Identification of memory mechanism in tissue-resident stem cells via ANGPTL4 beyond immune cells upon viral antigen exposure.

Although memory functions of immune cells characterized by increased resistance to subsequent infections after initial pathogen exposure are well-established, it remains unclear whether non-immune cells, especially tissue-resident stem cells, exhibit similar memory mechanisms. The present study revealed that detrimental effects of initial viral antigen exposure (human papillomavirus [HPV]) on diverse stem cell functions were significantly exacerbated upon subsequent secondary exposure both in vitro and in vivo. Importantly, endometrial stem cells exhibited robust memory functions following consecutive HPV antigen exposures, whereas fully differentiated cells such as fibroblasts and vesicular cells did not show corresponding changes in response to the same antigen exposures. Deficiency of angiopoietin-like 4 (ANGPTL4) achieved through small hairpin RNA knockdown in vitro and knockout (KO) mice in vivo highlighted the critical role of ANGPTL4 in governing memory functions associated with various stem cell processes. This regulation occurred through histone H3 methylation alterations and PI3K/Akt signaling pathways in response to successive HPV antigen exposures. Furthermore, memory functions associated with various stem cell functions that were evident in wild-type mice following consecutive exposures to HPV antigen were not observed in ANGPTL4 KO mice. In summary, our findings strongly support the presence of memory mechanism in non-immune cells, particularly tissue-resident stem cells.

Unveiling the potential effects of acetylsalicylic acid: insights into regeneration in endometrial stem cells.

BACKGROUND: Although acetylsalicylic acid has been widely used for decades to treat and prevent various diseases, its potential effects on endometrial receptivity and subsequent pregnancy rates are still controversial due to conflicting data: many reports have shown positive effects of acetylsalicylic acid, whereas others have found that it has no effect. Furthermore, the direct effects of acetylsalicylic acid on various functions of normal endometrial cells, especially endometrial stem cells, and their underlying molecular mechanisms have not yet been proven. Recently, studies have revealed that a reduced number of active stem/progenitor cells within endometrial tissue limits cyclic endometrial regeneration and subsequently decreases pregnancy success rates, suggesting that endometrial stem cells play a critical role in endometrial regeneration and subsequent endometrial receptivity. METHODS: We assessed whether aspirin treatment can inhibit various endometrial stem cell functions related to regenerative capacity, such as self-renewal, migration, pluripotency/stemness, and differentiation capacity, in vitro. Next, we evaluated whether SERPINB2 regulates the effects of aspirin on endometrial stem cell functions by depleting SERPINB2 expression with specific shRNA targeting SERPINB2. To further investigate whether aspirin also inhibits various endometrial stem cell functions in vivo, aspirin was administered daily to mice through intraperitoneal (i.p.) injection for 7 days. RESULTS: In addition to its previously identified roles, to the best of our knowledge, we found for the first time that acetylsalicylic acid directly inhibits various human endometrial stem cell functions related to regenerative capacity (i.e., self-renewal, migration, differentiation, and capacity) through its novel target gene SERPINB2 in vitro. Acetylsalicylic acid exerts its function by suppressing well-known prosurvival pathways, such as Akt and/or ERK1/2 signaling, through a SERPINB2 signaling cascade. Moreover, we also found that acetylsalicylic acid markedly inhibits regenerative capacity-related functions in endometrial stem cells within tissue. CONCLUSIONS: We have found that acetylsalicylic acid has diverse effects on various endometrial stem cell functions related to regenerative capacity. Our findings are a critical step toward the development of more effective therapeutic strategies to increase the chances of successful pregnancy. Video Abstract.

The prediction of surgical intervention in patients with tubo-ovarian abscess.

