Uterine Injury Research Articles

Bone marrow Mesenchymal Stem Cells improve Cyclophosphamide-Induced Ovarian and Uterine Injury in Adult Female Rats via T-Cell modulation

Bone marrow Mesenchymal Stem Cells improve Cyclophosphamide-Induced Ovarian and Uterine Injury in Adult Female Rats via T-Cell modulation

Dipeptidyl peptidase-4 inhibitor: Sitagliptin down-regulated toll-like receptor 4 signaling pathway to reduce uterine injury in rats.

Uterine ischemia is a common problem with ongoing controversy about its pathogenesis and prevention. The present study aimed to investigate the protective role of sitagliptin against uterine ischemia-reperfusion injury (IRI). Rats were allocated into 4 groups: control, sitagliptin (SIT) (5 mg/kg), IR; ischemia was induced followed by reperfusion, and IR+SIT; SIT was administered 1 hr before IRI. Uteri were removed for histopathological and biochemical observations. Malondialdehyde (MDA), total nitrites (NOx), reduced glutathione (GSH), superoxide dismutase (SOD) activity, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and toll-like receptor 4 (TLR4) were all measured. Hematoxylin and eosin (H&E) stain, Periodic acid-Schiff stain (PAS), and caspase-3 immunostaining were applied. In the IR+SIT group; NOx, GSH, and SOD activities increased significantly. Meanwhile, the levels of MDA, TNF-α, IL-6, TLR4, and caspase-3 immunoexpression showed a significant reduction, as compared with the IR group. In the IR+SIT group, an improvement in the histopathological picture was noticed. The results showed that sitagliptin confers protection against uterine IRI through anti-oxidant, anti-inflammatory, and anti-apoptotic effects with a possible role for TLR4.

A STUDY OF RUPTURE UTERUS CASES IN TERTIARY HOSPITAL OF CENTRAL INDIA

Background – Uterine rupture is a major cause of maternal and perinatal morbidity and mortality in developing countries. Uterine rupture can be prevented to some extent by understanding its etiology and early detection of high risk cases. Purpose- To assess the magnitude of uterine rupture, causes of uterine rupture, clinical presentation, site of uterine injury and its management. Material and Method – Total 80 women with uterine rupture were admitted during the year January 2016 to December 2020 were included in the study. Data was collected from the maternity records. Information regarding socio-demographic prole, clinical features, operative records, management, maternal and perinatal outcome was obtained. Results – Out of 49814 deliveries 80 cases were included in the study. Referred cases from rural areas were 92.5% and 68.75% women were unbooked. Mean age of women was 27 years. Multipara were 78.75% and grand multipara were 20%. Most prevalent gestation was between 35 – 40 weeks. Supercial fetal parts with vaginal bleeding or shock (53.75%) were most common presentation. Scarred uterus was the commonest cause of uterine rupture (42.5%), followed by obstructed labour (35%). Lower segment uterine rupture was most common site of uterine injury in scarred and unscarred uterus (77.5%). Uterine rent repair was done in 65%. Hysterectomy was performed in 25% cases; subtotal hysterectomy with bladder repair was in 8.75% cases. Conclusion – Women with no antenatal visit, scarred uterus and labour started at home, was having more chances of uterine rupture. Strengthening of peripheral health services will be helpful in reducing uterine rupture.

Evaluation of Chemokine (C–X–C motif) Ligand 12 (CXCL12) Function on Homing and Recovering of Stem Cell in Rats with Asherman Syndrome Uterine Injury

