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Physiological Reviews Jul 2020The physiological functions of the uterine endometrium (uterine lining) are preparation for implantation, maintenance of pregnancy if implantation occurs, and... (Review)
Review
The physiological functions of the uterine endometrium (uterine lining) are preparation for implantation, maintenance of pregnancy if implantation occurs, and menstruation in the absence of pregnancy. The endometrium thus plays a pivotal role in reproduction and continuation of our species. Menstruation is a steroid-regulated event, and there are alternatives for a progesterone-primed endometrium, i.e., pregnancy or menstruation. Progesterone withdrawal is the trigger for menstruation. The menstruating endometrium is a physiological example of an injured or "wounded" surface that is required to rapidly repair each month. The physiological events of menstruation and endometrial repair provide an accessible in vivo human model of inflammation and tissue repair. Progress in our understanding of endometrial pathophysiology has been facilitated by modern cellular and molecular discovery tools, along with animal models of simulated menses. Abnormal uterine bleeding (AUB), including heavy menstrual bleeding (HMB), imposes a massive burden on society, affecting one in four women of reproductive age. Understanding structural and nonstructural causes underpinning AUB is essential to optimize and provide precision in patient management. This is facilitated by careful classification of causes of bleeding. We highlight the crucial need for understanding mechanisms underpinning menstruation and its aberrations. The endometrium is a prime target tissue for selective progesterone receptor modulators (SPRMs). This class of compounds has therapeutic potential for the clinical unmet need of HMB. SPRMs reduce menstrual bleeding by mechanisms still largely unknown. Human menstruation remains a taboo topic, and many questions concerning endometrial physiology that pertain to menstrual bleeding are yet to be answered.
Topics: Animals; Endometrium; Female; Glucocorticoids; Humans; Menstruation; Pregnancy; Steroids
PubMed: 32031903
DOI: 10.1152/physrev.00031.2019 -
Annual Review of Cell and Developmental... Oct 2023The uterine lining (endometrium) regenerates repeatedly over the life span as part of its normal physiology. Substantial portions of the endometrium are shed during... (Review)
Review
The uterine lining (endometrium) regenerates repeatedly over the life span as part of its normal physiology. Substantial portions of the endometrium are shed during childbirth (parturition) and, in some species, menstruation, but the tissue is rapidly rebuilt without scarring, rendering it a powerful model of regeneration in mammals. Nonetheless, following some assaults, including medical procedures and infections, the endometrium fails to regenerate and instead forms scars that may interfere with normal endometrial function and contribute to infertility. Thus, the endometrium provides an exceptional platform to answer a central question of regenerative medicine: Why do some systems regenerate while others scar? Here, we review our current understanding of diverse endometrial disruption events in humans, nonhuman primates, and rodents, and the associated mechanisms of regenerative success and failure. Elucidating the determinants of these disparate repair processes promises insights into fundamental mechanisms of mammalian regeneration with substantial implications for reproductive health.
Topics: Female; Animals; Humans; Endometrium; Uterus; Fibrosis; Mammals
PubMed: 37843929
DOI: 10.1146/annurev-cellbio-011723-021442 -
Nature Genetics Dec 2021The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense...
The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma.
Topics: Cell Differentiation; Cell Lineage; Cellular Microenvironment; Endometrial Neoplasms; Endometrium; Female; Gonadal Steroid Hormones; Humans; In Vitro Techniques; Menstrual Cycle; Organoids; Receptors, Notch; Signal Transduction; Spatio-Temporal Analysis; Tissue Culture Techniques; Transcriptome; Uterus; Wnt Proteins
PubMed: 34857954
DOI: 10.1038/s41588-021-00972-2 -
Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium.Nature Cell Biology May 2017In humans, the endometrium, the uterine mucosal lining, undergoes dynamic changes throughout the menstrual cycle and pregnancy. Despite the importance of the endometrium...
In humans, the endometrium, the uterine mucosal lining, undergoes dynamic changes throughout the menstrual cycle and pregnancy. Despite the importance of the endometrium as the site of implantation and nutritional support for the conceptus, there are no long-term culture systems that recapitulate endometrial function in vitro. We adapted conditions used to establish human adult stem-cell-derived organoid cultures to generate three-dimensional cultures of normal and decidualized human endometrium. These organoids expand long-term, are genetically stable and differentiate following treatment with reproductive hormones. Single cells from both endometrium and decidua can generate a fully functional organoid. Transcript analysis confirmed great similarity between organoids and the primary tissue of origin. On exposure to pregnancy signals, endometrial organoids develop characteristics of early pregnancy. We also derived organoids from malignant endometrium, and so provide a foundation to study common diseases, such as endometriosis and endometrial cancer, as well as the physiology of early gestation.
