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Stem Cell Research & Therapy Jan 2022Numerous treatment strategies have so far been proposed for treating refractory thin endometrium either without or with the Asherman syndrome. Inconsistency in the... (Review)
Review
Numerous treatment strategies have so far been proposed for treating refractory thin endometrium either without or with the Asherman syndrome. Inconsistency in the improvement of endometrial thickness is a common limitation of such therapies including tamoxifen citrate as an ovulation induction agent, acupuncture, long-term pentoxifylline and tocopherol or tocopherol only, low-dose human chorionic gonadotropin during endometrial preparation, aspirin, luteal gonadotropin-releasing hormone agonist supplementation, and extended estrogen therapy. Recently, cell therapy has been proposed as an ideal alternative for endometrium regeneration, including the employment of stem cells, platelet-rich plasma, and growth factors as therapeutic agents. The mechanisms of action of cell therapy include the cytokine induction, growth factor production, natural killer cell activity reduction, Th17 and Th1 decrease, and Treg cell and Th2 increase. Since cell therapy is personalized, dynamic, interactive, and specific and could be an effective strategy. Despite its promising nature, further research is required for improving the procedure and the safety of this strategy. These methods and their results are discussed in this article.
Topics: Cell- and Tissue-Based Therapy; Chorionic Gonadotropin; Endometrium; Female; Gynatresia; Humans; Platelet-Rich Plasma
PubMed: 35090547
DOI: 10.1186/s13287-021-02698-8 -
Human Reproduction Update Oct 2024The establishment and maintenance of pregnancy depend on endometrial competence. Asherman syndrome (AS) and intrauterine adhesions (IUA), or endometrial atrophy (EA) and...
BACKGROUND
The establishment and maintenance of pregnancy depend on endometrial competence. Asherman syndrome (AS) and intrauterine adhesions (IUA), or endometrial atrophy (EA) and thin endometrium (TE), can either originate autonomously or arise as a result from conditions (i.e. endometritis or congenital hypoplasia), or medical interventions (e.g. surgeries, hormonal therapies, uterine curettage or radiotherapy). Affected patients may present an altered or inadequate endometrial lining that hinders embryo implantation and increases the risk of poor pregnancy outcomes and miscarriage. In humans, AS/IUA and EA/TE are mainly treated with surgeries or pharmacotherapy, however the reported efficacy of these therapeutic approaches remains unclear. Thus, novel regenerative techniques utilizing stem cells, growth factors, or tissue engineering have emerged to improve reproductive outcomes.
OBJECTIVE AND RATIONALE
This review comprehensively summarizes the methodologies and outcomes of emerging biotechnologies (cellular, acellular, and bioengineering approaches) to treat human endometrial pathologies. Regenerative therapies derived from human tissues or blood which were studied in preclinical models (in vitro and in vivo) and clinical trials are discussed.
SEARCH METHODS
A systematic search of full-text articles available in PubMed and Embase was conducted to identify original peer-reviewed studies published in English between January 2000 and September 2023. The search terms included: human, uterus, endometrium, Asherman syndrome, intrauterine adhesions, endometrial atrophy, thin endometrium, endometritis, congenital hypoplasia, curettage, radiotherapy, regenerative therapy, bioengineering, stem cells, vesicles, platelet-rich plasma, biomaterials, microfluidic, bioprinting, organoids, hydrogel, scaffold, sheet, miRNA, sildenafil, nitroglycerine, aspirin, growth hormone, progesterone, and estrogen. Preclinical and clinical studies on cellular, acellular, and bioengineering strategies to repair or regenerate the human endometrium were included. Additional studies were identified through manual searches.
OUTCOMES
From a total of 4366 records identified, 164 studies (3.8%) were included for systematic review. Due to heterogeneity in the study design and measured outcome parameters in both preclinical and clinical studies, the findings were evaluated qualitatively and quantitatively without meta-analysis. Groups using stem cell-based treatments for endometrial pathologies commonly employed mesenchymal stem cells (MSCs) derived from the human bone marrow or umbilical cord. Alternatively, acellular therapies based on platelet-rich plasma (PRP) or extracellular vesicles are gaining popularity. These are accompanied by the emergence of bioengineering strategies based on extracellular matrix (ECM)-derived hydrogels or synthetic biosimilars that sustain local delivery of cells and growth factors, reporting promising results. Combined therapies that target multiple aspects of tissue repair and regeneration remain in preclinical testing but have shown translational value. This review highlights the myriad of therapeutic material sources, administration methods, and carriers that have been tested.
WIDER IMPLICATIONS
Therapies that promote endometrial proliferation, vascular development, and tissue repair may help restore endometrial function and, ultimately, fertility. Based on the existing evidence, cost, accessibility, and availability of the therapies, we propose the development of triple-hit regenerative strategies, potentially combining high-yield MSCs (e.g. from bone marrow or umbilical cord) with acellular treatments (PRP), possibly integrated in ECM hydrogels. Advances in biotechnologies together with insights from preclinical models will pave the way for developing personalized treatment regimens for patients with infertility-causing endometrial disorders such as AS/IUA, EA/TE, and endometritis.