This study intends to discuss the action of CXCL12 on homing and recovering of stem cell in rats with Asherman Syndrome uterine injury. Forty SD rats were divided into blank group, AS group, CXCL12 group and group of CXCL12 and AMD3100 followed by analysis of the colocalization of cells derived from GFP-positive bone marrow by IF staining, the pathological form of uterus by Masson tricolor and Sirius red staining, as well as the pregnancy rate pregnant time and litter size along with evaluation of the condition of recovery of rats’ uterus. The positive rate of GFP, CD45 and CK in blank group was significantly lower than AS group without significant difference between AS group and AMD3100 group. However, it was significantly higher in CXCL12 group than AS group. There was no abnormal uterus tissue in blank group but notable fibrillation in AS group. The fibrosis level could be reduced in CXCL12 group and AMD3100 group. The pregnancy rate and litter size in blank group was higher than AS group and also higher in CXCL12 group than group of CXC12 with AMD3100. The pregnant time in blank group was less than AS group. The positive expression of GFP, CD45 and CK was upregulated by CXCL12 treatment. In conclusion, the homing and recovering of stem cell in rats with Asherman Syndrome uterine injury are improved and the pregnancy rate and litter size are elevated.

Umbilical Cord Mesenchymal Stem Cells Seeded on Small Intestinal Submucosa to Repair the Uterine Wall Injuries.

Objective: The effectiveness of tissue engineering materials combining porcine small intestine submucosa (SIS) and umbilical cord mesenchymal stem cells (UC-MSCs) on uterine injury in female rat after full-thickness uterine resection was evaluated as a basis for clinical treatment of postoperative uterine injury. Methods: After complex culture with SIS and UC-MSCs, cell adhesion, growth, and proliferation were assessed. Before the implantation, a surgical procedure of bilateral full-thickness uterine resection (0.5-2.0 cm long and 0.3 cm wide) was performed to obtain the rat uterine injury model, while the sham-operated rats were used as controls. Hematoxylin-eosin (H&E) staining results and fertility of female rats in each group were assessed to determine the critical resection length of the full-thickness uterine resection. Then SIS or UC-MSCs-SIS were implanted into the female rats from the uterine injury group, followed by assessments of H&E staining, the expression of ki67, α-SMA, and leukemia inhibitory factor (LIF), and fertility to determine the effectiveness of SIS and UC-MSCs-SIS on uterine injury in female rat. Results: At 24, 48, and 72 h, the cells grew progressively on the SIS material. In the 1.5 cm and 2.0 cm groups, the pregnancy rate, proportion of the uterus supporting live embryo growth, number of live embryos, and proportion of live embryos were all significantly less than those in the 0.5 cm and sham-operated groups. In the 2.0 cm group, there was little tissue regeneration at the center of the injury and not conducive to subsequent assessment. The UC-MSCs-SIS and SIS groups were better on morphological development, cell proliferation, LIF expression, and fertility than the control group. Conclusions: UC-MSCs show good adhesion, growth, and proliferation on the SIS scaffold material. The optimal resection length in full-thickness uterine resection on female rat is 1.5 cm. UC-MSCs-SIS is the effective treatment for repairing a injury after the full-thickness resection of the uterus in this research. Impact Statement The acquired severe uterus injury is a serious condition, which prone to uterine adhesions. Postoperative endometrial repairment and prevention of intrauterine adhesion recurrence are two major clinical challenges. Fortunately, the development of tissue engineering technology makes repairing a uterine injury possible. There are two main contributions from this study. First, due to ethical requirements, it is difficult to assess the repairing effect on uterus by invasive experiments in a clinical practice. Therefore, we constructed a full-thickness uterine injury rat model, which allows us to assess the repairing effect of treatments after severe uterine injuries in vivo. Second, it explored the effect of using a combination of and umbilical cord mesenchymal stem cells and small intestine submucosa materials on improving uterine repairments, providing a potential possibility for a future clinical practice.