Topics: Adult Stem Cells; Cell Culture Techniques; Cell Differentiation; Cell Lineage; Cell Proliferation; Cells, Cultured; Culture Media; Decidua; Endometrial Neoplasms; Endometrium; Estrogens; Female; Gene Expression Regulation, Developmental; Genotype; Humans; Organoids; Phenotype; Pregnancy; Progesterone; Time Factors; Tissue Engineering; Tumor Cells, Cultured
PubMed: 28394884
DOI: 10.1038/ncb3516 -
International Journal of Molecular... Nov 2019The etiopathogenesis of endometriosis is a multifactorial process resulting in a heterogeneous disease. Considering that endometriosis etiology and pathogenesis are... (Review)
Review
The etiopathogenesis of endometriosis is a multifactorial process resulting in a heterogeneous disease. Considering that endometriosis etiology and pathogenesis are still far from being fully elucidated, the current review aims to offer a comprehensive summary of the available evidence. We performed a narrative review synthesizing the findings of the English literature retrieved from computerized databases from inception to June 2019, using the Medical Subject Headings (MeSH) unique ID term "Endometriosis" (ID:D004715) with "Etiology" (ID:Q000209), "Immunology" (ID:Q000276), "Genetics" (ID:D005823) and "Epigenesis, Genetic" (ID:D044127). Endometriosis may origin from Müllerian or non-Müllerian stem cells including those from the endometrial basal layer, Müllerian remnants, bone marrow, or the peritoneum. The innate ability of endometrial stem cells to regenerate cyclically seems to play a key role, as well as the dysregulated hormonal pathways. The presence of such cells in the peritoneal cavity and what leads to the development of endometriosis is a complex process with a large number of interconnected factors, potentially both inherited and acquired. Genetic predisposition is complex and related to the combined action of several genes with limited influence. The epigenetic mechanisms control many of the processes involved in the immunologic, immunohistochemical, histological, and biological aberrations that characterize the eutopic and ectopic endometrium in affected patients. However, what triggers such alterations is not clear and may be both genetically and epigenetically inherited, or it may be acquired by the particular combination of several elements such as the persistent peritoneal menstrual reflux as well as exogenous factors. The heterogeneity of endometriosis and the different contexts in which it develops suggest that a single etiopathogenetic model is not sufficient to explain its complex pathobiology.
Topics: Endometriosis; Endometrium; Epigenesis, Genetic; Female; Humans; Stem Cells
PubMed: 31717614
DOI: 10.3390/ijms20225615 -
Molecular Cancer Mar 2023Endometrial cancer (EC) is one of the most common gynecologic cancers and its incidence is rising globally. Although advanced EC has a poor prognosis; diagnosing EC at... (Review)
Review
Endometrial cancer (EC) is one of the most common gynecologic cancers and its incidence is rising globally. Although advanced EC has a poor prognosis; diagnosing EC at an earlier stage could improve long-term patient outcomes. However, there is no consensus on the early detection strategies for EC and the current diagnostic practices such as transvaginal ultrasound, hysteroscopy and endometrial biopsy are invasive, costly and low in specificity. Thus, accurate and less invasive screening tests that detect EC in women with early stages of the disease are needed. Current research has revolutionized novel EC early detection methodologies in many aspects. This review aims to comprehensively characterizes minimally invasive screening techniques that can be applied to EC in the future, and fully demonstrate their potential in the early detection of EC.
Topics: Pregnancy; Female; Humans; Endometrial Neoplasms; Endometrium; Biopsy; Ultrasonography; Hysteroscopy; Early Detection of Cancer
PubMed: 36932368
DOI: 10.1186/s12943-023-01757-3 -
Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids.ELife Sep 2021Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust...
Decidual remodelling of midluteal endometrium leads to a short implantation window after which the uterine mucosa either breaks down or is transformed into a robust matrix that accommodates the placenta throughout pregnancy. To gain insights into the underlying mechanisms, we established and characterized endometrial assembloids, consisting of gland-like organoids and primary stromal cells. Single-cell transcriptomics revealed that decidualized assembloids closely resemble midluteal endometrium, harbouring differentiated and senescent subpopulations in both glands and stroma. We show that acute senescence in glandular epithelium drives secretion of multiple canonical implantation factors, whereas in the stroma it calibrates the emergence of anti-inflammatory decidual cells and pro-inflammatory senescent decidual cells. Pharmacological inhibition of stress responses in pre-decidual cells accelerated decidualization by eliminating the emergence of senescent decidual cells. In co-culture experiments, accelerated decidualization resulted in entrapment of collapsed human blastocysts in a robust, static decidual matrix. By contrast, the presence of senescent decidual cells created a dynamic implantation environment, enabling embryo expansion and attachment, although their persistence led to gradual disintegration of assembloids. Our findings suggest that decidual senescence controls endometrial fate decisions at implantation and highlight how endometrial assembloids may accelerate the discovery of new treatments to prevent reproductive failure.
