|
1
|
İnanç İ, Bender O, Atalay A, Köse SK, Erdemli E. Alterations in the Hippo Signaling Pathway During Adenogenesis Impairment in Postnatal Mouse Uterus. Reprod Sci 2025:10.1007/s43032-025-01793-y. [PMID: 40106220 DOI: 10.1007/s43032-025-01793-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 01/11/2025] [Indexed: 03/22/2025]
Abstract
The mouse uterus, which consists of single-layered epithelium and undifferentiated mesenchyme at birth, begins to differentiate in the postnatal period. The process of adenogenesis, defined as gland development, begins on the Postnatal (PN) Day 5, and this process is very evident on the PN Day 10. Although various signaling pathways effective in the adenogenesis process but the mechanism underlying this progress have not been clarified yet. Hippo signaling pathway have roles in many cellular functions, such as proliferation, differentiation and cell death. But the relationship between the Hippo signaling pathway and uterus adenogenesis is unknown. The objective of this study has been to determine if there is a change in the Hippo signaling pathway in mice with impaired gland development during the adenogenesis process. To that aim, we use mouse uterus with normal gland development (control group) and gland development inhibited by progesterone (experimental group). Animals were sacrificed on the PN Days 5, 10 and 15. YAP and p-YAP by immunohistochemistry and immunoblotting techniques to identify the main components of Hippo Signaling Pathway. YAP, LATS1, LATS 2, MST1, NF2 and TAZ used for the RT-qPCR methods. In conclusion, Hippo signaling pathway components were reduced during the adenogenesis process in mouse with impaired gland development.
Collapse
Affiliation(s)
- İrem İnanç
- Faculty of Medicine, Department of Histology and Embryology, Ankara University, Ankara, Turkey.
| | - Onur Bender
- Biotechnology Institute, Ankara University, Ankara, Turkey
| | - Arzu Atalay
- Biotechnology Institute, Ankara University, Ankara, Turkey
| | - Serdal Kenan Köse
- Faculty of Medicine, Department of Biostatistics, Ankara University, Ankara, Turkey
| | - Esra Erdemli
- Faculty of Medicine, Department of Histology and Embryology, Ankara University, Ankara, Turkey
| |
Collapse
|
|
2
|
Zhang WY, Wang HB, Deng CY. Advances in human umbilical cord mesenchymal stem cells-derived extracellular vesicles and biomaterial assemblies for endometrial injury treatment. World J Stem Cells 2025; 17:97905. [PMID: 39866901 PMCID: PMC11752459 DOI: 10.4252/wjsc.v17.i1.97905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 11/06/2024] [Accepted: 01/02/2025] [Indexed: 01/20/2025] Open
Abstract
Endometrial injury caused by repeated uterine procedures, infections, inflammation, or uterine artery dysfunction can deplete endometrial stem/progenitor cells and impair regeneration, thereby diminishing endometrial receptivity and evidently lowering the live birth, clinical pregnancy, and embryo implantation rates. Currently, safe and effective clinical treatment methods or gene-targeted therapies are unavailable, especially for severe endometrial injury. Umbilical cord mesenchymal stem cells and their extracellular vesicles are characterized by their simple collection, rapid proliferation, low immunogenicity, and tumorigenicity, along with their involvement in regulating angiogenesis, immune response, cell apoptosis and proliferation, inflammatory response, and fibrosis, Therefore, these cells and vesicles hold broad potential for application in endometrial repair. This article reviewed recent research on human umbilical cord mesenchymal stem cells as well as their extracellular vesicles in repairing endometrial injury.
