Endometrial Stem Cells Research Articles

Application of autologous endometrial mesenchymal stromal/stem cells increases thin endometrium receptivity: a\xa0case report

BackgroundPregnancy in cycles with the use of assisted reproductive technologies is possible only with the availability of good-quality embryos and a healthy receptive endometrium. The problem of lack of sensitivity of the endometrium is related to the syndrome of thin endometrium, which is caused by a number of factors. However, there is no single protocol for the treatment of this syndrome, the return/improvement of normal functionality of endometrial tissue, and obtaining the desired pregnancy.Case presentationWe report a case of a 38-year-old Ukrainian woman with a number of unsuccessful tries at pregnancy in cycles with the use of assisted reproductive technologies. We describe a clinical case of the use of mesenchymal stem cells of the human endometrium for a woman with thin endometrial syndrome to increase its receptivity for pregnancy. The basic steps of patient management, protocol of sampling material for obtaining a cell product based on endometrial stem cells, their basic morphofunctional characteristics, and post-treatment procedures to obtain the desired pregnancy are described.ConclusionApplication of autologous endometrial mesenchymal stem cells increases endometrial receptivity and the chance for pregnancy with use of assisted reproductive technologies.

Proanthocyanidin as a crosslinking agent for fibrin, collagen hydrogels and their composites with decellularized Wharton’s-jelly-extract for tissue engineering applications

In tissue engineering, natural hydrogel scaffolds gained considerable attention due to their biocompatibility and similarity to macromolecular-based components in the body. However, their low mechanical strength and high degradation degree limit their biomedical application. By varying the composition of hydrogels, their biochemical and mechanical properties can be improved. In this study, the stability of fibrin and collagen hydrogels and their composites with decellularized Wharton’s jelly extract (DEWJ) was improved using proanthocyanidin (PA) as a cross-linker, extracted from grape seeds. The cytocompatibility, physicochemical and mechanical properties of the hydrogels were evaluated. Human endometrial stem cells (hEnSCs) were seeded on the hydrogels and their attachment, morphology, and proliferation were investigated using a scanning electron and optical microscopy. Our results showed that hydrogels containing DEWJ along with PA enhance cell proliferation and showed higher mechanical properties compared with the fibrin and collagen hydrogel. The results present the potential utility of these hydrogels in tissue engineering and for application in three-dimensional culture.

LONG-TERM ENGRAFTMENT AND SAFETY OF HUMAN BONE MARROW DERIVED CD133+ CELLS IN A RAT MODEL OF ASHERMAN’S SYNDROME

Asherman Syndrome (AS) is defined by presence of intrauterine adhesions, due to the loss of endometrial stem cells. CD133+ bone marrow-derived stem cells (BMDSCs) contribute to human endometrium regeneration and represent an advanced cell therapy to treat this disease. Our aim is to describe the short-term and long term engraftment as well as safety and Mechanisms of Action (MoA) of pure and stable population of human CD133+ cells in a model of AS with athymic rats.

Comparison of different sources of platelet-rich plasma as treatment option for infertility-causing endometrial pathologies

To study the effect of human plasma from different sources, namely, umbilical cord blood and adult blood platelet-rich plasma (PRP), on the regeneration of endometrial damage. Composition analysis, invitro approaches, and a preclinical murine model using plasma to promote endometrial regeneration. Hospital and university laboratories. Adult plasma from four Asherman syndrome/endometrial atrophy patients and one fertile woman, commercial umbilical cord plasma, and uterine-damaged NOD/SCID mice model were used. Endometrial stromal cells from primary culture and an endometrial stem cell line were cultured invitro, and uterine-damaged NOD/SCID mice were treated with plasma samples from several origins. To investigate the possible beneficial effects of PRP from Asherman syndrome/endometrial atrophy patients. To test if plasma from human umbilical cord blood had a stronger effect than adult PRP in endometrial regeneration. To demonstrate if PRP from Asherman syndrome/endometrial atrophy patients was as effective as PRP from a healthy woman and could therefore be used for autologous treatment. All plasma samples contained molecules with a high potential for regeneration (stem cell factor, platelet-derived growth factor BB, thrombospondin-1, von Willebrand factor). Furthermore, the highest increase in invitro proliferation and migration rate was found when endometrial stromal cells were treated with umbilical cord plasma; adult PRP also revealed a significant increment. In the mouse model, a higher expression of Ki67 and Hoxa10 in the endometrium was detected after applying adult PRP, and the proteomic analysis revealed a specific protein expression profile depending on the treatment. The damaged uterine tissue showed more proregenerative markers after applying umbilical cord plasma (Stat5a, Uba3, Thy1) compared with the other treatments (nonactivated umbilical cord plasma, activated adult PRP, and no treatment). Human PRP possesses regeneration properties usable for endometrial pathologies. Besides that, these regenerative effects seem to be more apparent when the source of obtaining is umbilical cord blood.