The aim of this study was to compare the clinical characteristics of patients with tubo-ovarian abscess (TOA) who responded to medical treatment and those who underwent surgical intervention due to medical treatment failure. Electronic medical records were evaluated retrospectively to identify patients who were diagnosed with TOA. Demographic, clinical, and laboratory data including white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were compared between the medical treatment group and the surgical intervention group. Patient age, TOA diameter, WBC count, CRP, and ESR were significantly different between the groups. On multiple regression analysis, significant correlations were identified between age (p = .001), ESR (p = .045), and failure of medical treatment. TOA diameter (p = .065) showed a borderline association with surgical intervention. The risk of needing surgical intervention in TOA patients can be predicted using ESR in addition to age and TOA size as risk factors.IMPACT STATEMENTWhat is already known on this subject? For patients diagnosed with a tubo-ovarian abscess (TOA), the size of TOA and the patient's age are helpful for early identification of patients who are likely to need surgical treatment. Inflammatory markers such as C-reactive protein and white blood cell are also associated with the risk of surgical intervention.What do the results of this study add? Erythrocyte sedimentation rate (ESR) in addition to the size of TOA and the patient's age is a useful marker in determining whether to undergo surgery in patients with TOA.What are the implications of these findings for clinical practice and/or further research? ESR combined with the patient's age and the size of TOA is clinically useful in predicting the need for early surgical intervention in patients with TOA. Large prospective controlled studies are required to establish relationship between inflammatory markers and the risk of surgical intervention.

Gasless single-port access laparoscopy using a J-shaped retractor in patients undergoing adnexal surgery.

OBJECTIVE: The aim of this study was to compare gasless single-port access (SPA) laparoscopy using a J-shaped retractor and conventional SPA laparoscopy in patients undergoing adnexal surgery. Study design The medical records of 80 patients who underwent laparoscopic adnexal surgery between May 2017 and April 2019 were reviewed. Of the 80 patients, 40 patients underwent gasless SPA laparoscopy using a J-shaped retractor and 40 underwent conventional SPA laparoscopy. All surgeries were performed by one laparoscopic surgeon. Surgical outcomes were compared between the two groups. RESULTS: There are no significant differences in age, body mass index, parity, previous abdominal surgery, tumor marker, and tumor diameter between the gasless and conventional groups. The median retraction setup time from skin incision was 7 min (range 5-12 min) in gasless SPA laparoscopic adnexal surgery. The median total operation times were 55.5 min (range 30-155 min) in the gasless group and 55 min (range 30-165 min) in the conventional group without a significant difference. Additionally, there were no differences in operation type, conversion rate of laparotomy, use of an additional trocar, and pathological outcomes between the two groups. No major complications, such as urologic, bowel, and vessel injuries, were found in both groups. CONCLUSIONS: Gasless SPA laparoscopy using a J-shaped retractor appears to offer a better alternative to conventional SPA laparoscopy that avoids the potential negative effects of carbon dioxide gas in selected cases.

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 in vitro and in vivo 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 effects of human endometrial stem cells in various clinical applications.

Sonic Hedgehog, a Novel Endogenous Damage Signal, Activates Multiple Beneficial Functions of Human Endometrial Stem Cells.

Local endometrial stem cells play an important role in regulating endometrial thickness, which is an essential factor for successful embryo implantation and pregnancy outcomes. Importantly, defects in endometrial stem cell function can be responsible for thin endometrium and subsequent recurrent pregnancy losses. Therefore, many researchers have directed their efforts toward finding a novel stimulatory factor that can enhance the regenerative capacity of endometrial stem cells. Sonic hedgehog (SHH) is a morphogen that plays a key role in regulating pattern formation throughout embryonic limb development. In addition to this canonical function, we identified for the first time that SHH is actively secreted as a stem cell-activating factor in response to tissue injury and subsequently stimulates tissue regeneration by promoting various beneficial functions of endometrial stem cells. Our results also showed that SHH exerts stimulatory effects on endometrial stem cells via the FAK/ERK1/2 and/or phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways. More importantly, we also observed that endometrial stem cells stimulated with SHH showed markedly enhanced differentiation and migratory capacities and subsequent in vivo therapeutic effects in an endometrial ablation animal model.

