M2 Macrophages are Major Mediators of Germline Risk of Endometriosis and Explain Pleiotropy with Comorbid Traits.

Endometriosis is a common gynecologic condition that causes chronic life-altering symptoms including pain, infertility, and elevated cancer risk. There is an urgent need for new non-hormonal targeted therapeutics to treat endometriosis, but until very recently, the cellular and molecular signatures of endometriotic lesions were undefined, severely hindering the development of clinical advances. Integrating inherited risk data from analyses of >450,000 individuals with ∼350,000 single cell transcriptomes from 21 patients, we uncover M2-macrophages as candidate drivers of disease susceptibility, and nominate IL1 signaling as a central hub impacted by germline genetic variation associated with endometriosis.

3D Printed Mesh Geometry Modulates Immune Response and Interface Biology in Mouse and Sheep Model: Implications for Pelvic Floor Surgery.

Pelvic organ prolapse (POP) is a highly prevalent yet neglected health burden for women. Strengthening thepelvic floor with bioactive tissue-engineered meshes is an emerging concept. The study investigates tissue regenerative design parameters, including degradability, porosity, and angulation, to develop alternative degradable melt electrowritten (MEW) constructs for surgical applications of POP.

Investigating Menstruation and Adverse Pregnancy Outcomes: Oxymoron or New Frontier? A Narrative Review.

Not discounting the important foetal or placental contribution, the endometrium is a key determinant of pregnancy outcomes. Given the inherently linked processes of menstruation, pregnancy and parturition with the endometrium, further understanding of menstruation will help to elucidate the maternal contribution to pregnancy. Endometrial health can be assessed via menstrual history and menstrual fluid, a cyclically shed, easily and non-invasively accessible biological sample that represents the distinct, heterogeneous composition of the endometrial environment.

Photo-Cross-linked Gelatin Methacryloyl Hydrogels Enable the Growth of Primary Human Endometrial Stromal Cells and Epithelial Gland Organoids.

three-dimensional (3D) models are better able to replicate the complexity of real organs and tissues than 2D monolayer models. The human endometrium, the inner lining of the uterus, undergoes complex changes during the menstrual cycle and pregnancy. These changes occur in response to steroid hormone fluctuations and elicit crosstalk between the epithelial and stromal cell compartments, and dysregulations are associated with a variety of pregnancy disorders.

Immunobiology of foreign body response to composite PLACL/gelatin electrospun nanofiber meshes with mesenchymal stem/stromal cells in a mouse model: Implications in pelvic floor tissue engineering and regeneration.

Pelvic Organ Prolapse (POP) is a common gynaecological disorder where pelvic organs protrude into the vagina. While transvaginal mesh surgery using non-degradable polymers was a commonly accepted treatment for POP, it has been associated with high rates of adverse events such as mesh erosion, exposure and inflammation due to serious foreign body response and therefore banned from clinical use after regulatory mandates. This study proposes a tissue engineering strategy using uterine endometrium-derived mesenchymal stem/stromal cells (eMSC) delivered with degradable poly L-lactic acid-co-poly ε-caprolactone (PLACL) and gelatin (G) in form of a composite electrospun nanofibrous mesh (P + G nanomesh) and evaluates the immunomodulatory mechanism at the material interfaces.

Endometrial Origins of Stillbirth (EOS), a case-control study of menstrual fluid to understand and prevent preterm stillbirth and associated adverse pregnancy outcomes: study protocol.

Introduction: Current research aimed at understanding and preventing stillbirth focuses almost exclusively on the role of the placenta. The underlying origins of poor placental function leading to stillbirth, however, remain poorly understood. There is evidence demonstrating that the endometrial environment in which the embryo implants impacts not only the establishment of pregnancy but also the development of some pregnancy outcomes.

Radiotherapy exposure directly damages the uterus and causes pregnancy loss.

Female cancer survivors are significantly more likely to experience infertility than the general population. It is well established that chemotherapy and radiotherapy can damage the ovary and compromise fertility, yet the ability of cancer treatments to induce uterine damage, and the underlying mechanisms, have been understudied. Here, we show that in mice total-body γ-irradiation (TBI) induced extensive DNA damage and apoptosis in uterine cells.

New concepts on the etiology of endometriosis.

