Acta Biomaterialia
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2022
·
IF 10.633
Nanfang Nie,Lin Gong,Deming Jiang,Yanshan Liu,Jingwei Zhang,Jiaqi Xu,Xudong Yao,Bingbing Wu,Yu Li,Xiaohui Zou
Severe damage to the uterine endometrium , which results in scar formation and endometrial dysfunction, eventually leads to infertility or pregnancy-related complications. No effective therapeutic treatment is currently available for such injuries owing to the structural complexity, internal environment, and function of the uterus. Three-dimensional (3D) bio-printing to engineer biomimetic structural constructs provides a unique opportunity for tissue regeneration . Herein, using 3D extrusion-based bioprinting (EBB), we constructed a bilayer endometrial construct (EC) based on a sodium alginate-hyaluronic acid (Alg-HA) hydrogel for functional regeneration of the endometrium. The upper layer of the 3D bio-printed EC is a monolayer of endometrial epithelial cells (EECs), while the lower layer has a grid-like microstructure loaded with endometrial stromal cells (ESCs). In a partial full-thickness uterine excision rat model, our bilayer EC not only restored the morphology and structure of the endometrial wall (including organized luminal/ glandular epithelium, stroma, vasculature and the smooth muscle layer), but also significantly improved the reproductive outcome in the surgical area after implantation (75%, 12/16, p < 0.01). Therefore, repair of the uterine endometrium using the developed 3D bio-printed bilayer EC may represent an effective regenerative treatment for severe endometrial injury. Statement of significance Achieving structural and functional recovery of the endometrium following severe injury is still a challenge. Here, we designed a 3D bio-printed endometrial construct (EC) to mimic the native bilayer structure and cellular components of the endometrium. The bio-printed EC consists of a dense upper layer with endometrial epithelial cells and a lower layer with endometrial stromal cells. In particular, the 3D bio-printed EC significantly improved the reproductive outcome in the surgical area (75%, 12/16) compared to that of the cell-loaded non-printed group (12.5%, 2/16). This study demonstrates that a biomimetic bilayer construct can facilitate endometrial repair and regeneration. Therefore, an endometrial cells-loaded 3D-bioprinted EC is a promising therapeutic option for patients suffering from severe endometrial damage.
研究领域:
组织工程
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生殖医学
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生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
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2020
·Vol. 106
·期 2
·526-538
·
IF 5.399
Wu Ying-Ting,Ma Si-Yu,Sun Wen-Qin,Shen Wei-Wei,Zhu Hui-Ting,Zhang Qin,Chen Hui-Fen
BackgroundEndometriosis (EM) is a benign gynecological disease that shares some characteristics with malignancy, such as proliferation and invasion. So far, the pathogenesis of EM is still unclear. In this study, we investigated whether TRIM65 can play a role in the development of EM.MethodsTRIM65 expression levels in eutopic, ectopic, and normal endometrium were detected by quantitative real-time PCR and Western blot. Cell proliferation and invasion of primary endometrial stromal (EMS) cells were detected by CCK-8 and Transwell analysis. The interaction between TRIM65 and DUSP6 or C-myc was measured by coimmunoprecipitation, ubiquitylation, dual luciferase, and chromatin immunoprecipitation analysis.ResultsWe found that TRIM65 was identified as an up-regulated gene in ectopic endometrial tissues and EMS cells compared with control groups without EM. TRIM65 expression was positively correlated with the levels of p-ERK1/2, C-myc, matrix metalloproteinase-2, and integrin β1 in ectopic endometrial tissues in patients and mice. TRIM65 promoted the cell proliferation and invasion of EMS cells via the ERK1/2/C-myc pathway through ubiquitination of DUSP6. C-myc promoted TRIM65 expression through inducing TRIM65 promoter activity. Additionally, the increased expression of TRIM65, C-myc, matrix metalloproteinase-2, integrin β1, and p-ERK1/2 and the decreased expression of DUSP6 in ectopic endometrial tissues were significantly suppressed by inhibition of ERK1/2 signaling pathway in ectopic endometrial tissues in experimental mice model.ConclusionIn conclusion, TRIM65 promotes invasion of ectopic EMS cells by activating a feedback loop with the ERK1/2/C-myc signaling pathway and may be a potential therapeutic target for EM.