Betulinic acid alleviates zearalenone-induced uterine injury in mice

Zearalenone (ZEA) is a mycotoxin with estrogen-like biological activity, which widely present in feed and raw materials, with strong reproductive system toxicity and a major threat to animal reproduction. Betulinic acid (BA) is a natural plant compound with antioxidant, anti-inflammatory and other pharmacological activities. However, the mechanism of ZEA-induced uterine injury and the protective effect of BA have not been reported. Our results show that ZEA could cause uterine histopathological damage and cellular ultrastructural damage, affecting the secretion of sex hormones, such as estradiol (E2) and progesterone (P4), and increase the mRNA and protein expression of estrogen receptor α (ERα). ZEA could inhibit the activities of catalase (CAT) and superoxide dismutase (SOD), increase the production of malondialdehyde (MDA) and reactive oxygen species (ROS), and cause uterine oxidative stress. Furthermore, ZEA affected the homeostasis of uterine cell proliferation and death by regulating the expression of proliferating cell nuclear antigen (PCNA) and activating the mitochondrial apoptotic pathway. ZEA-induced uterine injury might be related to the activation of p38/ERK MAPK signaling pathway. However, the regulatory effect of ZEA on the uterus was reversed after BA treatment. In conclusion, the uterus is an important target organ attacked by ZEA, and BA showed a good therapeutic effect.

Preserved oxytocin-induced myometrium contraction and sensitivity to progesterone inhibition following rat uterus thermal insult. Impact on fertility

Women seeking improved fertility often undergo diagnostic hysteroscopy that could cause uterine thermal injury with unclear impact on uterine contraction, embryo implantation and fertility. We tested whether uterine thermal insult adversely affects myometrium function and contraction related receptors, channels, junctional proteins and remodeling enzymes. Female Sprague-Dawley rats were anesthetized, the left uterine horn was infused with 85 ℃ hot saline (thermal Insult) and the right horn was infused with 25℃ warm saline (control) for 3 min. After 7-days recovery, uterine strips were prepared for tissue histology and measurement of contraction, and mRNA and protein levels of oxytocin receptor, progesterone (P4) receptor A (PR-A), membrane K+ channel TREK-1, junctional protein connexin-43 (CX-43) and matrix metalloproteinases MMP-2 and MMP-9. Uterine tissue histology showed cellular swelling and inflammatory cell infiltration immediately following thermal insult, and recovery with no difference from control 7-days later. KCl (96 mM) and oxytocin (10-13-10-7 M) caused significant contraction that was not different in thermal insult vs control uterine strips. Pretreatment with P4 (10-5 M) for 1 h caused marked inhibition of KCl and oxytocin contraction that was insignificantly greater in thermal vs control uterus. RT-PCR showed decreases in oxytocin receptor, PR-A, TREK-1, CX-43, MMP-2 and MMP-9 mRNA in thermal vs control uterus. Western blots showed decreases in oxytocin receptor, no change in TREK-1 and increased PRA, CX-43, MMP-2, and MMP-9 protein levels in thermal vs control uterus. To assess the impact on fertility, female rats were housed with male rats, and on gestational day 19, the litter size, pup weight and crown-rump length, and placenta weight were not different in thermal vs control uterus. Thus, after thermal insult-induced immediate inflammation and reduced heat-sensitive mRNA expression, the uterus undergoes a recovery and adaptation process involving preserved oxytocin-induced contraction, P4 inhibition and TREK-1 channels. The uterus self-healing process appears to require improved PR-A signaling, intercellular communication via CX-43 and tissue remodeling by MMP-2 and MMP-9. The uterine thermal recovery processes could be essential for maintaining fertility and future pregnancy outcome.

Icariin Alleviates Escherichia coli Lipopolysaccharide-Mediated Endometritis in Mice by Inhibiting Inflammation and Oxidative Stress.

