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Xin Wen X Wen, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Jiexia Wang J Wang, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Mengjie Qin M Qin, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Hu Wang H Wang, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Jingfeng Xu J Xu, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Xiaoju Guan X Guan, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Dan Shan D Shan, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Panpan Chen P Chen, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Jiajia Xie J Xie, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Jingjing Shao J Shao, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Ping Duan P Duan, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Congde Chen C Chen, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Haolin Chen H Chen, Department of Gynecology and Obstetrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China

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Background: Adult mammalian ovaries contain stem/progenitor cells necessary for folliculogenesis and ovulation-related tissue rupture repair. Theca cells are recruited and developed from progenitors during the folliculogenesis. Theca cell progenitors were not well-defined. The aim of current study is to compare the potential of four ovarian progenitors with defined markers (LY6A, EPCR, LGR5and PDGFRA) to form steroidogenic theca cells in vitro.

Methods: Ovarian progenitors were identified by the above four makers reported previously. The location of the cells was determined by immunohistochemistry and immunofluorescence staining of ovarian sections of adult mice. Different progenitor populations were purified by magnetic-activated cell sorting (MACS) and/or fluorescence-activated cell sorting (FACS) techniques from ovarian cell preparation and were tested for their abilities to generate steroidogenic theca cells in vitro. The cells were differentiated with a medium containing LH, ITS and DHH agonist for 12 days.

Results: EPCR+ and LGR5+ cells primarily distributed along ovarian surface epitheliums (OSE), while LY6A+ cells distributed in both OSE and parenchyma. However, PDGFRA+ cells were exclusively located in interstitial compartment. When the progenitors were purified by these markers and differentiated in vitro, LY6A+ and PDGFRA+ cells formed steroidogenic cells expressing both CYP11A1 and CYP17A1 and primarily producing androgens, showing characteristics of theca-like cells, while LGR5+ cells generated steroidogenic cells devoid of CYP17A1 expression and androgen production, showing a characteristic of progesterone-producing cells (granulosa- or lutea-like cells).

Conclusion: Progenitors from both OSE and parenchyma of adult mice are capable of generating steroidogenic cells with different steroidogenic capacities, showing a possible lineage preference.

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Xiaoyang Wen X Wen, 2. State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong250012, China. , Shandong University, Jinan, China

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Jingyang Zhang J Zhang, 2. State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong250012, China. , Shandong University, Jinan, China

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Zihan Xu Z Xu, 2. State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong250012, China. , Shandong University, Jinan, China

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Muzi Li M Li, 2. State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong250012, China. , Shandong University, Jinan, China

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Xiaotong Dong X Dong, 2. State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong250012, China. , Shandong University, Jinan, China

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Yanbo Du Y Du, 2. State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong250012, China. , Shandong University, Jinan, China

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Zhen Xu Z Xu, Center for Medical Genetics and Prenatal Diagnosis, Shandong Provincial Maternal and Child Health Care Hospital, Jinan, China

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Lei Yan L Yan, State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong250012, China., Shandong University, Jinan, China

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Previous studies from our group and others have shown increased IncRNA H19 expression in both the eutopic endometrium and the ectopic endometriosis tissue during endometriosis. In this study, we use immunofluorescence, immunohistochemistry and protein quantification to determine that levels of aerobic glycolysis and histone lactylation; which we show are increased in endometriosis tissues. In HESC cells (Human Endometrial Stromal Cells), we found that high H19 expression resulted in abnormal glucose metabolism by examining the levels of glucose, lactate, and ATP and measuring protein levels of enzymes that participate in glycolysis. At the same time, immunofluorescence and western blotting demonstrated increased histone lactylation in H19 overexpressing cells. Altering aerobic glycolysis and histone lactylation levels through the addition of Nala (sodium lactate) and 2-DG demonstrated that increased aerobic glycolysis and histone lactylation levels resulted in enhanced cell proliferation and cell migration, contributing to endometriosis. To validate these findings in vivo, we constructed an endometriosis mouse model, demonstrating similar changes in endometriosis tissues in vivo. Both aerobic glycolysis and histone lactylation levels were elevated in endometriotic lesions. Taken together, these data demonstrate elevated expression levels of H19 in endometriosis patients promote abnormal glucose metabolism and elevated histone lactylation levels in vivo, enhancing cell proliferation and migration and promoting the progression of endometriosis. Our study provides a functional link between H19 expression and histone lactylation and glucose metabolism in endometriosis, providing new insights into disease mechanisms that could result in novel therapeutic approaches.