Biological characteristics of endometriotic mesenchymal stem cells isolated from ectopic lesions of patients with endometriosis

BackgroundResearch into the pathogenesis of endometriosis (EMs) would substantially promote its effective treatment and early diagnosis. However, the aetiology of EMs is poorly understood and controversial despite the progress in EMs research in the last several decades. Currently, accumulating evidence has shed light on the importance of endometrial stem cells (EnSCs) residing in the basal layer of endometrium in the establishment and progression of endometriotic lesions. Therefore, we aimed to identify the differences between EnSCs isolated from the ectopic lesions of EMs patients (EnSC-EM-EC) and EnSCs isolated from eutopic endometrium of control group (EnSC-Control). We further performed preliminary exploration of the potential signalling pathways involved in the above abnormalities.MethodsEnSC-EM-EC (n = 12) and EnSC-Control (n = 13) were successfully isolated. Then, the proliferative capacity, migratory capacity and angiogenic potential of EnSCs were evaluated by conventional MTT assay, flow cytometry, wound healing assay, transwell assay, tube formation assay and chick embryo chorioallantoic membrane assay respectively. The expression of 11 angiogenesis-associated biological factors and 11 cytokines secreted by EnSCs and 17 adhesion molecules expressed on EnSCs were determined by protein array assays respectively. Differentially expressed genes (DEGs) between EnSC-EM-EC and EnSC-Control were analysed by RNA-sequence.ResultsEnSC-EM-EC exhibited unique biological characteristics, including prolonged mitosis, enhanced migratory capacity and enhanced angiogenic potential. Greater amounts of angiogenic factors (especially VEGF and PDGF) were secreted by EnSC-EM-EC than by EnSC-Control; however, the distinct profiles of cytokines secreted by EnSC-EM-EC and adhesion molecules expressed by EnSC-EM-EC require further investigation. A total of 523 DEGs between EnSC-EM-EC and EnSC-Control were identified and analysed using the KEGG and Gene Ontology databases.ConclusionsOur results not only improve the understanding of EMs but also contribute to the development of EnSC-EM-EC as a tool for EMs drug discovery. These cells could be of great help in exploiting promising therapeutic targets and new biomarkers for EMs treatment and prognosis.

Impact of atorvastatin loaded exosome as an anti-glioblastoma carrier to induce apoptosis of U87 cancer cells in 3D culture model

Exosomes (EXOs) are naturally occurring nanosized lipid bilayers that can be efficiently used as a drug delivery system to carry small pharmaceutical, biological molecules and pass major biological barriers such as the blood-brain barrier. It was hypothesized that EXOs derived from human endometrial stem cells (hEnSCs-EXOs) can be utilized as a drug carrier to enhance tumor-targeting drugs, especially for those have low solubility and limited oral bioactivity. In this study, atorvastatin (Ato) loaded EXOs (AtoEXOs) was prepared and characterized for its physical and biological activities in tumor growth suppression of 3 D glioblastoma model. The AtoEXOs were obtained in different methods to maximize drug encapsulation efficacy. The characterization of AtoEXOs was performed for its size, stability, drug release, and in vitro anti-tumor efficacy evaluated comprising inhibition of proliferation, apoptosis induction of tumor cells. Expression of apoptotic genes by Real time PCR, Annexin V/PI, tunnel assay was studied after 72 h exposing U87 cells where encapsulated in matrigel in different concentrations of AtoEXOs (5, 10 μM). The results showed that the prepared AtoEXOs possessed diameter ranging from 30–150 nm, satisfying stability and sustainable Ato release rate. The AtoEXOs was up taken by U87 and generated significant apoptotic effects while this inhibited tumor growth of U87 cells. Altogether, produced AtoEXOs formulation due to its therapeutic efficacy has the potential to be an adaptable approach to treat glioblastoma brain tumors.