Icariin (ICA) is a naturally occurring phytochemical agent primarily extracted from Epimedium Brevicornum Maxim (Family Berberidaceae) with a broad spectrum of bioactivities. Endometritis is a uterine disease that causes enormous losses in the dairy industry worldwide. In this study, anti-inflammatory and anti-oxidant properties of ICA were investigated against lipopolysaccharide (LPS)-induced endometritis in mice to investigate possible underlying molecular mechanisms. Sixty heathy female Kunming mice were randomly assigned to four groups (n = 15), namely control, LPS, LPS + ICA, and ICA groups. The endometritis was induced by intrauterine infusion of 50 µL of LPS (1 mg/mL). After 24 h of onset of LPS-induced endometritis, ICA groups were injected thrice by ICA intraperitoneally six hours apart. Histopathological examination, enzyme linked immunosorbent assay (ELISA), real time quantitative polymerase chain reaction (RT-qPCR), western blotting, and immunohistochemistry were used in this study. Histological alterations revealed that ICA markedly mitigated uterine tissue injury caused by LPS. The results showed that the ICA inhibited the production of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and boosted the production of anti-inflammatory cytokines (IL-10). Additionally, ICA modulated the expression of malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase 1 (SOD1), catalase (CAT), and glutathione peroxidase 1 (Gpx1) induced by LPS. The administration of ICA significantly (p < 0.05) improved the mRNA and protein expression of Toll-like receptor (TLR) 4. The western blotting and ELISA finding revealed that the ICA repressed LPS-triggered NF-κB pathway activation. Moreover, ICA improved the antioxidant defense system via activation of the Nrf2 pathway. The results revealed that ICA up-regulated the mRNA and protein expression of Nuclear erythroid-2-related factor (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and glutamate-cysteine ligase catalytic subunit (GCLC) under LPS exposure. Conclusively, our findings strongly suggested that ICA protects endometritis caused by LPS by suppressing TLR4-associated NF-κB and Nrf2 pathways. Altogether, these innovative findings may pave the way for future studies into the therapeutic application of ICA to protect humans and animals against endometritis.

Literature Review: Komplikasi Maternal dan Neonatal Akibat Persalinan Macet

Obstructed labor significantly occur in developing countries including Indonesia, contributing to maternal and neonatal health. The burden of obstructed labor and adverse fetomaternal outcomes appears to remain high and is a common challenge. One of them is caused by delays in making decisions regarding referral approval due to lack of information about complications that occur in maternal and neonatal. Therefore, identification of the outcomes of obstructed labor that occurs in maternal and neonatal is very important with the aim of knowing the maternal and neonatal complications resulting from obstructed labor. The method used is a literature study using an online database, namely Pubmed and Google Scholar based on inclusion criteria. The results of this study obtained 13 articles showing maternal complications due to obstructed labor, namely uterine rupture, postpartum hemorrhage, anemia, shock, sepsis, blood transfusion, hysterectomy, bladder rupture and injury, fistula, perineal and cervical lacerations, pelvic floor sequelae, musculoskeletal disorders, genitourinary, postpartum depression and death while fetal complications were sepsis, asphyxia, respiratory distress, meconium aspiration syndrome, seizures, jaundice, stillbirth, perinatal and neonatal death. Prevention of obstructed labor is carried out through a multidisciplinary approach aimed in the short term to identify high-risk cases since pregnancy. In the long term, improving education and better health from health workers for mothers and families related to maternal and neonatal complications due to evidence-based obstructed labor so as not to hesitate in making decisions regarding approval of referral actions so that cases of obstructed labor can be handled on time and do not cause dangerous complications. for mother and baby.

Resveratrol inhibits the inflammatory response and oxidative stress induced by uterine ischemia reperfusion injury by activating PI3K-AKT pathway.