Collapse
Affiliation(s)
- Wan-Yu Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Han-Bi Wang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100730, China
| | - Cheng-Yan Deng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing 100730, China.
| |
Collapse
|
|
3
|
Wang H, Zhu L, Zhu H, Meng J, Liang H, Li D, Hu Y, Zhou Z. Multi-parametric MRI combined with radiomics for the diagnosis and grading of endometrial fibrosis. Abdom Radiol (NY) 2025:10.1007/s00261-024-04785-9. [PMID: 39841225 DOI: 10.1007/s00261-024-04785-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 12/20/2024] [Accepted: 12/21/2024] [Indexed: 01/23/2025]
Abstract
PURPOSE To evaluate the application of multi-parametric MRI (MP-MRI) combined with radiomics in diagnosing and grading endometrial fibrosis (EF). METHODS A total of 74 patients with severe endometrial fibrosis (SEF), 41 patients with mild to moderate fibrosis (MMEF) confirmed by hysteroscopy, and 40 healthy women of reproductive age were prospectively enrolled. The enrolled data were randomly stratified and divided into a train set (108 cases: 28 healthy women, 29 with MMEF, and 51 with SEF) and a test set (47 cases: 12 healthy women, 12 MMEF and 23 SEF) at a ratio of 7:3. All participants underwent T2 and DWI sequence scans. By freely delineating the volume of interest (VOI) of the endometrium in three subgroups, radiomic features were extracted and selected. Two feature selection methods and four machine learning (ML) classifiers were combined in pairs to establish five prediction models [model1 (T2 + ADC + clinical data), model2 (T2 + ADC), model3 (T2), model4 (ADC), and model5 (clinical data)], resulting in a total of 40 classification models. The predictive performance of all models was evaluated using the area under the curve (AUC), F1-score, and accuracy (ACC). RESULTS The "UFS-LR" model, which combined unsupervised feature selection (UFS) with the logistic regression (LR) classifier, performed the best, with an average AUC of 0.92 on the test set. Among the five models constructed via UFS-LR, model1 exhibited the best performance, with average AUC, F1-score, and ACC values of 0.92, 0.80, and 0.81, respectively. T2-related features were the most significant in distinguishing fibrosis levels, with T2_wavelet-LLL_gldm_DependenceVariance being the most important characteristic among them. CONCLUSION MP-MRI radiomics analysis using ML has excellent performance in grading EF. This approach is non-invasive and has the potential to reduce the reliance on hysteroscopy.
Collapse
Affiliation(s)
- Huanhuan Wang
- Department of Radiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Li Zhu
- Department of Radiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Hui Zhu
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Jie Meng
- Department of Radiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Huanhuan Liang
- Department of Radiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, No. 321 Zhongshan Road, Nanjing, 210008, China
| | - Danyan Li
- Department of Radiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, No. 321 Zhongshan Road, Nanjing, 210008, China.
| | - Yali Hu
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, No. 321 Zhongshan Road, Nanjing, 210008, China.
| | - Zhengyang Zhou
- Department of Radiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, No. 321 Zhongshan Road, Nanjing, 210008, China.
| |
Collapse
|
|
4
|
Abd-Elkareem M, Khormi MA, Alfattah MA, Hassan MS. Uterine histomorphological and immunohistochemical investigation during the follicular phase of estrous cycle in Saidi sheep. BMC Vet Res 2025; 21:16. [PMID: 39806411 PMCID: PMC11727546 DOI: 10.1186/s12917-024-04456-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 12/19/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Saidi sheep are one of the most important farm animals in Upper Egypt, particularly in the Assiut governorate. Since they can provide meat, milk, fiber, and skins from low-quality roughages, sheep are among the most economically valuable animals bred for food in Egypt. Regarding breeding, relatively little is known about the Saidi breed. In mammals, the uterus is a crucial reproductive organ. Therefore, the purpose of this work was to provide further details on the histological, histochemical, and immunohistochemical analyses of superoxide dismutase 2 (SOD2), glutathione reductase (GR), and progesterone receptor alpha (PRA) as well as terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling assay (TUNEL) of the uterus during the follicular phase of estrous cycle in Saidi sheep. Thus, 11 healthy Saidi ewes (38.5 ± 2.03 kg weight) ranging in age from 2 to 5 years were used to examine the histological changes in the uterus. RESULTS In Saidi sheep, the uterine histological and immunological picture during the follicular phase of the estrous cycle was characterized by epithelial and stromal proliferation and apoptosis. Leucocytic recruitment (lymphocytes, plasma, and mast cells) was also observed. Uterine gland adenogenesis, vascular angiogenesis, oxidative marker expression, and PRA expression in the muscles, stroma, and epithelium were the most noticeable features of the follicular phase. CONCLUSION This study provides new evidence of the role of PRA, SOD2, GR, and mast cells in controlling uterine epithelial proliferation and apoptosis in the Saidi sheep during the follicular phase of the estrus cycle. These findings have growing significance in understanding the key mechanisms that characterize successful reproduction and enhancing the fertility and reproductive efficiency in Saidi Sheep.