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Marlyne Squatrito Laboratory of Biology of Tumor and Development, GIGA-Cancer, University of Liège, Liège, Belgium

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Julie Vervier Laboratory of Biology of Tumor and Development, GIGA-Cancer, University of Liège, Liège, Belgium
Department of Obstetrics and Gynecology, Hôpital de la Citadelle, University of Liège, Liège, Belgium

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Jules Bindels Laboratory of Biology of Tumor and Development, GIGA-Cancer, University of Liège, Liège, Belgium

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Laëtitia Bernet Laboratory of Biology of Tumor and Development, GIGA-Cancer, University of Liège, Liège, Belgium

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Silvia Blacher Laboratory of Biology of Tumor and Development, GIGA-Cancer, University of Liège, Liège, Belgium

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Michelle Nisolle Department of Obstetrics and Gynecology, Hôpital de la Citadelle, University of Liège, Liège, Belgium

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Carine Munaut Laboratory of Biology of Tumor and Development, GIGA-Cancer, University of Liège, Liège, Belgium

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In brief

The impact of adenomyosis on reproductive health needs to be fully understood. By using a murine model, this study provides novel insights into the nuanced mechanisms associated with fertility challenges and offers a foundation for targeted interventions.

Abstract

This study investigates the intricate relationship between adenomyosis and reproductive health using a murine model, offering novel insights into this prevalent gynecological disorder. Adenomyosis, characterized by the invasive growth of endometrial tissue into the myometrium, is believed to negatively impact fertility. However, the challenge lies in disentangling this influence, as adenomyosis often coexists with other gynecological diseases. A tamoxifen-induced mice model presents a significant advantage by enabling the specific study of adenomyosis, devoid of confounding influences of concurrent gynecological diseases such as endometriosis. Focusing exclusively on adenomyosis, our study aims to elucidate pathogenic mechanisms underlying fertility issues, focusing on estrous cyclicity, ovarian follicle development, and overall fertility. Our findings uncover disruptions in estrous cyclicity, characterized by an increased duration of time spent in the estrus phase in adenomyosis-induced mice. These disturbances are potentially linked to observed compromised folliculogenesis and the remarkable reduction in litter number and size in mice affected by adenomyosis. Moreover, this study unveils potential drivers of subfertility such as progesterone resistance and altered endometrial receptivity. Within the uteri of mice with adenomyosis, reduced expression of the progesterone receptor and a decreased expression of two implantation-related markers (HoxA10 and integrin β3) were observed. This comprehensive examination sheds light on the nuanced complexities of adenomyosis-associated reproductive challenges, providing a foundation for targeted interventions in addressing fertility issues related to this disease.

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José V. V. Isola J Isola, Aging and Metabolism Research Program, OMRF, Oklahoma City, United States

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Jéssica D. Hense J Hense, Dept of Nutrition, Universidade Federal de Pelotas, Pelotas, Brazil

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Cesar A. P. Osorio C Osorio, Nutrition, Universidade Federal de Pelotas, Pelotas, Brazil

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Subhasri Biswas S Biswas, Aging, OMRF, Oklahoma City, United States

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Jose Alberola-Ila J Alberola-Ila, Immunology, OMRF, Oklahoma City, United States

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Sarah R. Ocanas S Ocanas, GHD, OMRF, Oklahoma City, United States

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Augusto Schneider A Schneider, Dept of Nutrition, Universidade Federal de Pelotas, Pelotas, 96010-610, Brazil

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Michael B. Stout M Stout, Aging and Metabolism, Oklahoma Medical Research Foundation, Oklahoma City, United States