Uterus transplantation is a complex surgical procedure. Uterine ischemia reperfusion (I/R) injury that occurs during this process may cause a loss of function of the uterus and the failure of transplantation. Resveratrol (RSV) is a naturally occurring polyphenol found abundantly in the skin of grapes and red wine, and it has also been used as a dietary supplement in clinical practice. RSV possesses strong anti-inflammatory and anti-oxidative effects, and exhibits a role in immune system regulation. However, the role of RSV in protecting the uterus against I/R-induced injury is yet to be fully elucidated. The aim of the present study was to investigate the effects and mechanisms underlying RSV in I/R-induced uterus injury. A total of 48 Sprague-Dawley rats were randomly divided into four groups: Control (sham operation) group, the uterus I/R group, the 20 mg/kg RSV-pre-treated I/R (I/R+RSV/20) group and the 40 mg/kg RSV-pre-treated I/R (I/R+ RSV/40) group. A regular I/R model was established to induce uterus injury in rats. RSV at 20 or 40 mg/kg was intraperitoneally administrated into rats in both I/R+ RSV groups once per day for five consecutive days prior to ischemia. The control and I/R only groups received an intraperitoneal injection of the vehicle (ethanol) for the same period prior to ischemia. Samples from blood and uterine horns were collected 3 h after reperfusion. Changes in the levels of malondialdehyde, interleukin (IL)-6, tumor necrosis factor-α, IL-10 and IL-37 were determined using ELISA, the activity levels of myeloperoxidase, catalase, and superoxidase dismutase were also determined using ELISA, the protein expression levels of PI3K, phosphorylated (p)-PI3K, AKT and p-AKT were determined using western blot analysis, and the uterine histology was investigated using H&E staining. Results of the present study demonstrated that treatment with RSV increased the capacity of antioxidants and suppressed uterine oxidative injury induced by I/R. Moreover, treatment with RSV decreased the levels of pro-inflammatory cytokines and increased the levels of anti-inflammatory cytokines. In addition, RSV promoted the phosphorylation of PI3K and AKT, thus activating the PI3K-AKT signaling pathway. Therefore, administration of RSV prior to uterine I/R effectively alleviated inflammatory response and oxidative stress via activation of the PI3K-AKT pathway, suggesting that RSV may play a protective role in I/R-induced uterus injury.

An injectable gelatin/sericin hydrogel loaded with human umbilical cord mesenchymal stem cells for the treatment of uterine injury.

Abnormal endometrial receptivity is a major cause of the failure of embryo transplantation, which may lead to infertility, adverse pregnancy, and neonatal outcomes. While hormonal treatment has dramatically improved the fertility outcomes in women with endometriosis, a substantial unmet need persists in the treatment. In this study, methacrylate gelatin (GelMA) and methacrylate sericin (SerMA) hydrogel with human umbilical cord mesenchymal stem cells (HUMSC) encapsulation was designed for facilitating endometrial regeneration and fertility restoration through in situ injection. The presented GelMA/10%SerMA hydrogel showed appropriate swelling ratio, good mechanical properties, and degradation stability. In vitro cell experiments showed that the prepared hydrogels had excellent biocompatibility and cell encapsulation ability of HUMSC. Further in vivo experiments demonstrated that GelMA/SerMA@HUMSC hydrogel could increase the thickness of endometrium and improve the endometrial interstitial fibrosis. Moreover, regenerated endometrial tissue was more receptive to transfer embryos. Summary, we believed that GelMA/SerMA@HUMSC hydrogel will hold tremendous promise to repair or regenerate damaged endometrium.

Comparing the Characteristics of Amniotic Membrane-, Endometrium-, and Urinary-Derived ECMs and Their Effects on Endometrial Regeneration in a Rat Uterine Injury Model

The decellularized extracellular matrices (d-ECMs) currently utilized to repair endometrial injuries are derived from three tissue sources, the endometrium (dE-ECM), placental amniotic membrane (dA-ECM), and urinary (dU-ECM). Notably, the structures of dU-ECM and dE-ECM are similar. These d-ECMs are derived from different tissues, and their specific roles in endometrial injury repair remain unclear. This study aimed to analyse the characteristics of the tissue microstructures and compositions to confirm specific differences among the three ECM types. And using a rat model of endometrial injury, the effects of all the matrices after implantation in vivo on the promotion of endometrial regeneration were analysed. After decellularization, dE-ECM had more residual active factors than the other two ECM types, while dA-ECM had significantly less DNA, α-Gal antigen components and extracellular matrix components than the other two groups. Although the three ECMs had no effect on the proliferation of stromal cells in vitro, dA-ECM may have increased the sensitivity of stromal cells to oestradiol (E2) responses. In vivo experiments confirmed the promotional effect of dA-ECM on endometrial regeneration. For example, the endometrial thickness, collagen deposition, endometrial tissue regeneration, vascular regeneration and pregnancy outcomes were significantly better in this group than in the other two groups. These findings might be associated with the excellent immune tolerance of dA-ECM. Therefore, when selecting a d-ECM for the treatment of endometrial injury, dE-ECM, which has the strongest tissue specificity, is not the preferred choice. Controlling the inflammatory responses in local lesions at the early stage may be a prerequisite for ECMs to exert their functions.