Collapse
Affiliation(s)
- Mahmoud Abd-Elkareem
- Department of Cell and Tissues, Faculty of Veterinary Medicine, Assiut University, Assiut, 71526, Egypt.
| | - Mohsen A Khormi
- Department of Biology, College of Science, Jazan University, P.O. Box. 114, Jazan, 45142, Kingdom of Saudi Arabia
| | - Mohammed A Alfattah
- Department of Biology, College of Science, Jazan University, P.O. Box. 114, Jazan, 45142, Kingdom of Saudi Arabia
| | - Mervat S Hassan
- Theriogenology Department, Faculty of Veterinary Medicine, New-Valley University, New Valley, 725211, Egypt
| |
Collapse
|
|
5
|
Akthar I, Yousef MS, Mansouri A, Shimada M, Miyamoto A. Sperm hyperactivation in the uterus and oviduct: a double-edged sword for sperm and maternal innate immunity toward fertility. Anim Reprod 2024; 21:e20240043. [PMID: 39176001 PMCID: PMC11340796 DOI: 10.1590/1984-3143-ar2024-0043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 06/25/2024] [Indexed: 08/24/2024] Open
Abstract
In cattle, artificial insemination (AI) is a technique that allows breeding by depositing frozen-thawed and extended semen into the female reproductive tract. The semen contains sperm with various motility patterns including dead, progressive and hyperactivated. Sperm hyperactivation is high amplitude, asymmetrical beating of sperm tail which usually occurs in the oviduct as part of the capacitation process, but it can also be induced by cryopreservation. After insemination, sperm enter the uterine glands and trigger a pro-inflammatory response in the uterus. Hyperactivated sperm, stimulated by sperm-Toll-like receptor 2 (TLR2), penetrates the mucus and uterine glands more efficiently and enhances the immune response. This facilitates the clearance of excess and dead sperm from the uterus. Some sperm escape the immune response and reach the oviduct either before or after the immune response is initiated. In the oviduct, sperm bind to the epithelium and form a reservoir. This triggers an anti-inflammatory response and preserves the fertilization potential of sperm. Hyperactivation facilitates sperm detaching from the epithelium, swimming through the viscous mucus and cumulus cells, and penetrating the egg's zona pellucida. Sperm-TLR2 activation enhances Ca2+-influx and acrosome reaction, which enables sperm to penetrate and fertilize oocytes during in vitro fertilization. Altogether, post-AI in cattle, sperm and maternal immunity interact differentially depending upon the site of sperm hyperactivation - whether it occurs within the uterus or oviduct. Specifically, hyperactivated sperm that enter the uterus after AI or are triggered via sperm-TLR2 activation or other stimuli contribute to sperm-induced uterine inflammation. Such hyperactivated sperm may impede their capacity to ascend to the oviduct. Conversely, sperm that become hyperactivated within the oviduct modulate their interactions with the oviduct and oocytes, which is pivotal during fertilization process. Indeed, the location and timing of sperm hyperactivation partially via TLR2 activation are critical determinants of their different influence on fertility.
