welfare, Wrocław University of Environmental and Life Sciences, Chełmońskiego 38C, Wrocław, Poland.
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28
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Chermuła B, Kranc W, Celichowski P, Stelmach B, Piotrowska-Kempisty H, Mozdziak P, Pawelczyk L, Spaczyński RZ, Kempisty B. Cellular Processes in Human Ovarian Follicles Are Regulated by Expression Profile of New Gene Markers—Clinical Approach. J Clin Med 2021; 11:jcm11010073. [PMID: 35011815 PMCID: PMC8745700 DOI: 10.3390/jcm11010073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/18/2021] [Accepted: 12/20/2021] [Indexed: 11/16/2022] Open
Abstract
In the growing ovarian follicle, the maturing oocyte is accompanied by cumulus (CCs) and granulosa (GCs) cells. Currently, there remain many unanswered questions about the epithelial origin of these cells. Global and targeted gene transcript levels were assessed on 1, 7, 15, 30 days of culture for CCs and GCs. Detailed analysis of the genes belonging to epithelial cell-associated ontological groups allowed us to assess a total of 168 genes expressed in CCs (97 genes) and GCs (71 genes) during long-term in vitro culture. Expression changes of the analyzed genes allowed the identification of the group of genes: TGFBR3, PTGS2, PRKX, AHI1, and IL11, whose expression decreased the most and the group of ANXA3, DKK1, CCND1, STC1, CAV1, and SFRP4 genes, whose expression significantly increased. These genes’ expression indicates CCs and GCs epithelialization processes and their epithelial origin. Expression change analysis of genes involved in epithelization processes in GCs and CCs during their in vitro culture made it possible to describe the most significantly altered of the 11 genes. Detailed analysis of gene expression in these two cell populations at different time intervals confirms their ovarian surface epithelial origin. Furthermore, some gene expression profiles appear to have tumorigenic properties, suggesting that granulosa cells may play a role in cancerogenesis.
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Affiliation(s)
- Błażej Chermuła
- Department of Gynecology, Division of Infertility and Reproductive Endocrinology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, 33 Polna St., 60-535 Poznan, Poland; (B.C.); (B.S.); (L.P.); (R.Z.S.)
| | - Wiesława Kranc
- Department of Anatomy, Poznan University of Medical Sciences, 6 Swiecickiego St., 60-781 Poznan, Poland;
| | - Piotr Celichowski
- Department of Histology and Embryology, Poznan University of Medical Sciences, 6 Swiecickiego St., 60-781 Poznan, Poland;
| | - Bogusława Stelmach
- Department of Gynecology, Division of Infertility and Reproductive Endocrinology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, 33 Polna St., 60-535 Poznan, Poland; (B.C.); (B.S.); (L.P.); (R.Z.S.)
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd St., 60-631 Poznan, Poland;
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Toruń, 7 Gagarina St., 87-100 Torun, Poland
| | - Paul Mozdziak
- Physiology Graduate Program, North Carolina State University, Raleigh, NC 27695, USA;
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA
| | - Leszek Pawelczyk
- Department of Gynecology, Division of Infertility and Reproductive Endocrinology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, 33 Polna St., 60-535 Poznan, Poland; (B.C.); (B.S.); (L.P.); (R.Z.S.)
| | - Robert Zygmunt Spaczyński
- Department of Gynecology, Division of Infertility and Reproductive Endocrinology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, 33 Polna St., 60-535 Poznan, Poland; (B.C.); (B.S.); (L.P.); (R.Z.S.)