REGISTRATION NUMBER
https://osf.io/th8yf/.
Topics: Humans; Female; Endometrium; Uterine Diseases; Gynatresia; Regenerative Medicine; Tissue Engineering; Biotechnology; Pregnancy; Stem Cell Transplantation; Tissue Adhesions
PubMed: 38796750
DOI: 10.1093/humupd/dmae013 -
International Journal of Molecular... Feb 2021Cell-cell communication is an essential mechanism for the maintenance and development of various organs, including the female reproductive system. Today, it is... (Review)
Review
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.
Topics: Biomarkers; Endometrial Neoplasms; Endometriosis; Exosomes; Female; Genital Diseases, Female; Gynatresia; Humans; MicroRNAs; Ovarian Neoplasms; Polycystic Ovary Syndrome; Pre-Eclampsia; Pregnancy; Primary Ovarian Insufficiency; Uterine Cervical Neoplasms
PubMed: 33671587
DOI: 10.3390/ijms22042165 -
International Journal of Women's Health 2019Intrauterine adhesions with symptoms like hypomenorrhea or infertility are known under the term Asherman's syndrome. Although the syndrome has been widely investigated,... (Review)
Review
Intrauterine adhesions with symptoms like hypomenorrhea or infertility are known under the term Asherman's syndrome. Although the syndrome has been widely investigated, evidence of both prevention of the syndrome and the ideal treatment are missing. Understanding the pathogenesis of intrauterine adherences is necessary for the prevention of the formation of intrauterine scarring. Intrauterine adhesions can develop from lesion of the basal layer of the endometrium caused by curettage of the newly pregnant uterus. The syndrome may also occur after hysteroscopic surgery, uterine artery embolization or uterine tuberculosis. For initial diagnosis the less invasive contrast sonohysterography or hysterosalpingography is useful. The final diagnosis is based on hysteroscopy. Magnetic resonance imaging is required in cases with totally obliterated uterine cavity. Intrauterine adherences are classified in accordance with different classification systems based on the hysteroscopic diagnosis of severity and localization of adherences. Classification is necessary for the planning of surgery, information on prognosis and scientific purposes. Surgery is performed in symptomatic patients with either infertility or with painful periods. Intrauterine adherences are divided with a hysteroscope using scissors or a power instrument working from the central part of the uterus to the periphery. Peroperative ultrasonography is useful in an outpatient setting for the prevention of complications. Hysteroscopy with fluoroscopy is a solution in difficult cases. Use of intrauterine devices like balloon catheters or intrauterine contraceptive devices seems to be the preferred methods for the prevention of re-occurrence of adhesions after treatment. Both primary prevention after hysteroscopic surgery or curettage and secondary prevention of new adhesions after adhesiolysis have been investigated. The aim of this review was to summarize the literature on diagnosis, classification, treatment and prevention, based on a literature search with a wide range of search terms.
PubMed: 30936754
DOI: 10.2147/IJWH.S165474 -
Nature Communications Sep 2023Asherman's Syndrome is characterized by intrauterine adhesions or scarring, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss. The...
Asherman's Syndrome is characterized by intrauterine adhesions or scarring, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss. The pathophysiology of this syndrome remains unknown, with treatment restricted to recurrent surgical removal of intrauterine scarring, which has limited success. Here, we decode the Asherman's Syndrome endometrial cell niche by analyzing data from over 200,000 cells with single-cell RNA-sequencing in patients with this condition and through in vitro analyses of Asherman's Syndrome patient-derived endometrial organoids. Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation. We describe syndrome-associated alterations in cell-to-cell communication and gene expression profiles that support a dysfunctional pro-fibrotic, pro-inflammatory, and anti-angiogenic environment.
Topics: Female; Pregnancy; Humans; Cicatrix; Gynatresia; Uterine Diseases; Cell Communication; Embryo Implantation
PubMed: 37735465
DOI: 10.1038/s41467-023-41656-1 -
The British Journal of General Practice... Jul 2023
Topics: Humans; Female; Gynatresia
PubMed: 37385758
DOI: 10.3399/bjgp23X733365 -
Reproductive Sciences (Thousand Oaks,... Jun 2021Impairment of uterine structure and function causes infertility, pregnancy loss, and perinatal complications in humans. Some types of uterine impairments such as... (Review)
Review
Impairment of uterine structure and function causes infertility, pregnancy loss, and perinatal complications in humans. Some types of uterine impairments such as Asherman's syndrome, also known as uterine synechiae, can be treated medically and surgically in a standard clinical setting, but absolute defects of uterine function or structure cannot be cured by conventional approaches. To overcome such hurdles, partial or whole regeneration and reconstruction of the uterus have recently emerged as new therapeutic strategies. Transplantation of the whole uterus into patients with uterine agenesis results in the successful birth of children. However, it remains an experimental treatment with numerous difficulties such as the need for continuous and long-term use of immunosuppressive drugs until a live birth is achieved. Thus, the generation of the uterus by tissue engineering technologies has become an alternative but indispensable therapeutic strategy to treat patients without a functional or well-structured uterus. For the past 20 years, the bioengineering of the uterus has been studied intensively in animal models, providing the basis for clinical applications. A variety of templates and scaffolds made from natural biomaterials, synthetic materials, or decellularized matrices have been characterized to efficiently generate the uterus in a manner similar to the bioengineering of other organs and tissues. The goal of this review is to provide a comprehensive overview and perspectives of uterine bioengineering focusing on the type, preparation, and characteristics of the currently available scaffolds.