Cephalo-caudal V transverse expansion during caesarean section: Systematic review

Caesarean section is the most common surgical operation worldwide. Haemorrhage is the most common complication of this procedure. One of the methods to decrease blood loss is the blunt expansion of the caesarean incision whenever needed. The aim of this review is to compare the evidence for cephalo-caudal versus transverse expansion during caesarean section. Medline, Scopus, ClinicalTrials.Gov, EMBASE, the Cochrane Central Register of Controlled Trials, and Google Scholar database were searched for eligible clinical trials with no language restrictions. 6 clinical trials were included published between 2008 and 2019. There was a moderate risk of bias due to absence of allocation concealment in most of the trials. Cephalic-caudal expansion less associated with unintended incision extension (RR 0.62; 95%CI 0.45 - 0.86), less uterine artery injury (RR 0.55; 95%CI 0.41 - 0.73), less need for additional suture placement (RR 0.62; 95%CI 0.31 - 4.12) and less transfusion rates (RR 0.75; 95%CI 0.28 - 2.03). Thus, this review found that cephalic-caudal expansion is far safer than transverse expansion. Accordingly, this review supports the use of cephalic- caudal expansion whenever needed during caesarean section.

Uterus bioengineering as a future alternative to uterus transplantation

Objective: To review the current knowledge on uterus bioengineering and discuss potential future directives. Uterus bioengineering may solve two major hurdles in organ transplantation of a uterus, organ shortage and control of rejection by immunosuppression. Mechanism: Literature search using PubMed. Findings in brief: Sixty-seven references were summarized that describe the scientific progress made on uterus bioengineering, including other studies related to the topic. Most articles describe work on rat models, including proof-of-concept that uterus bioengineering can be used to restore fertility after a partial uterine injury. These promising results are currently being translated to larger and more clinically relevant animal models. In particular, uterus-specific scaffolds produced by a process called “decellularization” that were developed for the mouse, rat, rabbit, pig, goat, and sheep. These scaffolds stimulated angiogenesis and regeneration in vitro and in vivo, and successfully harbored various types of cells for an extended time in vitro. Additionally, applications for endometrial extracellular matrix-specific hydrogels derived from decellularized uterus tissue is discussed. Current challenges for uterus bioengineering are also addressed, e.g., the cellular reconstruction phase, and how they might be improved. Conclusions: Significant progress was made during the last decade with convincing evidence from multiple independent groups in experiments with small animal models. Initial steps towards large animal uterus bioengineering were made. The future continuation of such studies will provide important data required to translate these ideas to an experimental phase in the human. Partial uterus reconstruction through a bioengineered tissue transplantation is closer to a clinical reality compared to whole uterus bioengineering principles aimed to replace a donor in a UTx setting.

Genetically engineered FGF1-sericin hydrogel material treats intrauterine adhesion and restores fertility in rat.