Current use of the pelvic organ prolapse quantification system in clinical practice among Korean obstetrician-gynecologists.

BACKGROUND: To assess current use of the Pelvic Organ Prolapse Quantification (POP-Q) system in clinical practice among Korean obstetrician-gynecologists. METHODS: A web-based questionnaire was sent to 780 Korean Society of Obstetrics and Gynecology members. The items evaluated in the questionnaire were demographic characteristics and current use of the POP-Q system in the evaluation of pelvic organ prolapse (POP) and surgical decision-making. Differences between POP-Q users and nonusers were analyzed by using the two-sample t-test and chi-squared test. RESULTS: One hundred twenty-six members (16%) responded to the survey. Of the respondents, 48% reported using the POP-Q system in the evaluation of POP. Members who were female, urogynecologists, or performed a high volume of prolapse surgery were more likely to use the POP-Q system (p < 0.05). All but one of the POP-Q users reported using the specific criteria to determine whether each compartmental prolapse should be corrected during prolapse surgery. Most respondents used stage 2 or the hymen as a threshold for prolapse to be corrected for all compartments. CONCLUSIONS: Less than half of Korean obstetrician-gynecologists use the POP-Q system in the evaluation of POP. Almost all of POP-Q users make a surgical decision based on the results of the POP-Q examination.

An Endogenous Anti-aging Factor, Sonic Hedgehog, Suppresses Endometrial Stem Cell Aging through SERPINB2.

Endometrial stem cells are located in the basal layer of the endometrium, and they are responsible for the cyclic regeneration of the uterus during the menstrual cycle. Recent studies have revealed that recurrent pregnancy loss is associated with an age-related stem cell deficiency in the endometrium. Therefore, intensive study of endometrial stem cell aging may provide new insights for preventing recurrent pregnancy loss. Sonic hedgehog (SHH) signaling has been identified as a morphogen during the embryonic development processes. In addition to this canonical function, we found that the age-associated decline in regenerative potential in the endometrium may be due to decreased SHH-signaling integrity in local stem cells with aging. Importantly, the current study also showed that SHH activity clearly declines with aging both in vitro and in vivo, and exogenous SHH treatment significantly alleviates various aging-associated declines in multiple endometrial stem cell functions, suggesting that SHH may act as an endogenous anti-aging factor in human endometrial stem cells. Moreover, we found that stem cell senescence may enhance SERPINB2 expression, which in turn mediates the effect of SHH on alleviating senescence-induced endometrial stem cell dysfunctions, suggesting that SERPINB2 is a master regulator of SHH signaling during the aging process.

Robotic Radical Hysterectomy Is Not Superior to Laparoscopic Radical Hysterectomy in Perioperative Urologic Complications: A Meta-Analysis of 23 Studies.

OBJECTIVE: This study aimed to compare the risks of intraoperative and postoperative urologic complications after robotic radical hysterectomy (RRH) compared with laparoscopic radical hysterectomy (LRH). DATA SOURCES: We searched Pubmed, EMBASE, and the Cochrane Library for studies published up to March 2019. Related articles and relevant bibliographies of published studies were also checked. METHODS OF STUDY SELECTION: Two researchers independently performed data extraction. We selected comparative studies that reported perioperative urologic complications. TABULATION, INTEGRATION, AND RESULTS: Twenty-three eligible clinical trials were included in this analysis. When all studies were pooled, the odds ratio for the risk of any urologic complication after RRH compared with LRH was .91 (95% confidence interval [CI], .64-1.28; p = .585). The odds ratios for intraoperative and postoperative complications after RRH versus LRH were .86 (95% CI, .48-1.55; p = .637) and .94 (95% CI, .64-1.38; p = .767), respectively. In a secondary analysis study quality, study location, and the publication year were not associated with intraoperative or postoperative urologic complications. CONCLUSION: Current evidence suggests that RRH is not superior to LRH in terms of perioperative urologic complications.