研究领域:
妇科学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2025
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IF 4.7
Linfang Wu,Jing Wang,Yonghuan Yan,Lu Wang,Qi Huang,Jinyong Peng,Lili Li
Endometritis is a prevalent condition of the reproductive system that leads to significant tissue damage in the uterus, thereby seriously impacting the health and quality of life of these patients. Hesperidin (HES), a natural flavonoid glycoside, displays various biological activities. Nonetheless, the protective effect of HES treatment against endometritis remains uncertain. In this study, we examined the protective effects of HES on endometritis induced by lipopolysaccharide (LPS) both in vivo and in vitro . In vitro experimental results showed that HES reduced the levels of inflammatory factors, improved mitochondrial morphology, increased mitochondrial activity and inhibited ROS levels; moreover, it activated the AMPK/PGC-1 α signalling pathway in LPS-induced human endometrial endothelial cells (HEECs). AMPK served as a potential target of HES, which was further validated using molecular docking, molecular dynamic simulation, CETSA and SPR. Moreover, in vivo experimental results indicated that HES significantly mitigated the histopathological alterations in the uterus caused by LPS, as well as reduced the levels of inflammatory factors, MPO activity, the expression levels of CD38, and CD138 and activated the AMPK/PGC-1α signalling pathway. Overall, HES mitigated mitochondrial oxidative stress and inflammatory response primarily through activation of the AMPK/PGC-1α signalling pathway, thereby exerting protective effects against endometritis.
研究领域:
药理学
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免疫学
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细胞生物学
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分子生物学
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妇产科学
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产品关联
DOI
PubMed
高影响因子
Bioengineered
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2021
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IF 3.269
Xinyue Zhou,Zhenyu Chen,Lipeng Pei,Jingli Sun
Emerging evidence has exhibited an obvious decreased expression of miR-106a-5p in the ectopic endometrial tissue of endometriosis (EMS) patients. Thus far, the pathophysiological function of miR-106a-5p in EMS is unknown. A previous study showed an increased FOXC1 expression in the ectopic endometrial tissue of patients with EMS. Moreover, we found that there was a binding site of miR-106a-5p on the 3ʹUTR of FOXC1 through bioinformatics predictions. Hence, we speculated that miR-106a-5p might affect the development of EMS via targeting FOXC1. We first showed a decreased level of miR-106a-5p and an increased level of FOXC1 mRNA in ectopic endometrial tissues compared with normal tissues. Functionally, we transfected ectopic endometrial stromal cells (ESCs) with miR-106a-5p mimics or NC mimics and indicated an inhibitory role of miR-106a-5p on ESC proliferation, invasion, and migration. Mechanistically, FOXC1 was found to be a target gene of miR-106a-5p. To confirm whether miR-106a-5p exerted an inhibitory activity in ESCs via targeting FOXC1, miR-106a-5p mimic was co-transfected into ESCs with the FOXC1-plasmid or vector. We found that FOXC1 overexpression evidently reversed the results caused by a miR-106a-5p mimic in ESCs. Additionally, our results demonstrated that miR-106a-5p mimic inhibited the expression of p-Akt and p-PI3K. Collectively, these results revealed that miR-106a-5p inhibited the proliferative, migratory, and invasive ability of ESCs via directly binding to FOXC1, likely through the suppression of the PI3K and its downstream signaling pathway, which offered a potential and novel therapeutic strategy for EMS treatment.