Endometriosis is a serious, chronic disorder where endometrial tissue grows outside the uterus, causing severe pelvic pain and infertility. It affects 11% of women. Endometriosis is a multifactorial disorder of unclear etiology, although retrograde menstruation plays a major role.

Subtle changes in perivascular endometrial mesenchymal stem cells after local endometrial injury in recurrent implantation failure.

Improvements in reproductive techniques have resulted in the live birth rates from IVF procedures increasing from 5% to approximately 30% in recent decades but has plateaued since. Emerging preclinical and clinical data implicates endometrial receptivity deficiencies in patients with recurrent implantation failure (RIF) as the predominant factor hindering successful implantation. Mechanisms on how local endometrial injury (LEI) improves implantation rates in patients with RIF are currently unknown.

Endometrial Stem/Progenitor Cells-Their Role in Endometrial Repair and Regeneration.

The human endometrium is a remarkable tissue, undergoing ~450 cycles of proliferation, differentiation, shedding (menstruation), repair, and regeneration over a woman's reproductive lifespan. Post-menstrual repair is an extremely rapid and scar-free process, with re-epithelialization of the luminal epithelium completed within 48 h of initiation of shedding. Following menstruation, the functionalis grows from the residual basalis layer during the proliferative phase under the influence of rising circulating estrogen levels.

Platelet lysate can support the development of a 3D-engineered skin for clinical application.

Safety concerns associated with foetal bovine serum (FBS) have restricted its translation into clinics. We hypothesised that platelet lysate (PL) can be utilised as a safe alternative to produce serum-free 3D-engineered skin. PL supported a short-term expansion of fibroblasts, with negligible replication-induced senescence and directed epidermal stratification.

Endometrial Stem/Progenitor Cells: Prospects and Challenges.

The human endometrium is one of the most regenerative tissues in the body, undergoing over 400 cycles of menstrual shedding and regeneration during reproductive life [...

ENDOCELL-Seud: a Delphi protocol to harmonise methods in endometrial cell culturing.

In Vitro: culturing of endometrial cells obtained from the uterine mucosa or ectopic sites is used to study molecular and cellular signalling relevant to physiologic and pathologic reproductive conditions. However, the lack of consensus on standard operating procedures for deriving, characterising and maintaining primary cells in two- or three-dimensional cultures from eutopic or ectopic endometrium may be hindering progress in this area of research. Guidance for unbiased in vitro research methodologies in the field of reproductive science remains essential to increase confidence in the reliability of in vitro models.

Vaginal pressure sensor measurement during maximal voluntary pelvic floor contraction correlates with vaginal birth and pelvic organ prolapse-A pilot study.

Aims: To measure the force applied along the anterior and posterior vaginal walls in a cohort of 46 patients measured by a fiber-optic pressure sensor and determine if this correlates with vaginal parity and pelvic organ prolapse (POP).

Methods: An intravaginal fiber-optic sensor measured pressure at nine locations along the anterior and posterior vaginal walls during a maximal voluntary pelvic floor muscle contraction (MVC). An automated probe dilation cycle measured the tissue resistance incorporating the vagina and surrounding anatomy.

The fate of human SUSD2+ endometrial mesenchymal stem cells during decidualization.

Regeneration of the endometrial stromal compartment in premenopausal women is likely maintained by the perivascular endometrial mesenchymal stem/stromal cells (eMSC) expressing sushi domain containing 2 (SUSD2). The fate of SUSD2+ eMSC during pregnancy and their role in decidualization is not fully known. The aim of our study was to determine the effect of progesterone on the stemness of the SUSD2+ eMSC isolated from non-pregnant uterine samples.

Comparison of Organoids from Menstrual Fluid and Hormone-Treated Endometrium: Novel Tools for Gynecological Research.

Endometrial organoids (EMO) are an important tool for gynecological research but have been limited by generation from (1) invasively acquired tissues and thus advanced disease states and (2) from women who are not taking hormones, thus excluding 50% of the female reproductive-aged population. We sought to overcome these limitations by generating organoids from (1) menstrual fluid (MF; MFO) using a method that enables the concurrent isolation of menstrual fluid supernatant, stromal cells, and leukocytes and (2) from biopsies and hysterectomy samples from women taking hormonal medication (EMO-H). MF was collected in a menstrual cup for 4-6 h on day 2 of menstruation.