| | - Bartosz Kempisty
- Department of Anatomy, Poznan University of Medical Sciences, 6 Swiecickiego St., 60-781 Poznan, Poland;
- Department of Histology and Embryology, Poznan University of Medical Sciences, 6 Swiecickiego St., 60-781 Poznan, Poland;
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 1 Lwowska St., 87-100 Torun, Poland
- Correspondence: ; Tel.: +48-61-854-6418; Fax: +48-61-854-6440
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Liu T, Liu M, Zheng C, Zhang D, Li M, Zhang L. Exosomal lncRNA CHL1-AS1 Derived from Peritoneal Macrophages Promotes the Progression of Endometriosis via the miR-610/MDM2 Axis. Int J Nanomedicine 2021; 16:5451-5464. [PMID: 34408418 PMCID: PMC8367089 DOI: 10.2147/ijn.s323671] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/03/2021] [Indexed: 12/15/2022] Open
Abstract
Background Exosomes secreted by peritoneal macrophages (pMφ) are deeply involved in the development of endometriosis (EMs). Exosomes can mediate cell-to-cell communication by transferring biological molecules. This study aimed to explore the effect and mechanism of exosomal long non-coding RNA (lncRNA) CHL1-AS1 derived from pMφ on EMs. Materials and Methods Exosomes (exo) from pMφ were isolated, identified, and co-cultured with ectopic endometrial stromal cells (eESCs) to investigate the biological functions of pMφ-exo. qRT-PCR was used to detect the expression of lncRNA CHL1-AS1 in pMφ-exo from EMs and control patients and verify the transportation of lncRNA CHL1-AS1 from pMφ to eESCs. The effects of exosomal lncRNA CHL1-AS1 on eESC proliferation, migration, invasion, and apoptosis were also detected. The relationships among lncRNA CHL1-AS1, miR-610, and MDM2 (mouse double minute 2) were verified by dual-luciferase reporter assay. The in vivo experiments were conducted to verify the effects of exosomal lncRNA on EMs using a xenograft model of EMs. Results Exosomes from pMφ were successfully isolated. EMs-pMφ-exo promoted eESC proliferation, migration, and invasion and inhibited their apoptosis. lncRNA CHL1-AS1 was upregulated in EMs-pMφ-exo and transported from pMφ to eESCs via exosomes. lncRNA CHL1-AS1 was found to act as a competing endogenous RNA of miR‑610 to promote the expression of MDM2. EMs-pMφ-exo shuttled lncRNA CHL1-AS1 to promote eESC proliferation, migration, and invasion and inhibit apoptosis by downregulating miR-610 and upregulating MDM2. Furthermore, exosomal lncRNA CHL1-AS1 promoted EMs lesions growth by increasing MDM2 in vivo. Conclusion The results demonstrate that exosomal lncRNA CHL1-AS1 promotes the proliferation, migration, and invasion of eESCs and inhibits their apoptosis by downregulating miR-610 and upregulating MDM2, which might be a potential therapeutic target for EMs.
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Affiliation(s)
- Ting Liu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
| | - Mei Liu
- Department of Obstetrics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, People's Republic of China
| | - Caihua Zheng
- Department of Obstetrics, Changle County Hospital of Traditional Chinese Medicine, Changle, 262400, People's Republic of China
| | - Daoyan Zhang
- Department of Obstetrics and Gynecology, People's Hospital of Qihe County, Qihe, 251100, People's Republic of China
| | - Mingbao Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
| | - Lu Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China
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30
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Zolfaghari MA, Arefnezhad R, Parhizkar F, Hejazi MS, Motavalli Khiavi F, Mahmoodpoor A, Yousefi M. T lymphocytes and preeclampsia: The potential role of T-cell subsets and related MicroRNAs in the pathogenesis of preeclampsia. Am J Reprod Immunol 2021; 86:e13475. [PMID: 34043850 DOI: 10.1111/aji.13475] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/11/2021] [Accepted: 05/22/2021] [Indexed: 12/13/2022] Open
Abstract
Innate and adaptive immune systems have a crucial role in initiating and progressing some pregnancy disorders such as preeclampsia (PE), which is one of the pregnancy-specific disorders that could result in neonatal and maternal morbidity and mortality. The dysregulation of the spiral artery and inadequate trophoblast invasion lead to PE symptoms through producing various inflammatory cytokines and anti-angiogenic factors from the placenta. T lymphocytes play a special role in the epithelium and stroma of the human endometrium. CD4+ T helper (Th) cells, Th1/Th2, and Th17/T regulatory (Treg) balance mainly contribute to the establishment of a pregnancy-favorable environment. This review examined the dysregulation of some cytokines produced from T cells, the dysregulation of the transcription factors of Th cells, the expression of chemokine receptors on T cells, as well as the effects of some factors including vitamin D on the activity of T cells, and finally, the dysregulation of various miRNAs related to T cells, which could cause PE.