Collapse
Affiliation(s)
- Ihshan Akthar
- Global Agromedicine Research Center (GAMRC), Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
| | - Mohamed Samy Yousef
- Global Agromedicine Research Center (GAMRC), Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
- Department of Theriogenology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
| | - Alireza Mansouri
- Global Agromedicine Research Center (GAMRC), Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
| | - Masayuki Shimada
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan
| | - Akio Miyamoto
- Global Agromedicine Research Center (GAMRC), Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
| |
Collapse
|
|
6
|
Li N, Mao J, Wang M, Qi J, Jiang Z, Li Y, Yan G, Hu Y, Li S, Sun H, Ding L. Transplantation of human endometrial perivascular stem cells with hydroxy saffron yellow A promotes uterine repair in rats. Stem Cell Res Ther 2024; 15:217. [PMID: 39020406 PMCID: PMC11256499 DOI: 10.1186/s13287-024-03821-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 06/27/2024] [Indexed: 07/19/2024] Open
Abstract
BACKGROUND Intrauterine adhesions (IUAs) jeopardise uterine function in women, which is a great challenge in the clinic. Previous studies have shown that endometrial perivascular cells (En-PSCs) can improve the healing of scarred uteri and that hydroxysafflor yellow A (HSYA) promotes angiogenesis. The purpose of this study was to observe whether the combination of En-PSCs with HSYA could improve the blood supply and fertility in the rat uterus after full-thickness injury. METHODS En-PSCs were sorted by flow cytometry, and the effect of HSYA on the proliferation and angiogenesis of the En-PSCs was detected using CCK-8 and tube formation assays. Based on a previously reported rat IUA model, the rat uteri were sham-operated, spontaneously regenerated, or treated with collagen-loaded PBS, collagen-loaded HSYA, collagen-loaded En-PSCs, or collagen-loaded En-PSCs with HSYA, and then collected at both 30 and 90 days postsurgery. HE staining and Masson staining were used to evaluate uterine structure and collagen fibre deposition, and immunohistochemical staining for α-SMA and vWF was used to evaluate myometrial regeneration and neovascularization in each group. A fertility assay was performed to detect the recovery of pregnancy function in each group. RNA-seq was performed to determine the potential mechanism underlying En-PSCs/HSYA treatment. Immunofluorescence, tube formation assays, and Western blot were used to validate the molecular mechanism involved. RESULTS The transplantation of Collagen/En-PSCs/HSYA markedly promoted uterine repair in rats with full-thickness injury by reducing fibrosis, increasing endometrial thickness, regenerating myometrium, promoting angiogenesis, and facilitated live births. RNA sequencing results suggested that En-PSCs/HSYA activated the NRG1/ErbB4 signaling pathway. In vitro tube formation experiments revealed that the addition of an ErbB inhibitor diminished the tube formation ability of cocultured En-PSCs and HUVECs. Western blot results further showed that elevated levels of NRG1 and ErbB4 proteins were detected in the Collagen/En-PSCs/HSYA group compared to the Collagen/En-PSCs group. These collective results suggested that the beneficial effects of the transplantation of Collagen/En-PSCs/HSYA might be attributed to the modulation of the NRG1/ErbB4 signaling pathway. CONCLUSIONS The combination of En-PSCs/HSYA facilitated morphological and functional repair in rats with full-thickness uterine injury and may promote endometrial angiogenesis by regulating the NRG1/ErbB4 signaling pathway.
Collapse
Affiliation(s)
- Ning Li
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Jialian Mao
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Miaomiao Wang
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Jiahui Qi
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, 210008, China
| | - Zhiwei Jiang
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China
| | - Yifan Li
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Guijun Yan
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Yali Hu
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Shiyuan Li
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
- Department of Vascular Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
| | - Haixiang Sun
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China.
| | - Lijun Ding
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, China.
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, 210008, China.
- Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China.
- Clinical Center for Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| |
Collapse
|
|
7
|
Bao H, Sun Y, Deng N, Zhang L, Jia Y, Li G, Gao Y, Li X, Tang Y, Cai H, Lu J, Wang H, Deng W, Kong S. PR-SET7 epigenetically restrains uterine interferon response and cell death governing proper postnatal stromal development. Nat Commun 2024; 15:4920. [PMID: 38858353 PMCID: PMC11164956 DOI: 10.1038/s41467-024-49342-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 05/31/2024] [Indexed: 06/12/2024] Open
Abstract
The differentiation of the stroma is a hallmark event during postnatal uterine development. However, the spatiotemporal changes that occur during this process and the underlying regulatory mechanisms remain elusive. Here, we comprehensively delineated the dynamic development of the neonatal uterus at single-cell resolution and characterized two distinct stromal subpopulations, inner and outer stroma. Furthermore, single-cell RNA sequencing revealed that uterine ablation of Pr-set7, the sole methyltransferase catalyzing H4K20me1, led to a reduced proportion of the inner stroma due to massive cell death, thus impeding uterine development. By combining RNA sequencing and epigenetic profiling of H4K20me1, we demonstrated that PR-SET7-H4K20me1 either directly repressed the transcription of interferon stimulated genes or indirectly restricted the interferon response via silencing endogenous retroviruses. Declined H4K20me1 level caused viral mimicry responses and ZBP1-mediated apoptosis and necroptosis in stromal cells. Collectively, our study provides insight into the epigenetic machinery governing postnatal uterine stromal development mediated by PR-SET7.