Topics: Cellular Senescence; Coculture Techniques; Decidua; Embryo Implantation; Endometrium; Female; Humans; Organoids; Pregnancy; Stromal Cells
PubMed: 34487490
DOI: 10.7554/eLife.69603 -
Fertility and Sterility Dec 2017The aim of the present review was to evaluate the contribution of clinical examination and imaging techniques, mainly transvaginal sonography and magnetic resonance... (Review)
Review
The aim of the present review was to evaluate the contribution of clinical examination and imaging techniques, mainly transvaginal sonography and magnetic resonance imaging (MRI) to diagnose deep infiltrating (DE) locations using prisma statement recommendations. Clinical examination has a relative low sensitivity and specificity to diagnose DE. Independently of DE locations, for all transvaginal sonography techniques a pooled sensitivity and specificity of 79% and 94% are observed approaching criteria for a triage test. Whatever the protocol and MRI devices, the pooled sensitivity and specificity for pelvic endometriosis diagnosis were 94% and 77%, respectively. For rectosigmoid endometriosis, pooled sensitivity and specificity of MRI were 92% and 96%, respectively fulfilling criteria of replacement test. In conclusion, advances in imaging techniques offer high sensitivity and specificity to diagnose DE with at least triage value and for rectosigmoid endometriosis replacement value imposing a revision of the concept of laparoscopy as the gold standard.
Topics: Endometriosis; Endometrium; Female; Humans; Magnetic Resonance Imaging; Predictive Value of Tests; Prognosis; Radionuclide Imaging; Reproducibility of Results; Tomography, X-Ray Computed; Ultrasonography
PubMed: 29202963
DOI: 10.1016/j.fertnstert.2017.10.026 -
Stem Cell Research & Therapy Feb 2018Repair deficiency after endometrial injury is an important reason for intra-uterine adhesions, amenorrhea, and infertility in females. Bone marrow-derived mesenchymal...
BACKGROUND
Repair deficiency after endometrial injury is an important reason for intra-uterine adhesions, amenorrhea, and infertility in females. Bone marrow-derived mesenchymal stem cell (BMSC) transplantation is effective in repairing the damaged endometrium. However, the possibility of using umbilical cord-derived MSCs (UC-MSCs) to treat endometrial injury is rarely reported.
METHODS
Ethanol (95%) was injected into rat uterus to establish a model of endometrial injury. UC-MSCs were injected through the tail vein, either as a single, twice, or thrice administration. Functional restoration of the uterus was assessed by testing embryo implantation rates. Endometrial morphological alteration was observed by hematoxylin and eosin staining. Endometrial fibrosis, markers of epithelial and stromal cells of endometrium, cell proliferation and angiogenesis, and inflammatory factors were detected using immunohistochemistry, Western blotting, and quantitative reverse-transcription polymerase chain reaction.
RESULTS
Endometrial morphology and embryo implantation rates were significantly improved on day 8 of transplantation among single-, twice-, or thrice-administered rats. Moreover, UC-MSCs could alleviate fibrosis in general, and reduced the expression of fibrosis markers, α-smooth muscle actin (α-SMA) and transforming growth factor (TGF)-β. The cell proliferation marker Ki-67 had a positive expression in the injured endometrium after UC-MSC transplantation. The endometrial stromal marker vimentin and epithelial marker cytokeratin-19 (CK-19) expressions were visibly increased. The expression of vascular markers CD31, vascular endothelial growth factor (VEGF)A, and matrix metalloprotein (MMP)9 was generally upregulated. Proinflammatory factors interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-2 were significantly downregulated in the rats administered UC-MSCs twice and thrice.
CONCLUSIONS
UC-MSC transplantation contributed to the repair of endometrial injury and restoration of fertility, likely through the suppression of excessive fibrosis and inflammation, and enhancement of endometrial cell proliferation and vascular remodeling.
Topics: Animals; Antigens, Differentiation; Chronic Disease; Endometrium; Female; Heterografts; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Rats; Rats, Sprague-Dawley; Umbilical Cord; Uterine Diseases
PubMed: 29433563
DOI: 10.1186/s13287-018-0777-5 -
Frontiers in Endocrinology 2021The uterine endometrium, which lines the mammalian uterus, is essential for embryo implantation. This lining undergoes significant changes during sexual and menstrual... (Review)
Review
The uterine endometrium, which lines the mammalian uterus, is essential for embryo implantation. This lining undergoes significant changes during sexual and menstrual cycles. The endometrium is also associated with hormone-related diseases such as endometriosis and endometrial cancer. Circular RNAs (circRNAs) play a role in various biological processes. Recent studies have determined that circRNAs function in both normal and pathological endometrial environments. Here, we review high-throughput studies pertaining to circRNAs as well as individual circRNAs active in the endometrium, in order to explore the myriad functions of circRNAs in the endometrium and mechanisms underlying these functions, from panoramic and individual perspectives. Owing to their abundant expression, stability, and small size, circRNAs have displayed potential usefulness as diagnostic markers and treatment targets for endometrial-related diseases. Therefore, the specific role of circRNAs in the endometrium warrants systematic investigation in the future.
Topics: Animals; Endometriosis; Endometrium; Female; Humans; RNA, Circular
PubMed: 34122342
DOI: 10.3389/fendo.2021.668073