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Ovarian aging results in reduced fertility, disrupted endocrine signaling, and an increased burden of chronic diseases. The factors contributing to the natural decline of ovarian follicles throughout reproductive life are not fully understood. Nevertheless, local inflammation may play an important role in driving ovarian aging. Inflammation progressively rises in aged ovaries during the reproductive window, potentially affecting fertility. In addition to inflammatory markers, recent studies show an accumulation of specific immune cell populations in aging ovaries, particularly lymphocytes. Other hallmarks of the aging ovary include the formation and accumulation of multinucleated giant cells, increased collagen deposition, and increased markers of cellular senescence. Collectively, these changes significantly impact the quantity and quality of ovarian follicles and oocytes. This review explores recent literature on the alterations associated with inflammation, fibrosis, cell senescence, and the accumulation of immune cells in the aging ovary.

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Bettina P. Mihalas B Mihalas, Discipline of Women’s Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia

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Adele L. Marston A Marston, Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, Wellcome Centre for Cell Biology, Edinburgh, United Kingdom of Great Britain and Northern Ireland

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Lindsay E Wu L Wu, School of Biomedical Sciences, University of New South Wales, Sydney, Australia

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Robert B Gilchrist R Gilchrist, Discipline of Women’s Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia

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Advanced maternal age is a major cause of infertility, miscarriage, and congenital abnormalities. This is principally caused by a decrease in oocyte quality and developmental competence with age. Oocyte ageing is characterised by an increase in chromosome missegregation and aneuploidy. However, the underlying mechanisms of age-related aneuploidy have not been fully elucidated and are still under active investigation. In addition to chromosome missegregation, oocyte ageing is also accompanied by metabolic dysfunction. In this review, we integrate old and new perspectives on oocyte ageing, chromosome segregation and metabolism in mammalian oocytes and make direct links between these processes. We consider age-related alterations to chromosome segregation machinery, including the loss of cohesion, microtubule stability and the integrity of the spindle assembly checkpoint. We focus on how metabolic dysfunction in the ageing oocyte disrupts chromosome segregation machinery to contribute to and exacerbate age-related aneuploidy. More specifically, we discuss how mitochondrial function, ATP production and the generation of free radicals are altered during ageing. We also explore recent developments in oocyte metabolic ageing, including altered redox reactions (NAD+ metabolism) and the interactions between oocytes and their somatic nurse cells. Throughout the review we integrate the mechanisms by which changes in oocyte metabolism influence age-related chromosome missegregation.

Open access
Wenqian Xiong W Xiong, Department of Obstetrics and Gynecology, Wuhan Union Hospital Department of Obstetrics and Gynecology, Wuhan, 430022, China

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Jie Jin J Jin, Department of Obstetrics and Gynecology, Wuhan Union Hospital Department of Obstetrics and Gynecology, Wuhan, China

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Yi Liu Y Liu, Department of Obstetrics and Gynecology, Wuhan Union Hospital Department of Obstetrics and Gynecology, Wuhan, China

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Mesenchymal-epithelial transition (MET)-mediated endometrial decidualization is pivotal for achieving endometrial receptivity and successful pregnancy. We observed blockade of MET in the eutopic secretory endometrium of patients with endometriosis, but the underlying mechanism is unknown. In this study, real-time PCR was used to detect PRL and IGFBP1 expression, whereas western blotting was used to detect the expression of MET markers and METTL3. Phalloidin staining was used to identify changes in cell morphology. M6A levels were quantified using a colorimetric method and m6A dot blots, and functional analysis was performed using spheroid adhesion assays. We first found that increased E-cadherin expression was accompanied by decreased Vimentin and Slug expression in the eutopic secretory endometrium of individuals with endometriosis. We also detected a significant increase in both the m6A level and the expression of the related methyltransferase METTL3. Finally, METTL3 expression was negatively correlated with PRL, IGFBP1and MET markers expression. Collectively, our findings suggest that METTL3 mediates m6A modification, thereby inhibiting MET formation within the eutopic secretory endometrium of patients with endometriosis. Increased METTL3-mediated m6A modification plays a crucial role in attenuating MET formation and decidualization impairment in endometrial stromal cells, ultimately contributing to compromised endometrial receptivity in individuals with endometriosis. These insights could lead to the identification of potential therapeutic targets for improving both endometrial receptivity and pregnancy rate among individuals affected by endometriosis.