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Affiliation(s)
- Mohammad Ali Zolfaghari
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Arefnezhad
- Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Forough Parhizkar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Saeid Hejazi
- Department of Molecular Medicine, Faculty of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Motavalli Khiavi
- Medical Biotechnology Research Center, AJA University of Medical Sciences, Tehran, Iran.,Pasteur Institute of Iran, Department of Virology, Tehran, Iran
| | - Ata Mahmoodpoor
- Department of Anesthesiology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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31
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Yousefzadeh Y, Soltani-Zangbar MS, Hemmatzadeh M, Shomali N, Mahmoodpoor A, Ahmadian Heris J, Yousefi M. Fetomaternal Immune Tolerance: Crucial Mechanisms of Tolerance for Successful Pregnancy in Humans. Immunol Invest 2021; 51:1108-1125. [PMID: 33830854 DOI: 10.1080/08820139.2021.1909061] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
For many years, the question of how the maternal immune system tolerates the foreign fetus has remained unanswered, and numerous studies have considerably attempted to elucidate underlying mechanisms for fetomaternal tolerance. This review aimed at discussing various significant mechanisms in fetomaternal compatibility. At the fetomaternal interface, in addition to having efficient control against infections, innate and adaptive maternal immune systems selectively prevent fetal rejection. In general, understanding the complex mechanisms of fetomaternal tolerance is critical for immunologic tolerance induction and spontaneous abortion prevention in high-risk populations. Different cells and molecules, such as regulatory T-cells, dendritic cells, decidua cells, IDO, Class I HLA molecules, TGF-β, and IL-10, induce maternal immune tolerance in the fetus in numerous ways. The findings on fetomaternal immune tolerance have remained controversial and require further research.
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Affiliation(s)
- Yousef Yousefzadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Committee Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Sadegh Soltani-Zangbar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Hemmatzadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Navid Shomali
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ata Mahmoodpoor
- Department of Anesthesiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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32
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Zolfaghari MA, Motavalli R, Soltani-Zangbar MS, Parhizkar F, Danaii S, Aghebati-Maleki L, Noori M, Dolati S, Ahmadi M, Samadi Kafil H, Jadidi-Niaragh F, Ahmadian Heris J, Mahmoodpoor A, Hejazi MS, Yousefi M. A new approach to the preeclampsia puzzle; MicroRNA-326 in CD4 + lymphocytes might be as a potential suspect. J Reprod Immunol 2021; 145:103317. [PMID: 33813342 DOI: 10.1016/j.jri.2021.103317] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/19/2021] [Accepted: 03/24/2021] [Indexed: 02/09/2023]
Abstract
BACKGROUND Alongside many complications in understanding the etiology of Preeclampsia (PE), several determinants, such as the imbalanced proportion of anti-angiogenic/proangiogenic T-cell subsets, especially CD4+ (Th17/Treg), as well as alterations in the expression profile of related cytokines, miRNAs, and transcription factors might have been implicated in PE pathogenesis. MATERIAL AND METHOD After sample collection and preparation, CD4+ cells were isolated from PE and non-PE pregnant woman and were cultured. Furthermore, analysis such as flow cytometry, real-time PCR, western blotting, and ELISA were performed to assess determinants related to PE manifestation, including sFlt-1, sEng, STAT-3, RORγt, SMAD-7, Foxp3, IL-17, IL-22, Ets-1, and miRNA-326. RESULTS Our results showed that the miRNA-326 expression level increased in CD4+ Cells and Th17 in PE patients which downregulated Ets-1 expression that acts as a negative control for Th17 development. Furthermore, we showed that the number and expression level of Th17 s and transcription factor RORγt escalated, respectively. While Treg and its related transcription factor (Foxp3) demonstrated a decrease. Flow cytometry analysis illustrated that the Th17/Treg ratio increased in PE. Additionally, we demonstrated that expression and concentration levels of cytokines (IL-17 and IL22) and anti-angiogenic molecules (sEng and sFlt-1) soared in isolated CD4+ cells from PE patients, which could be correlated with PE pathogenicity. CONCLUSION In conclusion, we comprehensively evaluated immunological factors and molecules involved in PE manifestation. Interestingly, the CD4+ T-cell subset could be an extra source of antiangiogenic factors for the maintenance of this hypertension disorder.