Topics: Adult Stem Cells; Animals; Bioengineering; Decellularized Extracellular Matrix; Embryonic Stem Cells; Female; Genital Diseases, Female; Gynatresia; Humans; Induced Pluripotent Stem Cells; Tissue Engineering; Tissue Scaffolds; Urogenital Abnormalities; Uterus
PubMed: 33826100
DOI: 10.1007/s43032-021-00503-8 -
Cell Transplantation 2023Asherman's syndrome is an endometrial regeneration disorder resulting from injury to the endometrial basal layer, causing the formation of scar tissue in the uterus and...
Asherman's syndrome is an endometrial regeneration disorder resulting from injury to the endometrial basal layer, causing the formation of scar tissue in the uterus and cervix. This usually leads to uterine infertility, menstrual disorders, and placental abnormalities. While stem cell therapy has shown extensive progress in repairing the damaged endometrium and preventing intrauterine adhesion, issues of low engraftment rates, rapid senescence, and the risk of tumorigenesis remain to be resolved for efficient and effective application of this technology in endometrial repair. This study addressed these challenges by developing a co-culture system to generate multi-lineage endometrial organoids (MLEOs) comprising endometrial epithelium organoids (EEOs) and endometrial mesenchymal stem cells (eMSCs). The efficacy of these MLEOs was investigated by seeding them on a biocompatible scaffold, the human acellular amniotic membrane (HAAM), to create a biological graft patch, which was subsequently transplanted into an injury model of the endometrium in rats. The results indicated that the MLEOs on the HAAM patch facilitated endometrial angiogenesis, regeneration, and improved pregnancy outcomes. The MLEOs on the HAAM patch could serve as a promising strategy for treating endometrial injury and preventing Asherman's syndrome.
Topics: Humans; Female; Rats; Animals; Pregnancy; Gynatresia; Amnion; Placenta; Endometrium; Uterus
PubMed: 38097275
DOI: 10.1177/09636897231218408 -
Acta Obstetricia Et Gynecologica... May 2019An update on the current state of endometrial cell therapies in terms of cell types, mechanisms of action, delivery, safety, regulatory frameworks and future... (Review)
Review
An update on the current state of endometrial cell therapies in terms of cell types, mechanisms of action, delivery, safety, regulatory frameworks and future perspectives. This review focuses on clinical trials using angiogenesis-promoting therapies and stromal therapies piloted in the last 10 years for alleviating Asherman's syndrome and long-term infertility. All studies present promising preliminary results, indicating increased endometrial thickness and resumed menstruation. Further characterization of individual cell products, their mode of action and larger clinical trials will be essential to establishing cell therapy as a viable option for the treatment of infertility and fertility preservation.
Topics: Cell- and Tissue-Based Therapy; Endometrium; Female; Gynatresia; Humans; Infertility, Female; Neovascularization, Physiologic
PubMed: 30815850
DOI: 10.1111/aogs.13598 -
Cell Transplantation 2021Asherman syndrome (AS) has an adverse effect on reproductive health and fertility by affecting endometrial regeneration. Stem cell-based therapies hold promise for... (Review)
Review
Asherman syndrome (AS) has an adverse effect on reproductive health and fertility by affecting endometrial regeneration. Stem cell-based therapies hold promise for future use in activating non-functional endometrium and reconstructing the endometrium in vivo. It has been postulated that various endometrial stem cells (EnSCs) are responsible for endometrial regeneration. Numerous studies have focused on bone marrow-derived stem cells (BMDSCs), which may provide new ideas for repairing endometrial lesions and reconstructing the endometrium. Other sources of stem cells, such as menstrual blood, umbilical cord, and amniotic membrane, have also attracted much attention as candidates for transplantation in AS. This review discusses the features and specific biomarkers among four types of resident endometrial stem cells, applications of four different sources of exogenous stem cells in AS, and development of stem cell therapy using biomaterials and exosomes.
Topics: Female; Humans; Gynatresia; Stem Cell Transplantation
PubMed: 34105392
DOI: 10.1177/09636897211020734