Pluripotent Stem (VSELs) and Progenitor (EnSCs) Cells Exist in Adult Mouse Uterus and Show Cyclic Changes Across Estrus Cycle.

We have earlier reported pluripotent, very small embryonic-like stem cells (VSELs) and slightly bigger endometrial stem cells (EnSCs) in adult mouse uterus and their regulation by gonadotropin and steroid hormones. VSELs can differentiate into cells of all three lineages in vitro; however, they neither expand readily in vitro nor compliment a developing embryo. In the present study, a robust protocol is described to enrich uterine stem/progenitor cells along with their characterization and variation across estrus cycle. After enzymatic digestion of adult mouse uterus, single-cell suspension obtained was spun at 1000rpm (250g) to pellet majority of cells. Stem cells remain buoyant at this speed and were pelleted by spinning supernatant at 3000rpm (1000g). Spherical, darkly stained VSELs (2-6μm) with high nucleo-cytoplasmic ratio and EnSCs (> 6μm) expressed OCT-4, NANOG, SSEA-1, SCA-1, and c-KIT. OCT-4-positive cells co-expressed SSEA-1, ERα, ERβ, PR, and FSHR. Transcripts specific for pluripotent state (Oct-4, Oct-4a, Sox-2, Nanog), primordial germ cells (Stella, Fragilis), and receptors for pituitary and steroid hormones (ERα, ERβ, PR, FSHR 1 and 3) were studiedby RT-PCR in 3000rpm pellet. Cell pellet collected at 3000rpm showed 10-fold enrichment of VSELs (2-6μm, viable cells with surface phenotype of LIN-CD45-SCA-1+) by flow cytometry and upregulation of pluripotent transcripts by qRT-PCR compared with 1000rpm pellet. VSELs were maximal during estrus and metestrus phases of estrus cycle. To conclude, VSELs/EnSCs can be enriched from adult uterus using the strategy described here, vary in numbers across estrus cycle, and are vulnerable to endocrine disruption as they express steroid receptors.

Small Molecule Differentiate PDX1-Expressing Cells Derived from Human Endometrial Stem Cells on PAN Electrospun Nanofibrous Scaffold: Applications for the Treatment of Diabetes in Rat.

In this study, we designed an engineered tissue and transplanted it to an animal model, trying to take an effective step toward meeting the needs of diabetic patients. Here, human endometrial cells were differentiated into PDX1-expressing cells using a small molecule of Y-27632 on polyacrylonitrile (PAN) electrospun scaffolds and transplanted into diabetic rats. PAN nanofibers were made by electrospinning. RT-PCR and immunocytochemical analysis were performed to express pancreatic precursor (PP) genes. The differentiated cells were then transplanted into the abdominal cavity of diabetic rats with Streptozotocin. In another group of rats, differentiated cells were injected through the tail. Blood glucose was measured 7, 14, and 28days after transplantation, and rat weight was also measured. The results showed that the expression of PP markers including Sox-17, Ngn3, Pdx1, and NKx2.2 genes was significantly increased in differentiated cells compared to the control group. In diabetic rats receiving differentiated cells, both transplanted and injected, glucose concentration as well as body weight improved compared to the control group. Rats receiving transplants in the peritoneum had a lower blood glucose concentration than those in the cell receiving group by injection, and the cell receiving group in the form of injections was more effective in increasing the body weight of rats than in the other groups. According to the results of the study, the transplantation of PP from endometrium using PAN scaffolding at the site of peritoneum could be recommended for the treatment of diabetes, although further studies are needed to provide a complete cure.