Development of a novel testis-on-a-chip that demonstrates reciprocal crosstalk between Sertoli and Leydig cells in testicular tissue.

The reciprocal crosstalk between testicular Sertoli and Leydig cells plays a vital role in supporting germ cell development and maintaining testicular characteristics and spermatogenesis. Conventional 2D and the recent 3D assay systems fail to accurately replicate the dynamic interactions between these essential endocrine cells. Furthermore, most in vitro testicular tissue models lack the ability to capture the complex multicellular nature of the testis. To address these limitations, we developed a 3D multicellular testis-on-a-chip platform that effectively demonstrates the reciprocal crosstalk between Sertoli cells and the adjacent Leydig cells while incorporating various human testicular tissue constituent cells and various natural polymers infused with blood coagulation factors. Additionally, we identified SERPINB2 as a biomarker of male reproductive toxicity that is activated in both Sertoli and Leydig cells upon exposure to various toxicants. Leveraging this finding, we designed a fluorescent reporter-conjugated toxic biomarker detection system that enables both an intuitive and quantitative assessment of material toxicity by measuring the converted fluorescence intensity. By integrating this fluorescent reporter system into the Sertoli and Leydig cells within our 3D multicellular chip platform, we successfully developed a testis-on-chip model that can be utilized to evaluate the male reproductive toxicity of potential drug candidates. This innovative approach holds promise for advancing toxicity screening and reproductive research.

Exploring Memory Function Beyond Immune Cells: ANGPTL4-Mediated Memory Functions in Tissue Resident Stem Cells.

Adapted immune cells are known to develop memory functions that increase resistance to subsequent infections after initial pathogen exposure, however, it is unclear whether non-immune cells, like tissue-resident stem cells, have similar memory functions. Here, it is found that tissue-resident stem cells crucial for tissue regeneration show diminished adverse effects on diverse stem cell functions against successive exposure to foreign antigen (ß-glucan) to maintain tissue homeostasis and stability both in vitro and in vivo. These data suggest that endometrial stem cells may possess a robust memory function, in contrast, fully differentiated cells like fibroblasts and vesicular cells do not show these memory mechanisms upon consecutive antigen exposure. Moreover, the pivotal role of Angiopoietin-like 4 (ANGPTL4) in regulating the memory functions of endometrial stem cells is identified through specific shRNA knockdown in vitro and knockout mice in vivo experiments. ANGPTL4 is associated with the alteration of diverse stem cell functions and epigenetic modifications, notably through histone H3 methylation changes and two pathways (i.e., PI3K/Akt and FAK/ERK1/2 signaling) upon consecutive antigen exposure. These findings imply the existence of inherent self-defense mechanisms through which local stem cells can adapt and protect themselves from recurrent antigenic challenges, ultimately mitigating adverse consequences.

A microscale 3D organ on a chip for recapitulating reciprocal neuroendocrine crosstalk between the hypothalamus and the pituitary gland.

Conventional 2D or even recently developed 3Din vitroculture models for hypothalamus and pituitary gland cannot successfully recapitulate reciprocal neuroendocrine communications between these two pivotal neuroendocrine tissues known to play an essential role in controlling the body's endocrine system, survival, and reproduction. In addition, most currentvitroculture models for neuroendocrine tissues fail to properly reflect their complex multicellular structure. In this context, we developed a novel microscale chip platform, termed the 'hypothalamic-pituitary (HP) axis-on-a-chip,' which integrates various cellular components of the hypothalamus and pituitary gland with biomaterials such as collagen and hyaluronic acid. We used non-toxic blood coagulation factors (fibrinogen and thrombin) as natural cross-linking agents to increase the mechanical strength of biomaterials without showing residual toxicity to overcome drawbacks of conventional chemical cross-linking agents. Furthermore, we identified and verified SERPINB2 as a reliable neuroendocrine toxic marker, with its expression significantly increased in both hypothalamus and pituitary gland cells following exposure to various types of toxins. Next, we introduced SERPINB2-fluorescence reporter system into loaded hypothalamic cells and pituitary gland cells within each chamber of the HP axis on a chip, respectively. By incorporating this SERPINB2 detection system into the loaded hypothalamic and pituitary gland cells within our chip platform, Our HP axis-on-chip platform can better mimic reciprocal neuroendocrine crosstalk between the hypothalamus and the pituitary gland in the brain microenvironments with improved efficiency in evaluating neuroendocrine toxicities of certain drug candidates.