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Affiliation(s)
- Mohammad Ali Zolfaghari
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Roza Motavalli
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Forough Parhizkar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahla Danaii
- Gynecology Department, Eastern Azerbaijan ACECR ART Center, Eastern Azerbaijan Branch of ACECR, Tabriz, Iran
| | | | - Mohammad Noori
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanam Dolati
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Samadi Kafil
- Drug Applied Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ata Mahmoodpoor
- Department of Anesthesiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Saeid Hejazi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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33
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Esfandyari S, Elkafas H, Chugh RM, Park HS, Navarro A, Al-Hendy A. Exosomes as Biomarkers for Female Reproductive Diseases Diagnosis and Therapy. Int J Mol Sci 2021; 22:ijms22042165. [PMID: 33671587 PMCID: PMC7926632 DOI: 10.3390/ijms22042165] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/14/2021] [Accepted: 02/18/2021] [Indexed: 12/12/2022] Open
Abstract
Cell-cell communication is an essential mechanism for the maintenance and development of various organs, including the female reproductive system. Today, it is well-known that the function of the female reproductive system and successful pregnancy are related to appropriate follicular growth, oogenesis, implantation, embryo development, and proper fertilization, dependent on the main regulators of cellular crosstalk, exosomes. During exosome synthesis, selective packaging of different factors into these vesicles happens within the originating cells. Therefore, exosomes contain both genetic and proteomic data that could be applied as biomarkers or therapeutic targets in pregnancy-associated disorders or placental functions. In this context, the present review aims to compile information about the potential exosomes with key molecular cargos that are dysregulated in female reproductive diseases which lead to infertility, including polycystic ovary syndrome (PCOS), premature ovarian failure (POF), Asherman syndrome, endometriosis, endometrial cancer, cervical cancer, ovarian cancer, and preeclampsia, as well as signaling pathways related to the regulation of the reproductive system and pregnancy outcome during these pathological conditions. This review might help us realize the etiology of reproductive dysfunction and improve the early diagnosis and treatment of the related complications.
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Affiliation(s)
- Sahar Esfandyari
- Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612, USA; (S.E.); (H.E.); (R.M.C.)
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Hoda Elkafas
- Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612, USA; (S.E.); (H.E.); (R.M.C.)
- Department of Pharmacology and Toxicology, Egyptian Drug Authority (EDA) Formally, (NODCAR), Cairo 35521, Egypt
| | - Rishi Man Chugh
- Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612, USA; (S.E.); (H.E.); (R.M.C.)
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hang-soo Park
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA; (H.-s.P.); (A.N.)
| | - Antonia Navarro
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA; (H.-s.P.); (A.N.)
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA; (H.-s.P.); (A.N.)
- Correspondence: ; Tel.: +1-773-832-0742
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34
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Zhou G, Gu Y, Zhou F, Zhang M, Zhang G, Wu L, Hua K, Ding J. The Emerging Roles and Therapeutic Potential of Extracellular Vesicles in Infertility. Front Endocrinol (Lausanne) 2021; 12:758206. [PMID: 34745016 PMCID: PMC8569852 DOI: 10.3389/fendo.2021.758206] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 09/28/2021] [Indexed: 12/20/2022] Open
Abstract
Infertility is becoming much more common and affects more couples. The past years witnessed the rapid development of the diagnosis and treatment upon infertility, which give numerous coupled more opportunities become parents. Extracellular vesicles are known as nano-sized membrane vesicles to play a major role in intracellular communication. In recent years, several basic and clinical studies have tried to investigate the correlation between the reproductive health/disorder and extracellular vesicles. However, the mechanism is still unclear. In this review, we reviewed the relationship between reproductive physiology and extracellular vesicles, and then collectively focused on the recent findings on the relationship between extracellular and infertility, and its consequent influence on the novel insight regarding the therapeutic strategies for infertility in the future clinical practice.
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Affiliation(s)
- Guannan Zhou
- Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Yuanyuan Gu
- Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, China
| | - Fangyue Zhou
- Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Menglei Zhang
- Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Ganrong Zhang
- Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Ligang Wu
- State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
- *Correspondence: Jingxin Ding, ; Keqin Hua, ; Ligang Wu,
| | - Keqin Hua
- Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
- *Correspondence: Jingxin Ding, ; Keqin Hua, ; Ligang Wu,
| | - Jingxin Ding
- Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- Department of Gynecology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
- *Correspondence: Jingxin Ding, ; Keqin Hua, ; Ligang Wu,
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