研究领域:
妇科学
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分子生物学
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细胞生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Ming Chen,Xuemin Liu,Xiaoxia Song,Xiaofeng Ye,Zeshen Liang,Guoqing Chen,Peixian Cheng,Huihua Yang,Ling Shuai,Dongdong Li,Liping Wang
Thin endometrium (TE), a major cause of embryo implantation failure, increases the risk of early miscarriage, ectopic pregnancy, and perinatal complications. Owing to the poor utilization and short-term effectiveness of current stem cell therapies, their efficacy in improving reproductive outcomes in patients with TE is limited. Endometrial extracellular matrix (EMECM) modified hemispherical hydrogels (ECMHPs) are developed to deliver menstrual blood-derived stem cells (MenSCs) to promote TE repair. The irregular porous structure on one side of the hemispherical hydrogel microspheres significantly enhances their retention capability on the uterine wall, whereas the bioactive decellularized EMECM promotes MenSCs proliferation and paracrine function. In vitro experiments demonstrate that ECMHPs@MenSCs promote the proliferation of damaged human endometrial stromal cells (HESCs) while inhibiting their fibrosis and apoptosis. In TE rat models, intrauterine transplantation of the ECMHPs delivering MenSCs system (ECMHPs@MenSCs) extends retention time, promotes endometrial thickness by 2.3-fold, increases glandular number by 3.7-fold, inhibits endometrial fibrosis. Additionally, this system improves endometrial regeneration markers and uterine receptivity, and restores fertility, with a mean gestational sac number of 11.0 ± 2.8 compared with only 2.3 ± 2.1 in the untreated group. This study provides an efficient and convenient therapeutic strategy for TE repair and fertility restoration.
研究领域:
生殖医学
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组织工程
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干细胞治疗
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生物材料
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再生医学
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妇产科学
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细胞治疗
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产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
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2024
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IF 4.4
Jingwen Shi,Wenda Jing,Yueyun He,Ying Huang
Despite decades of research, endometriosis remains a mysterious gynecological disease with unknown etiology and pathogenesis. Krüppel-like Factor 6 (KLF6), a transcription factor, has a wide expression profile and regulates a variety of biological processes. Here, we investigated the expression and function of KLF6 and its possible regulatory mechanisms in endometriosis. To determine the function of KLF6, knockdown and overexpression experiments were performed in eutopic endometrial stromal cells (EU-ESCs) and ectopic endometrial stromal cells (EC-ESCs), respectively. Cell viability, apoptosis, migration, invasion, and angiogenesis assays were conducted in ESCs. ChIP-sequencing and mRNA-sequencing were performed to investigate the functional mechanism of KLF6 in regulating ESCs. We found that KLF6 was highly expressed in eutopic endometrium of endometriosis patients, compared with ectopic endometrium. Similarly, the same was true in EU-ESCs, which was compared with EC-ESCs. Overexpression of KLF6 significantly suppressed EC-ESC proliferation, migration and invasion and induced cell apoptosis, while knockdown of KLF6 resulted in the opposite effects on EU-ESCs. Overexpression of KLF6 significantly inhibited EC-ESC angiogenesis. Mechanistically, the results of ChIP sequencing and mRNA sequencing revealed that CTNNB1 may be a transcriptional target regulated by KLF6. Reintroduction of KLF6 reversed the effects of KLF6 knockdown on EU-ESCs. KLF6 inhibited the proliferation, migration and angiogenesis of EC-ESCs by inhibiting the expression of CTNNB1. Our findings provided a new perspective on the role of KLF6 in endometriosis progression and inspire potential targeted therapeutic strategies.
研究领域:
妇科学
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分子生物学
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转录因子
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疾病发病机制
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产品关联
DOI
PubMed
高影响因子
MOLECULAR HUMAN REPRODUCTION
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2023
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IF 4
Dong Xiaoyu,Xu Le,Wang Shuang,Jiao Xue,Yan Shumin,Huang Yufei,Yuan Ming,Wang Guoyun
Ferroptosis is an iron-dependent programmed cell death process characterised by the accumulation of lethal oxidative damage. Localised iron overload is a unique clinical phenomenon in ovarian endometriosis. However, the role and mechanism of ferroptosis in the course of ovarian endometriosis remain unclear. Traditionally, autophagy promotes cell survival. However, a growing body of research suggests that autophagy promotes ferroptosis under certain conditions. This study aimed to clarify the status of ferroptosis in ovarian endometriosis and explore the mechanism(s) by which iron overload causes ferroptosis and ectopic endometrial resistance to ferroptosis in human. The results showed increased levels of iron and reactive oxygen species in ectopic endometrial stromal cells. Some ferroptosis and autophagy proteins in the ectopic tissues differed from those in the eutopic endometrium. In vitro, iron overload caused decreased cellular activity, increased lipid peroxidation levels, and mitochondrial morphological changes, whereas ferroptosis inhibitors alleviated these phenomena, illustrating activated ferroptosis. Iron overload increased autophagy, and ferroptosis caused by iron overload was inhibited by autophagy inhibitors, indicating that ferroptosis caused by iron overload was autophagy-dependent. We also confirmed the effect of iron overload and autophagy on lesion growth in vivo by constructing a mouse endometriosis model; the results were consistent with those of the in vitro experiments of human tissue and endometrial stomal cells. However, ectopic lesions in patients can resist ferroptosis caused by iron overload, which can promote cystine/glutamate transporter hyperexpression by highly expressing activating transcription factor 4 (ATF4). In summary, local iron overload in ovarian endometriosis can activate autophagy-related ferroptosis in endometrial stromal cells, and ectopic lesions grow in a high-iron environment via ATF4-xCT while resisting ferroptosis. The effects of iron overload on other cells in the endometriosis environment require further study. This study deepens our understanding of the role of ferroptosis in ovarian endometriosis.