Development of cell-laden multimodular Lego-like customizable endometrial tissue assembly for successful tissue regeneration.

BACKGROUND: The endometrium, the inner lining of the uterine cavity, plays essential roles in embryo implantation and its subsequent development. Although some positive results were preliminarily archived, the regeneration of damaged endometrial tissues by administrating stem cells only is very challenging due to the lack of specific microenvironments and their low attachment rates at the sites of injury. In this context, various biomaterial-based scaffolds have been used to overcome these limitations by providing simple structural support for cell attachment. However, these scaffold-based strategies also cannot properly reflect patient tissue-specific structural complexity and thus show only limited therapeutic effects. METHOD: Therefore, in the present study, we developed a customizable Lego-like multimodular endometrial tissue architecture by assembling individually fabricated tissue blocks. RESULTS: Each tissue block was fabricated by incorporating biodegradable biomaterials and certain endometrial constituent cells. Each small tissue block was effectively fabricated by integrating conventional mold casting and 3D printing techniques. The fabricated individual tissue blocks were properly assembled into a larger customized tissue architecture. This structure not only properly mimics the patient-specific multicellular microenvironment of the endometrial tissue but also properly responds to key reproductive hormones in a manner similar to the physiological functions. CONCLUSION: This customizable modular tissue assembly allows easy and scalable configuration of a complex patient-specific tissue microenvironment, thus accelerating various tissue regeneration procedures.

Dysadherin expression promotes the motility and survival of human breast cancer cells by AKT activation.

High dysadherin expression has been recognized as a biological predictor of metastasis and poor prognosis for many different cancer types; however, the molecular mechanisms of how dysadherin affects cancer progression are still poorly understood. In this study, we examined whether AKT signaling could link dysadherin expression with downstream events that promote the metastatic potential of human breast cancer cells. Immunohistochemical analysis of breast cancer tissues showed that dysadherin expression was highly associated with elevated expression of phospho-AKT. The introduction of dysadherin cDNA into BT-474, MCF-7 and T-47D breast cancer cell lines enhanced their levels of AKT phosphorylation, while knockdown of dysadherin in MDA-MB-231 and Hs578T breast cancer cell lines suppressed AKT phosphorylation. Treatment with the AKT inhibitor triciribine suppressed dysadherin-mediated pro-metastatic effects, including epithelial-mesenchymal transition, cell motility and drug resistance. These findings suggest that dysadherin might contribute to breast cancer progression through AKT activation.

Inhibition of Wnt1 expression reduces the enrichment of cancer stem cells in a mouse model of breast cancer.

Breast cancer is the leading cause of deaths from cancer in women. Cancer recurrence is the most common cause of mortality in breast cancer patients. The cancer stem cell (CSC) hypothesis proposes that CSCs are the center of cancer development and recurrence. Targeting CSCs, in combination with standard chemotherapy, may prevent cancer recurrence and improve long-term survival. Stem cells can be enriched in non-adherent sphere cultures. To identify molecular targets in breast CSCs, we evaluated the transcription levels of stem cell-related genes in 4T1 mouse mammary cancer cells grown as spheres or in a monolayer culture. The most differentially expressed gene was found to be wingless-type MMTV integration site family member 1 (Wnt1) in the 4T1 sphere culture. Functionally, knockdown of Wnt1 in breast cancer cell lines suppressed the in vitro properties of the stem-like cells, including their sphere-forming ability and ALDH activity, whereas the addition of recombinant Wnt1 to breast cancer cell lines enhanced the in vitro properties of these stem-like cells. In addition, knockdown of Wnt1 in 4T1 cells affected the properties of the stem-like cells in vivo, including their tumorigenic potential and tumor initiation ability. Collectively, these results suggest that Wnt1 expression may give rise to the properties of CSCs in breast tumors. Therefore, targeting Wnt1-associated signaling proteins may provide an effective therapeutic approach for the treatment of advanced breast cancer.