Endometrial injury can cause intrauterine adhesions (IUA) and induce the formation of endometrial fibrosis, leading to infertility and miscarriage. At present, there is no effective treatment method for severe IUA and uterine basal injury with adhesion area larger than one-third of the uterus. In this study, we prepared FGF1 silk sericin hydrogel material (FGF1-SS hydrogel) to treat endometrial injury and prevent endometrial fibrosis. Compared with the silk sericin hydrogel material (WT-SS hydrogel), FGF1-SS hydrogel significantly promotes the cell migration and infiltration ability of endometrial stromal cells (ESCs). More importantly, FGF1-SS hydrogel can release FGF1 stably for a long time and inhibit the ESCs injury model forms fibrosis through the TGF-β/Smad pathway. In the IUA rat model, FGF1-SS hydrogel treatment effectively restored the number of uterine glands and uterine wall thickness in rats, with a fertility rate of 65.1% ± 6.4%. The results show that FGF1-SS hydrogel is expected to be a candidate to prevent IUA.

Intrauterine infusion of clinically graded human umbilical cord-derived mesenchymal stem cells for the treatment of poor healing after uterine injury: a phase I clinical trial

BackgroundIntrauterine adhesion and cesarean scar diverticulum are the main complications of poor healing after uterine injury. Human umbilical cord MSCs transplantation has been regarded as the most potential treatment in the clinic, the safety and efficacy of which in the clinic, however, remains unclear.MethodsIn this study, ten patients were enrolled: six with intrauterine adhesion and four with cesarean scar diverticulum. All the patients were injected with human umbilical cord MSCs twice into the uterus. Beside the chest X-ray, ECG and abdominal ultrasound, many laboratory tests including blood routine, liver and renal function, ovarian function, tumor biomarkers, and immune function were used to estimate the safe after stem cell transplanted. In addition, the efficacy of stem cell transplanted was shown by the endometrial thickness, the volume of the uterus, and cesarean scar diverticulum based on 3D ultrasound imaging.ResultsWe found that all results of these laboratory tests were normal in these enrolled patients before and after cell injection. Meanwhile, the results of the chest X-ray and ECG were also normal in the treatment process. The abdominal ultrasound showed that the size of the left and right kidneys was inconsistent in one patient after cell therapy, while those of other patients were normal. In addition, endometrial thickness, the volume of the uterus, and cesarean scar diverticulum showed an improving tendency, but no significant difference was noted.ConclusionIn summary, intrauterine injection of clinically graded human umbilical cord MSCs was safe for poor healing after uterus injury.Trial registration NCT03386708. Registered 27 December 2017, https://clinicaltrials.gov/ct2/show/NCT03386708?cond=CSD&cntry=CN&draw=2&rank=2

Kynurenic acid ameliorates lipopolysaccharide-induced endometritis by regulating the GRP35/NF-κB signaling pathway

Endometritis is a serious reproductive disease in mammals that commonly results in reproductive loss and even permanent infertility. Kynurenic acid (KYNA) is the main bioactive metabolite of tryptophan degradation and exhibits neuroprotective and anticonvulsant properties. However, little is known about the role of KYNA in achieving endometritis remission. This study investigated the protective effects and mechanisms of KYNA using a mouse model of against lipopolysaccharide (LPS)-induced endometritis. The endometritis model was induced by an intrauterine injection of LPS, and KYNA was intraperitoneally injected before and two hours after LPS treatment. Twenty-four hours after LPS administration, pathological changes in uterine tissues were observed by hematoxylin- and eosin (H&E) staining. The levels of the inflammatory factors, TNF-α and IL-1β, were measured by ELISA. The myeloperoxidase (MPO) activity in uterine tissues was detected using MPO kits and immunohistochemistry. Furthermore, the expression of signaling pathway proteins and tight junction proteins occludin and ZO-1 in uterine tissues was detected by western blot. KYNA prominently inhibited uterine pathological injury and neutrophil infiltration and restricted the secretion of TNF-α and IL-1β in the uteri of subjects with endometritis. Furthermore, KYNA upregulated the levels of the tight junction proteins (TJPs)occludin and ZO-1 in the uterus. In vitro, KYNA inhibited LPS-induced TNF-α and IL-1β production, and NF-κB activation in mouse endometrial epithelial cells (mEECs). In addition, KYNA increased the expression of G protein-coupled receptor 35 (GPR35) and inhibition of GPR35 reversed the anti-inflammatory effects of KYNA. In conclusion, KYNA protected against LPS-induced endometritis by maintaining epithelial barrier permeability and suppressing proinflammatory responses via the GRP35/NF-κB signaling pathway.