研究领域:
妇科学
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细胞生物学
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分子生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
Journal of Hazardous Materials Advances
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2025
·
IF 7.7
Peigen Chen,Lina Chen,Xing Yang,Tingting Li,Cong Fang
The pervasive contamination by Di(2-ethylhexyl) phthalate (DEHP) and nanoplastics (NPs) poses a significant threat to reproductive health, yet the combined effects of these pollutants on endometrial receptivity remain poorly understood. Our study investigates the impact of chronic DEHP and NPs co-exposure on endometrial ciliary function in mice and explores the potential protective role of dietary inulin. Utilizing a multifaceted approach—including transcriptomic analysis, immunohistochemistry, scanning electron microscopy, and immunofluorescence—we reveal that DEHP and NPs synergistically impair endometrial cilia, crucial for embryo implantation. Remarkably, inulin supplementation restores ciliary structure and function, mitigating the detrimental effects of these pollutants. Our findings suggest that dietary interventions could offer a practical strategy to counteract the reproductive toxicity of environmental contaminants, providing new insights into maintaining reproductive health in polluted environments. This research underscores the urgency of addressing environmental pollutants and highlights the potential of inulin as a protective agent against reproductive toxicity.
研究领域:
生殖生物学
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环境医学
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营养学
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产品关联
DOI
高影响因子
Reproductive and Developmental Medicine
·
2024
·Vol. 9
·期 1
·22
·
IF 0.7
Chen Xi,Zuo Wei-Wen,Zhang Guo-Dong,Xu Cong-Jian
Objective: Immune dysfunction plays an important role in the pathogenesis of endometriosis. C5a, a by-product of complement activation, binds to its receptor (C5a receptor 1, C5aR1) in various cells, including macrophages. The combination of C5a and C5aR1 in macrophages induces M2 polarization. There is no consistent conclusion regarding macrophage polarization status and its participation in the pathogenesis of endometriosis. Methods: We analyzed the expression of C5aR1 and the immunophenotype of macrophages in samples from patients with endometriosis using immunohistochemistry and flow cytometry. We tested the equivalent item in a mouse model and the THP-1 cell line in vivo and in vitro . Single-cell RNA sequencing (scRNA-seq) from the Gene Expression Omnibus (GEO, GSE213216) was used to investigate the phenotype and function of C5aR1 + macrophages. Results: The infiltration of C5aR1 + macrophages was associated with the severity of endometriosis. C5aR1 + macrophages polarized more toward the M2 phenotype and transformed into an immunosuppressive state. Inhibiting C5aR1 using PMX-53 decreased the expression of C5aR1 + macrophages and reduced their polarization to the M2 phenotype, consequently shrinking lesion size in a mouse model. Conclusion: Our study emphasizes the importance of C5aR1 and the macrophage phenotype in the pathogenesis of endometriosis. We propose PMX-53 as a potential therapeutic agent for endometriosis.