The Higher Inherent Therapeutic Potential of Biomaterial-Based hDPSCs and hEnSCs for Pancreas Diseases.

Human endometrial stem cells (hEnSCs), dental pulp stem cells (hDPSCs) and adipose tissue-derived stem cells (hADSCs) are considered to be the promising candidates for the treatment of pancreas diseases. The prognosis is better with in situ injection of mesenchymal stem cells (MSCs) to the damaged pancreas compared with intravenous injection. However, the clinical application of these cells are limited, due to poor engraftment of transplanted cells after delivery. On the other hand, understanding the role of the biomaterials in cell therapy is essential to promote the therapeutic effects of MSCs. Matrigel, a basement membrane matrix biomaterial, is rich in laminin and collagen IV. The aim of this study is to investigate the difference of biological characteristics of hEnSCs, hDPSCs and hADSCs in vitro and their survival situation with Matrigel post intrapancreatic transplantation in vivo. Our findings showed, firstly, there was no significant difference in morphology and immunophenotype of these MSCs. Secondly, the biological properties, including cell proliferation, the ability of adipogenic and osteogenic differentiation and the mRNA expression levels of pancreas development-related genes, have been showed distinct difference among these MSCs. Thirdly, Matrigel can improve the survival of MSCs in vivo, especially for Matrigel-based hDPSCs and Matrigel-based hEnSCs in pancreas parenchyma of SD rats. These results suggest that hDPSCs and hEnSCs are with the greater inherent therapeutic potential for pancreas diseases compared with hADSCs.

Tryptophanyl-tRNA Synthetase, a Novel Damage-Induced Cytokine, Significantly Increases the Therapeutic Effects of Endometrial Stem Cells

The major challenges of most adult stem cell-based therapies are their weak therapeutic effects caused by the loss of multilineage differentiation capacity and homing potential. Recently, many researchers have attempted to identify novel stimulating factors that can fundamentally increase the differentiation capacity and homing potential of various types of adult stem cells. Tryptophanyl-tRNA synthetase (WRS) is a highly conserved and ubiquitously expressed enzyme that catalyzes the first step of protein synthesis. In addition to this canonical function, we found for the first time that WRS is actively released from the site of injury in response to various damage signals both invitro and invivo and then acts as a potent nonenzymatic cytokine that promotes the self-renewal, migratory, and differentiation capacities of endometrial stem cells to facilitate the repair of damaged tissues. Furthermore, we also found that WRS, through its functional receptor cadherin-6 (CDH-6), activates major prosurvival signaling pathways, such as Akt and extracellular signal-regulated kinase (ERK)1/2 signaling. Our current study provides novel and unique insights into approaches that can significantly enhance the therapeutic effectsof human endometrial stem cells in various clinical applications.

Chitosan/gelatin hydrogel and endometrial stem cells with subsequent atorvastatin injection impact in regenerating spinal cord tissue

Central nervous system trauma can cause loss of functional sensory neurons and motor functions that results in death of neuronal cells and axon degeneration. For this purpose, therapeutic approaches to enhance repair mechanisms spinal cord injury (SCI) is reflected to be a difficult task that requires thoughtful strategy. Hydrogel scaffolds in the presence of stem cells could repair damaged SCI due to their ability to support cellular viability, motility, and differentiation. In this study, we investigated the effectiveness of a biomimetic composite hydrogel of chitosan and gelatin containing endometrial stem cells (EnSCs) as a minimally invasive treatment of SCI in an animal model. Moreover, the simultaneous, effect of intraperitoneal injection of atorvastatin drug was assessed for animal models. From the results, morphological and cell viability studies demonstrated favorable seeding microenvironment and viability in the hydrogel. The transplanted hydrogel containing EnSCs into hemisected SCI rats showed recovery of sensory and motor functions by confirming locomotor activity evaluation using Basso, Beattie, and Bresnahan test. The growth of neuronal cells confirmed with immunohistochemical study. The findings in this study suggested that combination therapy using biomimetic hydrogel seeded with stem cells as well as atorvastatin injection has the potential to heal SCI through neuroinflammation attenuation, improvement of functional recovery, and limit the secondary damages.