Collapse
Affiliation(s)
- Haili Bao
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Yang Sun
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Na Deng
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Leilei Zhang
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Yuanyuan Jia
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Gaizhen Li
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Yun Gao
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Xinyi Li
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Yedong Tang
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Han Cai
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Jinhua Lu
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Haibin Wang
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
| | - Wenbo Deng
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
| | - Shuangbo Kong
- Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
| |
Collapse
|
|
8
|
Wei S, Li Z, Xia H, Wang Z, Deng J, Li L, Huang R, Ye T, Huang Y, Yang Y. An endometrial biomimetic extracellular matrix (ECM) for enhanced endometrial regeneration using hyaluronic acid hydrogel containing recombinant human type III collagen. Int J Biol Macromol 2024; 268:131723. [PMID: 38649072 DOI: 10.1016/j.ijbiomac.2024.131723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/13/2024] [Accepted: 04/18/2024] [Indexed: 04/25/2024]
Abstract
Endometrial injury poses a significant challenge in tissue regeneration, with type III collagen (COL III) playing a pivotal role in maintaining endometrial integrity and facilitating repair. Our study explored the utility of recombinant human type III collagen (RHC) as an intervention for endometrial damage. To address the challenges associated with the inherent instability and rapid degradation of COL III in vivo, we developed an RHC-HA hydrogel by conjugating RHC with hyaluronic acid (HA), thus ensuring a more stable and sustained delivery. Our findings suggested that the RHC-HA hydrogel significantly promoted endometrial regeneration and restored fertility. The hydrogel facilitated prolonged retention of RHC in the uterus, leading to a substantial improvement in the repair process. The synergistic interaction between RHC and HA greatly enhances cell proliferation and adhesion, surpassing the efficacy of HA or RHC alone. Additionally, the RHC-HA hydrogel demonstrated notable anti-fibrotic effects, which are crucial for preventing abnormalities during endometrial healing. These findings suggested that the RHC-HA hydrogel presented a therapeutic strategy in the treatment of uterine endometrial injuries, which may improve female reproductive health.
Collapse
Affiliation(s)
- Siying Wei
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Ziyi Li
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Huan Xia
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Zhaoyang Wang
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Jingxian Deng
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Lu Li
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Rufei Huang
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Tao Ye
- Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Yadong Huang
- Department of Cell Biology, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China.
| | - Yan Yang
- Department of Cell Biology, Jinan University, Guangzhou 510632, China; Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China.
| |
Collapse
|
|
9
|
Flis W, Socha MW. The Role of the NLRP3 Inflammasome in the Molecular and Biochemical Mechanisms of Cervical Ripening: A Comprehensive Review. Cells 2024; 13:600. [PMID: 38607039 PMCID: PMC11012148 DOI: 10.3390/cells13070600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/27/2024] [Accepted: 03/27/2024] [Indexed: 04/13/2024] Open
Abstract
The uterine cervix is one of the key factors involved in ensuring a proper track of gestation and labor. At the end of the gestational period, the cervix undergoes extensive changes, which can be summarized as a transformation from a non-favorable cervix to one that is soft and prone to dilation. During a process called cervical ripening, fundamental remodeling of the cervical extracellular matrix (ECM) occurs. The cervical ripening process is a derivative of many interlocking and mutually driving biochemical and molecular pathways under the strict control of mediators such as inflammatory cytokines, nitric oxide, prostaglandins, and reactive oxygen species. A thorough understanding of all these pathways and learning about possible triggering factors will allow us to develop new, better treatment algorithms and therapeutic goals that could protect women from both dysfunctional childbirth and premature birth. This review aims to present the possible role of the NLRP3 inflammasome in the cervical ripening process, emphasizing possible mechanisms of action and regulatory factors.