研究领域:
免疫学
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生殖医学
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分子生物学
✓ 已验证
DOI
高影响因子
JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH
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2024
·Vol. 50
·期 12
·2338-2345
·
IF 1.6
Yang Wang,Wenxin Liu,Hui Xu,Liyuan Dong,Yalou Jiao,Zhe Qiao
Objective Thin endometrium caused by various factors affects the conception rate of females worldwide; however, current medications are still insufficient. Therefore, a novel approach is needed. We previously reported the effect of menstrual blood-derived mesenchymal stem cells (MenSCs) in ameliorating ethanol-induced endometrial injuries. In the present study, we aimed to investigate whether the effect of MenSCs is enhanced by a combination of platelet-rich plasma (PRP) infusion. Methods An endometrial injury mouse model was established by infiltrating 95% ethanol for 15 s into the uterus, followed by MenSCs, PRP, or MenSCs + PRP treatment. Pathological changes were observed by HE staining. The expression of CK18, vimentin, ItgαVβ3, and VEGF was determined using IHC staining and WB blotting. Results Compared with the model, MenSCs, PRP, and MenSCs + PRP treatments significantly improved endometrial damage and thickness, with the combined therapy displaying the most pronounced efficacy. The density of CK18-, vimentin-, and ItgαVβ3 positive cells increased most significantly in the MenSCs + PRP group of mice. In addition, the protein expression of CK18, vimentin, and VEGF was significantly upregulated after MenSCs + PRP, MenSCs, and PRP treatment, with MenSCs + PRP therapy showing the best efficacy. Conclusion MenSCs + PRP therapy is more beneficial for ameliorating ethanol-induced endometrial damage than MenSCs or PRP alone, providing a basis for the investigation of novel approaches for treating thin endometria.
研究领域:
生殖医学
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干细胞生物学
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妇科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2021
·
IF 7.561
Li Qiuju,Yuan Ming,Jiao Xue,Huang Yufei,Li Jing,Li Dong,Ji Miaomiao,Wang Guoyun
Background: Endometriosis is a common nonmalignant gynecological disorder that affects 10–15% women of reproductive age and causes several symptoms that result in decreased quality of life and a huge social burden. In recent decades, extracellular vesicles (EVs) have gained attention as a potential therapeutic tool; however, the therapeutic effects of EVs against endometriosis have not been reported. Accordingly, in this study, we investigated the feasibility of nanovesicles (NVs) derived from M1 macrophages (M1NVs) in treating endometriosis.Methods: M1NVs were prepared by serial extrusion. Co-culture assays were performed to investigate changes in tube formation and migration/invasion of eutopic endometrial stroma cells (ESCs) obtained from patients with endometriosis (EM-ESCs). A mouse model of endometriosis was established, and mice were treated with phosphate-buffered saline, M0NVs, or M1NVs to evaluate the efficacy and safety of M1NV for treating endometriosis.Results: M1NVs directly or indirectly inhibited the migration and invasion of EM-ESCs and reduced tube formation. In the mouse model, M1NVs suppressed the development of endometriosis through reprogramming of M2 macrophages, without causing damage to the organs.Conclusions: M1NVs inhibit the development of endometriosis directly, or through repolarizing macrophages from M2 to M1 phenotype. Hence, administration of M1NVs may represent a novel method for the treatment of endometriosis.
研究领域:
妇科学
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免疫学
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纳米技术
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2025
·
IF 3.3
Yue-Ying Li,Hui Liu,Jia-Lu Feng,Wen-Yan Tian,Juan Du,Li-Ping Zhang
Introduction Endometrial cancer (EC) is a growing global health concern. Understanding the molecular mechanisms driving EC is crucial for developing effective diagnostic and therapeutic strategies. This study investigates the roles of DLL3 and miR-508-5p in EC progression and explores a therapeutic approach using engineered exosomes to modulate their expression. Methods TCGA data were analyzed, in vitro and in vivo experiments were performed to assess DLL3 and miR-508-5p function, and bioinformatics was used to confirm their interaction. Mesenchymal stem cells (MSCs) were engineered to produce miR-508-5p-overexpressing exosomes, and their therapeutic effects were tested in mouse models. Results Elevated DLL3 and downregulated miR-508-5p were observed in EC and correlated with poor outcomes. miR-508-5p directly targets DLL3. Engineered exosomes restored miR-508-5p, inhibited DLL3, and reduced tumor growth and metastasis in mouse models. Discussion The findings highlight the roles of DLL3 and miR-508-5p in EC. Targeting the miR-508-5p/DLL3 axis via exosome-mediated delivery represents a promising therapeutic strategy for EC.
研究领域:
分子生物学
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肿瘤学
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基因治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）