STROBE: The relationship between asthma and early menarche in Korean adolescents.

ABSTRACT: We explored the relationship between asthma and early menarche in a representative sample of Korean adolescents.Web-based self-reported data collected from 2006 to 2015 by the Korean Youth Risk Behavior Web-based Survey were used. Menarche status was divided into "early" (<12 years of age, n = 69,520) and "not early" (≥12 years of age, n = 234,065).Adolescent girls with early menarche exhibited a higher incidence of asthma (8.1% vs 7.4%, P < .001), more frequent school absences because of asthma (10.8% vs 8.7%), and more frequent ≤4-day stretches of school absence (4.6% vs 2.4%) compared with girls with "not early" menarche (all P < .001). Multivariate analysis performed after adjusting for multiple confounders revealed a 1.04-fold (95% confidence interval [CI] 1.00-1.07) greater likelihood of asthma in the early menarche than not early menarche group. In addition, the odds ratios for missing school due to asthma for 1 to 3 and ≥4 days per year in the early menarche group were 1.00 (95% CI 1.00-1.02) and 1.21 (95% CI 1.01-1.46), respectively.Adolescents with early menarche exhibited increased incidences of asthma and severe asthma.

Current techniques used to perform surgery for anterior and posterior vaginal wall prolapse in South Korea.

OBJECTIVE: This study aimed to evaluate the current surgical techniques for anterior and posterior vaginal wall prolapse repair in South Korea. METHODS: A web-based questionnaire survey was sent to 780 members of the Korean Society of Obstetrics and Gynecology. The items assessed in the questionnaire were the demographic characteristics and current surgical techniques used for the correction of anterior and posterior vaginal wall prolapse. RESULTS: The response rate was 16%. There were variations in the suture materials and methods used for anterior and posterior colporrhaphy. Most respondents used only rapid absorbable suture materials to plicate the fibromuscular layer and close the mucosal layer of the anterior and posterior vaginal wall. Simple interrupted sutures are the most popular suture method for both the fibromuscular and mucosal layers. Thirty-one and eleven percent of the respondents used mesh for surgical correction of anterior and posterior vaginal wall prolapse, respectively. Concomitant perineorrhaphy was routinely performed with posterior vaginal wall repair by 42% of the respondents, whereas 58% performed perineorrhaphy only in cases with perineal defects. CONCLUSION: There is considerable diversity in the current surgical techniques for anterior and posterior vaginal wall prolapse repair in Korea. Further research is required to standardize the surgical techniques.

A novel role of follicle-stimulating hormone (FSH) in various regeneration-related functions of endometrial stem cells.

Follicle-stimulating hormone (FSH) promotes the production and secretion of estrogen, which in turn stimulates the growth and maturation of ovarian follicles. Therefore, consecutive FSH treatment to induce ovarian hyperstimulation (superovulation) is still considered the most cost-effective option for the majority of assisted reproductive technologies (ARTs). However, a relatively high cancellation rate and subsequent low pregnancy outcomes (approximately 15%) are the most challenging aspects of this FSH-based ART. Currently, the main cause for this low implantation rate of FSH-based ART has not yet been revealed. Therefore, we hypothesized that these high cancellation rates with FSH-based superovulation protocols might be associated with the harmful effects of consecutive FSH treatment. Importantly, several recent studies have revealed that tissue-resident stem cell deficiency can significantly reduce cyclic endometrial regeneration and subsequently decrease the pregnancy outcome. In this context, we investigated whether FSH treatment could directly inhibit endometrial stem cell functions and consequently suppress endometrial regeneration. Consistent with our hypothesis, our results revealed for the first time that FSH could inhibit various regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, and multilineage differentiation capacities, via the PI3K/Akt and ERK1/2 signaling pathways both in vitro and in vivo.