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L Kirsten Senn Department of Animal Science, University of Tennessee Institute of Agriculture, University of Tennessee, Knoxville, Tennessee, USA

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Katheryn D Peterson Department of Animal Science, University of Tennessee Institute of Agriculture, University of Tennessee, Knoxville, Tennessee, USA

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J Lannett Edwards Department of Animal Science, University of Tennessee Institute of Agriculture, University of Tennessee, Knoxville, Tennessee, USA

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Rebecca R Payton Department of Animal Science, University of Tennessee Institute of Agriculture, University of Tennessee, Knoxville, Tennessee, USA

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Daniel J Mathew Department of Animal Science, University of Tennessee Institute of Agriculture, University of Tennessee, Knoxville, Tennessee, USA

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In brief

Standard in vitro produced (IVP) bovine embryo culture media limit embryonic development. Culturing IVP bovine embryos in standard IVP bovine embryo culture media conditioned with oviduct and/or endometrial cells improves blastocyst formation and reduces the time to formation.

Abstract

In vitro embryo production in cattle greatly impacts blastomere biochemistry, embryo rate of development and pre- and post-transfer survival. In vivo, the bovine embryo migrates through the oviduct isthmus before entering the uterus on approximately day 4 of development where it remains unattached within the uterine lumen until day 20 of gestation. During this time, the embryo is sequentially exposed to oviduct followed by endometrial secretions that support embryonic development. Considering this, we tested the effect of culturing in vitro produced (IVP) bovine embryos sequentially in oviduct epithelial- (OEp; days 1–3) followed by endometrial epithelial- (EEp) or EEp and fibroblast cell (EEp/F; days 4–8)-conditioned media on embryonic development using a time-lapse monitoring system. Compared to control, culturing IVP embryos in EEp- or EEp/F-conditioned media without prior culture in OEp-conditioned media increased blastocyst formation (P < 0.05) and reduced the time to blastocyst formation (P < 0.05). Culturing IVP bovine embryos in OEp-conditioned media followed by EEp- or EEp/F-conditioned media, however, had the greatest impact on embryo developmental kinetics and increased morula and blastocyst formation (P < 0.05) and reduced time to formation (P < 0.05). Day 8 blastocyst cell numbers, diameter and quality were not significantly different, although, blastocyst quality scores were less (indicative of better quality) for all cell-conditioned media compared to control. In conclusion, IVP bovine embryo development may be improved using a sequential embryo culture system involving bovine oviduct followed by endometrial cell-conditioned media.

Open access
Robert John Aitken R Aitken, School of Environmental and Life Sciences, University of Newcastle, Callaghan, 2308, Australia

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Since the early 1960’s the world has witnessed the spectacular collapse of human fertility. As a result of this phenomenon several countries are already seeing their population numbers fall and more will follow in the coming decades. The causes of this fertility decline involve a complex interplay of socioeconomic, environmental, and biological factors that have converged to constrain fertility in posterity’s wake. Since large numbers of offspring are no longer needed to compensate for high infant mortality in contemporary society, couples have opted to have small families in a quality-over-quantity investment in their progeny’s future. Simultaneously, increases in female education, the enhanced participation of women in the paid workforce, and a resultant delay in childbearing has placed limits on achievable family size. Progressive urbanization, the improved availability of contraceptives and the socioeconomic pressures experienced by young adults in ageing societies, are also contributing to fertility’s demise. These factors together with the individualism that pervades modern society and the increasing social acceptability of voluntary childlessness, have firmly established a low fertility ethos in most post-transition countries. Since none of these forces are about to relent, it looks as if extremely low fertility might be with us for some time to come. This may have long-term consequences. The lack of selection pressure on high fertility genotypes, the ability of ART to retain poor fertility genotypes within the population and sustained exposure to reproductive toxicants in modern industrialized environments, may all contrive to leave a permanent mark on the fecundity of our species.