Collapse
Affiliation(s)
- Wojciech Flis
- Department of Perinatology, Gynecology and Gynecologic Oncology, Faculty of Health Sciences, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Łukasiewicza 1, 85-821 Bydgoszcz, Poland;
- Department of Obstetrics and Gynecology, St. Adalbert’s Hospital in Gdańsk, Copernicus Healthcare Entity, Jana Pawła II 50, 80-462 Gdańsk, Poland
| | - Maciej W. Socha
- Department of Perinatology, Gynecology and Gynecologic Oncology, Faculty of Health Sciences, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Łukasiewicza 1, 85-821 Bydgoszcz, Poland;
- Department of Obstetrics and Gynecology, St. Adalbert’s Hospital in Gdańsk, Copernicus Healthcare Entity, Jana Pawła II 50, 80-462 Gdańsk, Poland
| |
Collapse
|
|
10
|
Paping A, Ehrlich L, Melchior K, Ziska T, Wippermann W, Starke A, Heinichen K, Henrich W, Braun T. A Sustainable Translational Sheep Model for Planned Cesarean Delivery of Contraction-Free Ewes. Reprod Sci 2024; 31:791-802. [PMID: 37848643 PMCID: PMC10912125 DOI: 10.1007/s43032-023-01365-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 09/14/2023] [Indexed: 10/19/2023]
Abstract
We evaluated whether the sheep constitutes a useful translational model to evaluate anatomical and surgical aspects of cesarean delivery (CD) from a human medical perspective with the aim of both maternal and neonatal well-being. Our hypothesis was that CD in contraction-free ewes is not associated with major complications. Primary endpoint was the transferability of anatomical conditions and surgical techniques of CD from the ewe to the human. Secondary endpoints were maternal and fetal survival, occurrence of retained fetal membranes, metritis, mastitis, or wound infections. Forty-eight Merino ewes were delivered by CD after 95% gestation (142-144 days). Both ewes and newborn lambs were cared for intensively after the delivery. Ovine uterine anatomy during CD appeared slightly different but comparable to the human uterus. Uterine incisions were mostly performed in the uterine horns, not in the uterine corpus. The ovine uterine wall is thinner than in humans. All ewes survived without any major complications. Seventy-seven (88.5%) out of 87 live-born lambs survived without any complications. The contraction-free ewe constitutes an appropriate and safe model to evaluate anatomical and surgical aspects of CD from a human medical perspective. We present a step-by-step manual for successfully planned cesarean delivery for sheep including the perioperative management illustrated with photographs and a five-minute video. With adequate planning and a reasonable number of staff, it is possible to safeguard both maternal and neonatal survival. This sustainable translational medicine model offers additional potential for the offspring to be used for further research studies (e.g., transgenerational inheritance research).
Collapse
Affiliation(s)
- Alexander Paping
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Obstetrics, Augustenburger Platz 1, 13353, Berlin, Germany.
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of 'Experimental Obstetrics', Berlin, Germany.