Repair of injured spinal cord using platelet-rich plasma- and endometrial stem cells-loaded chitosan scaffolds

Engineering scaffolds that can not only act as a vehicle for stem cell delivery but also support axon regeneration, may significantly improve the treatment outcome of spinal cord injury (SCI). In this study, we developed chitosan scaffold containing human endometrial stem cells (hEnSCs) and platelet-rich plasma (PRP) to provide a controlled environment for facilitating cell ingrowth and differentiation and also to persuade axon nervous tissue repair. The results showed that 80 µL PRP-loaded chitosan scaffold has excellent hEnSCs viability and can promote the regeneration of nerve fibers and angiogenesis and prevent the formation of scar tissue in the repair of SCI.

High porous electrospun poly(ε-caprolactone)/gelatin/MgO scaffolds preseeded with endometrial stem cells promote tissue regeneration in full-thickness skin wounds: An in vivo study.

In the current study, electrospun poly(ε-caprolactone)-gelatin (PCL-Gel) fibrous scaffolds containing magnesium oxide (MgO) particles and preseeded with human endometrial stem cells (hEnSCs) were developed to use as wound care material in skin tissue engineering applications. Electrospun fibers were fabricated using PCL-Gel (1:1 [wt/wt]) with different concentrations of MgO particles (1, 2, and 4 wt%). The fibrous scaffolds were evaluated regarding their microstructure, mechanical properties, surface wettability, and in vitro and in vivo performances. The full-thickness excisional wound model was used to evaluate the in vivo wound healing ability of the fabricated scaffolds. Our findings confirmed that the wounds covered with PCL-Gel fibrous scaffolds containing 2 wt% MgO and preseeded with hEnSCs have nearly 79% wound closure ability while sterile gauze showed 11% of wound size reduction. Our results can be employed for biomaterials aimed at the healing of full-thickness skin wounds.

Increased Migration Ability of Adenomyosis-Derived Endometrial Mesenchymal Stem Cells

Adenomyosis is a form of endometriosis—a gynecological disease associated with abnormal functional activity of endometrial cells. Endometrial stem cells can play a key role in the pathogenesis of this disease. Despite the numerous studies that have been conducted of cultures of endometrial mesenchymal stem cells (eMSCs) obtained from patients with adenomyosis, information on their phenotypic and functional properties is very contradictory. In this work, a comparative study of morphological and migratory characteristics of human endometrial mesenchymal stem cells isolated from the menstrual blood of healthy donors (eMSCs) and a donor with adenomyosis (eMSCs-A) was performed. eMSC migration was evaluated by the method of “wound healing” using live-cell microscopy. It was established that the rate of wound healing of eMSCs-A is significantly higher compared to normal cells, which indicates an increased migration potential of eMSCs-A in adenomyosis. However, when transferring cells to a serum-free medium, eMSC-A migrated more slowly than normal cells. As a result of the assessment of morphological characteristics, it was found that eMSCs-A are smaller (in area and perimeter) than normal eMSCs, while the remaining morphometric parameters reflecting cell polarization did not differ. The data obtained allow the use of eMSCs in culture as a model for elucidating the membrane and intracellular mechanisms that underlie changes in cellular mechanics, motility, and invasive activity in various pathologies, including adenomyosis.