Endometrial SUSD2 Mesenchymal Stem/Stromal Cells in Tissue Engineering: Advances in Novel Cellular Constructs for Pelvic Organ Prolapse.

Cellular therapy is an emerging field in clinical and personalised medicine. Many adult mesenchymal stem/progenitor cells (MSC) or pluripotent derivatives are being assessed simultaneously in preclinical trials for their potential treatment applications in chronic and degenerative human diseases. Endometrial mesenchymal stem/progenitor cells (eMSC) have been identified as clonogenic cells that exist in unique perivascular niches within the uterine endometrium.

Cyclical endometrial repair and regeneration.

Uniquely among adult tissues, the human endometrium undergoes cyclical shedding, scar-free repair and regeneration during a woman's reproductive life. Therefore, it presents an outstanding model for study of such processes. This Review examines what is known of endometrial repair and regeneration following menstruation and parturition, including comparisons with wound repair and the influence of menstrual fluid components.

Menstrual fluid endometrial stem/progenitor cell and supernatant protein content: cyclical variation and indicative range.

Study Question: Does natural variation exist in the endometrial stem/progenitor cell and protein composition of menstrual fluid across menstrual cycles in women?

Summary Answer: Limited variation exists in the percentage of some endometrial stem/progenitor cell types and abundance of selected proteins in menstrual fluid within and between a cohort of women.

What Is Known Already: Menstrual fluid is a readily available biofluid that can represent the endometrial environment, containing endometrial stem/progenitor cells and protein factors. It is unknown whether there is natural variation in the cellular and protein content across menstrual cycles of individual women, which has significant implications for the use of menstrual fluid in research and clinical applications.

Endometrial stem/progenitor cells in menstrual blood and peritoneal fluid of women with and without endometriosis.

Research Question: Are endometrial stem/progenitor cells shed into uterine menstrual blood (UMB) and the peritoneal cavity in women with and without endometriosis during menstruation?

Design: Women with (n = 32) and without endometriosis (n = 29) at laparoscopy (total 61), carried out during the menstrual (n = 41) and non-menstrual phase (n = 20) were recruited. The UMB, peritoneal fluid and peripheral blood were analysed by clonogenicity assay and flow cytometry to quantify the concentrations of endometrial clonogenic cells, SUSD2 mesenchymal stem cells (eMSC) and N-cadherin epithelial progenitor cells (eEPC).

Results: Clonogenic endometrial cells, eMSC and eEPC were found in most UMB samples at similar concentrations in women with and without endometriosis.

Identification and characterisation of maternal perivascular SUSD2 placental mesenchymal stem/stromal cells.

Mesenchymal stem cells (MSCs) that meet the International Society for Cellular Therapy (ISCT) criteria are obtained from placental tissue by plastic adherence. Historically, no known single marker was available for isolating placental MSCs (pMSCs) from the decidua basalis. As the decidua basalis is derived from the regenerative endometrium, we hypothesised that SUSD2, an endometrial perivascular MSC marker, would purify maternal perivascular pMSC.

The Elusive Endometrial Epithelial Stem/Progenitor Cells.

The human endometrium undergoes approximately 450 cycles of proliferation, differentiation, shedding and regeneration over a woman's reproductive lifetime. The regenerative capacity of the endometrium is attributed to stem/progenitor cells residing in the basalis layer of the tissue. Mesenchymal stem cells have been extensively studied in the endometrium, whereas endometrial epithelial stem/progenitor cells have remained more elusive.

Comparing the Effect of TGF-β Receptor Inhibition on Human Perivascular Mesenchymal Stromal Cells Derived from Endometrium, Bone Marrow and Adipose Tissues.

Rare perivascular mesenchymal stromal cells (MSCs) with therapeutic properties have been identified in many tissues. Their rarity necessitates extensive in vitro expansion, resulting in spontaneous differentiation, cellular senescence and apoptosis, producing therapeutic products with variable quality and decreased potency. We previously demonstrated that A83-01, a transforming growth factor beta (TGF-β) receptor inhibitor, maintained clonogenicity and promoted the potency of culture-expanded premenopausal endometrial MSCs using functional assays and whole-transcriptome sequencing.