| | - Loreen Ehrlich
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of 'Experimental Obstetrics', Berlin, Germany
| | - Kerstin Melchior
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of 'Experimental Obstetrics', Berlin, Germany
| | - Thomas Ziska
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of 'Experimental Obstetrics', Berlin, Germany
| | - Wolf Wippermann
- Clinic for Ruminants and Swine, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | - Alexander Starke
- Clinic for Ruminants and Swine, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | - Karin Heinichen
- Oberholz Farm for Teaching and Research, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | - Wolfgang Henrich
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Obstetrics, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Thorsten Braun
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Obstetrics, Augustenburger Platz 1, 13353, Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of 'Experimental Obstetrics', Berlin, Germany
| |
Collapse
|
|
11
|
Song S, Wu S, Meiduo D, Chen P, Li H, He H. Nano-biomaterial Fibrinogen/P(LLA-CL) for prevention of intrauterine adhesion and restoration of fertility. J Biomed Mater Res A 2024; 112:167-179. [PMID: 37724479 DOI: 10.1002/jbm.a.37604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 06/14/2023] [Accepted: 08/22/2023] [Indexed: 09/20/2023]
Abstract
Endometrial damage resulting from surgical procedures is a significant cause of intrauterine adhesion, thin endometrium, and subsequent miscarriage and infertility. Unfortunately, there is currently no effective clinical solution to promote endometrial regeneration after severe injury. In this study, we combined fibrinogen (Fg) and P(LLA-CL) by electrostatic spinning to form a stable nano-biomaterial Fg/P(LLA-CL), which can promote endometrial regeneration. After inducing physical injury to rat endometrium, we found that Fg/P(LLA-CL) membranes placed in the uterine cavities increased endometrial thickness and the number of glands after injury, while reducing the area of endometrial fibrosis. In addition, Fg/P(LLA-CL) increased neovascularization and decreased COL1A1 deposition. The expression of TGF-β1, a cytokine that promotes fibrosis, was down-regulated in the early stage of injury. Finally, fertility assays confirmed that Fg/P(LLA-CL) improved the pregnancy rate in rats with endometrial injury, and its safety was verified by blood tests and pathological examination of heart, liver, spleen, lung, and kidney. Therefore, Fg/P(LLA-CL) shows great potential as a safe and nontoxic biomaterial for endometrial regeneration, ultimately improving pregnancy outcomes in patients with intrauterine adhesion.
Collapse
Affiliation(s)
- Sirui Song
- Department of Obstetrics and Gynecology, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China
| | - Siyu Wu
- Department of Obstetrics and Gynecology, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China
| | - Danzeng Meiduo
- Department of Obstetrics and Gynecology, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China
| | - Ping Chen
- School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Huaifang Li
- Department of Obstetrics and Gynecology, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China
| | - Hongbing He
- Shanghai Pine & Power Biotech Co. Ltd, Shanghai, China
| |
Collapse
|
|
12
|
Spencer TE, Lowke MT, Davenport KM, Dhakal P, Kelleher AM. Single-cell insights into epithelial morphogenesis in the neonatal mouse uterus. Proc Natl Acad Sci U S A 2023; 120:e2316410120. [PMID: 38019863 PMCID: PMC10710066 DOI: 10.1073/pnas.2316410120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
The uterus is vital for successful reproduction in mammals, and two different types of epithelia (luminal and glandular) are essential for embryo implantation and pregnancy establishment. However, the essential cellular and molecular factors and pathways governing postnatal epithelium maturation, determination, and differentiation in developing uterus are yet to be elucidated. Here, the epithelium of the neonatal mouse uterus was isolated and subjected to single-cell transcriptome (scRNA-seq) analysis. Both the undifferentiated epithelium and determined luminal epithelium were heterogeneous and contained several different cell clusters based on single-cell transcription profiles. Substantial gene expression differences were evident as the epithelium matured and differentiated between postnatal days 1 to 15. Two new glandular epithelium-expressed genes (Gas6 and Cited4) were identified and validated by in situ hybridization. Trajectory analyses provided a framework for understanding epithelium maturation, lineage bifurcation, and differentiation. A candidate set of transcription factors and gene regulatory networks were identified that potentially direct epithelium lineage specification and morphogenesis. This atlas provides a foundation important to discover intrinsic cellular and molecular mechanisms directing uterine epithelium morphogenesis during a critical window of postnatal development.