Open access
Monika Fluks Department of Embryology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, Warsaw, Poland

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Robert Milewski Department of Biostatistics and Medical Informatics, Medical University of Bialystok, Białystok, Poland

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Szymon Tamborski Institute of Physics, Faculty of Physics, Astronomy, and Informatics, Nicolaus Copernicus University in Torun, Toruń, Poland

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Maciej Szkulmowski Institute of Physics, Faculty of Physics, Astronomy, and Informatics, Nicolaus Copernicus University in Torun, Toruń, Poland

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Anna Ajduk Department of Embryology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, Warsaw, Poland

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In brief

Optical coherence microscopy non-invasively visualizes metaphase II spindles allowing for quantitative analysis of their volume and shape, which may prove useful in the assessment of the oocyte quality. Using a mouse model, we showed also that analysis of spindle length combined with morphokinetics improves the evaluation of the resulting embryos.

Abstract

The proper development of embryos strongly depends on the quality of oocytes, so the evaluation of oocytes may be a useful initial step in IVF procedures. Additionally, it enables embryologists to make more informed decisions regarding the treatments chosen for the patients and better manage patients’ expectations. Optical coherence microscopy (OCM) allows for non-invasive 3D visualization of intracellular structures, such as spindles or nuclei, which have been linked to the success of embryonic development. Here, we applied a mouse model to examine whether OCM imaging could be used in the quality assessment of metaphase II (MII) oocytes. We showed that quantitative parameters describing the shape and volume of the MII spindle were associated with the quality of the resulting embryos, including the likelihood of blastocyst formation and the embryos’ ability to differentiate the trophectoderm and primitive endoderm, but not the epiblast. We also created a multivariate linear regression model, combining OCM-based quantification of MII spindles with morphokinetic analysis of the embryos, that allowed for improved evaluation of the embryo quality. Finally, we proved that OCM does not interfere with the viability of the scanned cells, at least during the preimplantation development. Therefore, we believe that OCM-based quantitative assessment of MII spindles can improve the oocyte and embryo selection in IVF procedures.

Open access
Chuan-Mei Qin The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
Institute of Birth Defects and Rare Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Xiao-Wei Wei Shanghai Jiao Tong University School of Medicine Affiliated Sixth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Jia-Yi Wu The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
Institute of Birth Defects and Rare Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Xue-Qing Liu The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
Institute of Birth Defects and Rare Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Yi Lin Shanghai Jiao Tong University School of Medicine Affiliated Sixth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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In brief

The proliferation of the endometrium is regulated by histone methylation. This study shows that decreased NSD2 impairs proliferative-phase endometrial stromal cell proliferation in patients with recurrent implantation failure via epigenetic reprogramming of H3K36me2 methylation on the promoter region of MCM7.

Abstract

Recurrent implantation failure (RIF) is a formidable challenge in assisted reproductive technology because of its unclear molecular mechanism. Impaired human endometrial stromal cell (HESC) proliferation disrupts the rhythm of the menstrual cycle, resulting in devastating disorders between the embryo and the endometrium. The molecular function of histone methylation enzymes in modulating HESC proliferation remains largely uncharacterized. Herein, we found that the levels of histone methyltransferase nuclear receptor binding SET domain protein 2 (NSD2) and the dimethylation of lysine 36 on histone H3 are decreased significantly in the proliferative-phase endometrium of patients with RIF. Knockdown of NSD2 in an HESC cell line markedly impaired cell proliferation and globally reduced H3K36me2 binding to chromatin, leading to altered expression of many genes. Transcriptomic analyses revealed that cell cycle-related gene sets were downregulated in the endometrium of patients with RIF and in NSD2‑knockdown HESCs. Furthermore, RNA-sequencing and CUT&Tag sequencing analysis suggested that NSD2 knockdown reduced the binding of H3K36me2 to the promoter region of cell cycle marker gene MCM7 (encoding minichromosome maintenance complex component 7) and downregulated its expression. The interaction of H3K36me2 with the MCM7 promoter was verified using chromatin immunoprecipitation–quantitative real-time PCR. Our results demonstrated a unifying epigenome-scale mechanism by which decreased NSD2 impairs endometrial stromal cell proliferation in the proliferative-phase endometrium of patients with RIF.

Open access