Reconstructable Uterus-Derived Materials for Uterus Recovery toward Efficient Live Births.

Uterine factor infertility is increasingly common in modern society and has severely affected human life and health. However, the existing biomaterial scaffold-mediated systems remain limited in efficient uterus recovery, leading to low pregnancy rate and live births. Here, reconstructable uterus-derived materials (RUMs) are demonstrated by combining uterus-derived extracellular matrix and seeded chorionic villi mesenchymal stem cells for uterus recovery, achieving highly efficient live births in rats with severe uterine injury. The RUMs can be designed into different states (such as, liquid RUMs and solid RUMs) and shapes (such as, cuboid, triangular-prism, and cube) in terms of requirements. The RUMs can effectively prevent intrauterine adhesion, and promote endometrial regeneration and muscle collagen reconstruction, as well as, accelerate wound healing by constructing a physical barrier and secreting cytokines, allowing efficient uterus recovery. The injured uterus nearly achieves complete recovery after treating with the RUMs and has normal pregnancies for supporting fetal development and live births, similar to the normal rats. The study provides a regenerative medicine therapeutics for uterine factor infertility.

Extraction of breviscapine from Erigeron breviscapus and its effect on oxidative stress, inflammation, energy metabolism disorder and apoptosis in rats with uterine ischemia-reperfusion injury

This work aimed to prepare breviscapine from Erigeron breviscapus and investigate its protection mechanism on uterine ischemia-reperfusion injury (UIRI) in rats. Breviscapine was extracted and separated from Erigeron breviscapus. Sixty female SD rats were randomly divided into sham-operated, model and breviscapine groups. The breviscapine group was treated with 5 mg/kg breviscapine for three days. Then, the UIRI model was established in model and breviscapine groups via uterine artery ischemia for 30 min followed by reperfusion for 60 min. At the end of reperfusion, compared with model group, in breviscapine group the uterine tissue superoxide dismutase activity was increased, and the malondialdehyde level was decreased; the uterine tissue tumor necrosis factor α, interleukin (IL)-1β and IL-6 levels were decreased, and the IL-10 level was increased; the uterine tissue adenosine triphosphate, adenosine diphosphate, adenosine monophosphate and total adenine nucleotides levels were increased; the uterine cell apoptosis rate was decreased, the Bcl-2 protein expression level was increased, and the Bax protein expression level was decreased. In conclusion, breviscapine from Erigeron breviscapus can reduce the oxidative stress, inflammatory reaction, energy metabolism disorder and apoptosis in uterine tissue, thus exerting the protective effect on UIRI in rats.

Uterine Tissue Engineering: Where We Stand and the Challenges Ahead.

Tissue engineering is an innovative approach to develop allogeneic tissues and organs. The uterus is a very sensitive and complex organ, which requires refined techniques to properly regenerate and even, to rebuild itself. Many therapies were developed in 20th century to solve reproductive issues related to uterus failure and, more recently, tissue engineering techniques provided a significant evolution in this issue. Herein we aim to provide a broad overview and highlights of the general concepts involved in bioengineering to reconstruct the uterus and its tissues, focusing on strategies for tissue repair, production of uterine scaffolds, biomaterials and reproductive animal models, highlighting the most recent and effective tissue engineering protocols in literature and their application in regenerative medicine. In addition, we provide a discussion about what was achieved in uterine tissue engineering, the main limitations, the challenges to overcome, and future perspectives in this research field. Impact Statement This review presents the applications of tissue engineering in uterine reconstruction and in regenerative therapies of uterine wall injuries.