Tryptophanyl-tRNA synthetase (WRS), a novel damage-induced cytokine, significantly increases the therapeutic effects of endometrial stem cells

Background & Aim Aminoacyl-tRNA synthetases (AARSs) are highly conserved and ubiquitously expressed enzymes that catalyze the first step of protein synthesis by covalently attaching amino acids to their corresponding tRNA to form an aminoacyl tRNA during mRNA translation in the nucleus. Importantly, in addition to their known canonical activities, several studies have recently shown that some AARS family members may have non-canonical cytokine-like functions under specific physiological conditions, such as apoptosis, cell proliferation, glucose homeostasis, and inflammatory response, and vascularization. More recently, particular attention has been focused on the non-canonical functions of the one of their family member tryptophanyl-tRNA synthetase (WRS) in inflammatory response as a cytokine, due to its rapidly secretion upon pathogen infection to activate host defense pathways. These observations have raised the possibility that in addition to its previous reported canonical functions, WRS may exert diverse biological activities as a novel secreted cytokine. Therefore, in the present study, we devoted our attention to the discovery of the previously unidentified cytokine functions of WRS that regulates multiple functions of human stem cells. However, its non-canonical functions and its underlying molecular mechanisms in stem cells still remain unknown. Methods, Results & Conclusion Indeed, we found for the first time that WRS is actively released from the site of injury in response to various damage signals both in vitro and in vivo and then acts as a potent non-enzymatic cytokine that facilitates the self-renewal, migratory, and differentiation capacities of endometrial stem cells to repair damaged tissues. Furthermore, we found that WRS, through its functional receptor cadherin-6 (CDH-6), is shown to activate major pro-survival signaling pathways, such as Akt and ERK1/2 signaling, which are implicated in diverse cellular functions, including, differentiation/pluripotency, recruitment, and self-renewal capacity of various stem cell types. Taken together, these results suggest that, in addition to its well-known canonical functions (catalyzing enzyme for protein synthesis), WRS is actively secreted in response to tissue injury and subsequently enhances the therapeutic effects of stem cells in vitro and in vivo as a novel non-enzymatic cytokine. tissue injury and subsequently enhances the therapeutic effects of stem cells in vitro and in vivo as a novel non-enzymatic cytokine.

The effect of female sex steroid hormones on osteogenic differentiation of endometrial stem cells.

Bone regeneration is a significant and crucial health issue worldwide. Tissue bioengineering has shown itself to be the best substitute for common clinical treatment of bone loss. The suitable cell source is human endometrial stem cells (hEnSCs) which have several suitable characteristics for this approach. Since sex steroid hormones are involved in expansion and conservation of the skeleton, the effect of two sex steroid hormones known as estrogen (17-β estradiol) and progesterone on osteogenic differentiation of hEnSCs were examined. For this purpose, hEnSCs were treated with 17-β estradiol and progesterone separately (1 × 10-6 M) and simultaneously (1 × 10-7 M). Osteogenic differentiation tests including measurement of total mineral calcium content, Alizarin Red staining, the quantitative expression levels of some osteogenic markers by Real-time RT-PCR, and immunofluorescence staining were performed at 7 and 14days of differentiation. To exhibit the morphology of the cells in osteogenic and culture medium, the hEnSCs were stained with Acridine Orange (AO) solution. In this research, MTT assay and AO staining revealed progesterone and 17-β estradiol increase the proliferation of hEnSCs in a dose-dependent manner. Furthermore, the results of calcium content analysis, Real-time RT-PCR assay, and all tests of differentiation staining have shown that 17-β estradiol and progesterone cannot induce hEnSCs' osteogenic differentiation. In conclusion, it is indicated that 17-β estradiol and progesterone do not have positive effects on hEnSCs' osteogenic differentiation in vitro.

Contribution of senescence in human endometrial stromal cells during proliferative phase to embryo receptivity†.