Novel roles of luteinizing hormone (LH) in tissue regeneration-associated functions in endometrial stem cells.

Luteinizing hormone (LH) stimulates the synthesis and secretion of the key steroid hormone estrogen, which subsequently promotes ovarian follicular growth and development. Therefore, the administration of exogenous LH to achieve superovulation (multiple ovulations) and an LH surge is commonly used as the most effective therapeutic option in a majority of in vitro fertilization (IVF) clinics. However, a relatively low pregnancy rate (between 20% and 35%) is one of the most challenging aspects of LH-based infertility treatment. Furthermore, the major cause of this low pregnancy rate in LH-based infertility treatment remains unidentified. Recent studies have shown that endometrial stem cell loss or deficiency can significantly decrease tissue regeneration ability during the menstrual cycle and reduce endometrial receptivity. In this context, we postulated that the low pregnancy rates following LH-based ovarian hyperactivation may be the result of the adverse effects of consecutive exogenous LH administration on endometrial stem cells. To the best of our knowledge, this study revealed for the first time that in addition to its previously reported roles in stimulating ovarian functions through the pituitary-gonadal axis, LH brings about the extragonadal suppression of various tissue regeneration-associated functions in endometrial stem cells, such as self-renewal, migration ability, multilineage differentiation potential, and pluripotency/stemness, by inhibiting pro-survival Akt and ERK1/2 signaling pathways in vitro and in vivo, and as a consequence, it decreases the endometrial receptivity.

Effects of smoking on the tissue regeneration-associated functions of human endometrial stem cells via a novel target gene SERPINB2.

BACKGROUND: Smokers directly inhale mainstream cigarette smoke, which contains numerous known and potential toxic substances, and thus, smoking is expected to have broad harmful effects that cause tissue injury and dysfunction. Interestingly, many studies have suggested that the recent decline in female fertility and increased rate of spontaneous abortion could be associated with increased smoking rates. Indeed, women that smoked for 10 years or more were reported to have a ~ 20% higher infertility rate than women that had never smoked. However, the reasons for the underlying harmful aspects of smoking on female fertility remain a matter of debate. Importantly, a previous study revealed that resident endometrial stem cell deficiency significantly limits the cyclic regeneration potential of endometrium, which, in turn, decreases successful pregnancy outcomes. In this context, we postulated that exposure to mainstream cigarette smoke extracts might decrease female fertility by inhibiting the functions of resident endometrial stem cells. METHODS: We investigated whether cigarette mainstream smoke exposure directly inhibits various tissue regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, pluripotency, and differentiation capacity in vitro. Next, we determined whether SERPINB2 mediates cigarette smoke-induced suppressive effects on various tissue regeneration-associated functions by depleting SERPINB2 expression with specific shRNA targeting SERPINB2. Mice were injected intraperitoneally with low (0.5 mg/kg) or high (1 mg/kg) doses of cigarette smoke extract (10 times for two weeks), and endometrial stem cells were then isolated from mice uterine tissues. RESULTS: We found that exposure to cigarette smoke extracts remarkably suppressed various tissue regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, multilineage differentiation ability, and pluripotency in vitro and in vivo by activating the SERPINB2 gene. Indeed, cigarette smoke-induced inhibitory effects on various endometrial stem cell functions were significantly abolished by SERPINB2 knockdown. CONCLUSIONS: These findings provide valuable information on the harmful effects of cigarette smoking on resident endometrial stem cells and hopefully will facilitate the developments of promising therapeutic strategies for subfertile or infertile women that smoke cigarettes.