Successful assisted reproductive technology pregnancy depends on the viability of embryos and endometrial receptivity. However, the literature has neglected effects of the endometrial environment during the proliferative phase on implantation success or failure. Human endometrial stromal cells (hESCs) were isolated from endometrial tissues sampled at oocyte retrieval during the proliferative phase from women undergoing infertility treatment. Primary hESC cultures were used to investigate the relationship between stemness and senescence induction in this population and embryo receptivity. Patients were classified as receptive or non-receptive based on their pregnancy diagnosis after embryo transfer. Biomarkers of cellular senescence and somatic stem cells were compared between each sample. hESCs from non-receptive patients exhibited significantly higher (P < 0.01) proportions of senescent cells, mRNA expressions of CDKN2A and CDKN1A transcripts (P < 0.01), and expressions of genes encoding the senescence-associated secretory phenotype (P < 0.05). hESCs from receptive patients had significantly higher (P < 0.01) mRNA expressions of ABCG2 and ALDH1A1 transcripts. Our findings suggest that stemness is inversely associated with senescence induction in hESCs and, by extension, that implantation failure in infertility treatment may be attributable to a combination of senescence promotion and disruption of this maintenance function in this population during the proliferative phase of the menstrual cycle. This is a promising step towards potentially improving the embryo receptivity of endometrium. The specific mechanism by which implantation failure is prefigured by a loss of stemness among endometrial stem cells, and cellular senescence induction among hESCs, should be elucidated in detail in the future.

Adenosine‐5′‐triphosphate suppresses proliferation and migration capacity of human endometrial stem cells

Extracellular ATP through the activation of the P2X and P2Y purinergic receptors affects the migration, proliferation and differentiation of many types of cells, including stem cells. High plasticity, low immunogenicity and immunomodulation ability of mesenchymal stem cells derived from human endometrium (eMSCs) allow them to be considered a prominent tool for regenerative medicine. Here, we examined the role of ATP in the proliferation and migration of human eMSCs. Using a wound healing assay, we showed that ATP‐induced activation of purinergic receptors suppressed the migration ability of eMSCs. We found the expression of one of the ATP receptors, the P2X7 receptor in eMSCs. In spite of this, cell activation with specific P2X7 receptor agonist, BzATP did not significantly affect the cell migration. The allosteric P2X7 receptor inhibitor, AZ10606120 also did not prevent ATP‐induced inhibition of cell migration, confirming that inhibition occurs without P2X7 receptor involvement. Flow cytometry analysis showed that high concentrations of ATP did not have a cytotoxic effect on eMSCs. At the same time, ATP induced the cell cycle arrest, suppressed the proliferative and migration capacity of eMSCs and therefore could affect the regenerative potential of these cells.

Axin2+ endometrial stem cells: the source of endometrial regeneration and cancer

ABSTRACTMenstruation is one of the basic but poorly understood life processes in primates during which females shed inner uterine lining every month only to be completely regenerated back within a week. The definitive evidence for the existence and/or identity of stem cells responsible for this process has remained elusive for more than six decades now. Recently, we reported Axin2, a classical Wnt reporter gene, as a marker for endometrial stem cells that also serve as the cells of origin for endometrial cancer.

Endometrial Stem/Progenitor Cells

To summarize endometrial stem/progenitor cell biology and endometrial cancer stem cells. The subject is relatively new that only about 15 years ago, colony-forming units, as putative endometrial stem/progenitor cells, have been demonstrated in an endometrial sample. Earlier and some recent studies have justifiably focused on endometriosis as the serious gynecologic problem of women. However, on the side of endometrial stem cells research, many current studies are still working on in vitro methods, and the majority of the rest are on animal models. Reported cells as endometrial stem/progenitor cell populations have been heterogeneous such as endometrial mesenchymal stem cells, endometrial epithelial progenitor cells, and side population cells. After the recognition of putative endometrial stem cells, quite a few stem cell markers have been identified. Thereafter, cancer stem cell speculations have raised; in endometrial cancer, CD133+ and CXCR4+ cells, with potential cancer stem cell characteristics, have been shown to have higher antineoplastic resistance than that of other cell populations. Endometrial mesenchymal stem cells have plasticity characteristics and may differentiate into mature cells other than endometrium. On the other hand, bone marrow-derived stem cells can differentiate into endometrial cells. Since the endometrial stem/progenitor cells are easy to access, they can be an attractive source for regenerative medicine studies. Even though many markers have been identified for endometrial stem cells, more specific and sensitive marker combinations are yet to be defined for endometrial cancer stem cell in order to aim for more effective treatment approaches.