Collapse
Affiliation(s)
- Thomas E. Spencer
- Division of Animal Sciences, University of Missouri, Columbia, MO65211
- Division of Obstetrics, Gynecology, and Women’s Health, University of Missouri, Columbia, MO65211
| | - Makenzie T. Lowke
- Division of Animal Sciences, University of Missouri, Columbia, MO65211
| | | | - Pramod Dhakal
- Division of Animal Sciences, University of Missouri, Columbia, MO65211
| | - Andrew M. Kelleher
- Division of Obstetrics, Gynecology, and Women’s Health, University of Missouri, Columbia, MO65211
| |
Collapse
|
|
13
|
Zhou N, Zhu H, Jiang P, Hu Q, Feng Y, Chen W, Zhou K, Hu Y, Zhou Z. Quantification of Endometrial Fibrosis Using Noninvasive MRI T2 Mapping: Initial Findings. J Magn Reson Imaging 2023; 58:1703-1713. [PMID: 37074789 DOI: 10.1002/jmri.28746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 04/02/2023] [Accepted: 04/03/2023] [Indexed: 04/20/2023] Open
Abstract
BACKGROUND Endometrial fibrosis may cause infertility. Accurate evaluation of endometrial fibrosis helps clinicians to schedule timely therapy. PURPOSE To explore T2 mapping for assessing endometrial fibrosis. STUDY TYPE Prospective. POPULATION Ninety-seven women with severe endometrial fibrosis (SEF) and 21 patients with mild to moderate endometrial fibrosis (MMEF), diagnosed by hysteroscopy, and 37 healthy women. FIELD STRENGTH/SEQUENCE 3T, T2-weighted turbo spin echo (T2-weighted imaging) and multi-echo turbo spin echo (T2 mapping) sequences. ASSESSMENT Endometrial MRI parameters (T2, thickness [ET], area [EA], and volume [EV]) were measured by N.Z. and Q.H. (9- and 4-years' experience in pelvic MRI) and compared between the three subgroups. A multivariable model including MRI parameters and clinical variables (including age and body mass index [BMI]) was developed to predict endometrial fibrosis assessed by hysteroscopy. STATISTICAL TESTS Kruskal-Wallis; ANOVA; Spearman's correlation coefficient (rho); area under the receiver operating characteristic curve (AUC); binary logistic regression; intraclass correlation coefficient (ICC). P value <0.05 for statistical significance. RESULTS Endometrial T2, ET, EA, and EV of MMEF patients (185 msec, 8.2 mm, 168 mm2 , and 2181 mm3 ) and SEF patients (164 msec, 6.7 mm, 120 mm2 , and 1762 mm3 ) were significantly lower than those of healthy women (222 msec, 11.7 mm, 316 mm2 , and 3960 mm3 ). Endometrial T2 and ET of SEF patients were significantly lower than those of MMEF patients. Endometrial T2, ET, EA, and EV were significantly correlated to the degree of endometrial fibrosis (rho = -0.623, -0.695, -0.694, -0.595). There were significant strong correlations between ET, EA, and EV in healthy women and MMEF patients (rho = 0.850-0.908). Endometrial MRI parameters and the multivariable model accurately distinguished MMEF or SEF from normal endometrium (AUCs >0.800). Age, BMI, and MRI parameters in univariable analysis and age and T2 in multivariable analysis significantly predicted endometrial fibrosis. The reproducibility of MRI parameters was excellent (ICC, 0.859-0.980). DATA CONCLUSION T2 mapping has potential to noninvasively and quantitatively evaluate the degree of endometrial fibrosis. EVIDENCE LEVEL 2 Technical Efficacy: Stage 2.
Collapse
Affiliation(s)
- Nan Zhou
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Hui Zhu
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Peipei Jiang
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Qing Hu
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Yongjing Feng
- Department of Radiology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | | | - Kefeng Zhou
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Yali Hu
- Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Zhengyang Zhou
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| |
Collapse
|
|
14
|
Padilla-Banks E, Jefferson WN, Papas BN, Suen AA, Xu X, Carreon DV, Willson CJ, Quist EM, Williams CJ. Developmental estrogen exposure in mice disrupts uterine epithelial cell differentiation and causes adenocarcinoma via Wnt/β-catenin and PI3K/AKT signaling. PLoS Biol 2023; 21:e3002334. [PMID: 37856394 PMCID: PMC10586657 DOI: 10.1371/journal.pbio.3002334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 09/12/2023] [Indexed: 10/21/2023] Open
Abstract
Tissue development entails genetically programmed differentiation of immature cell types to mature, fully differentiated cells. Exposure during development to non-mutagenic environmental factors can contribute to cancer risk, but the underlying mechanisms are not understood. We used a mouse model of endometrial adenocarcinoma that results from brief developmental exposure to an estrogenic chemical, diethylstilbestrol (DES), to determine causative factors. Single-cell RNA sequencing (scRNAseq) and spatial transcriptomics of adult control uteri revealed novel markers of uterine epithelial stem cells (EpSCs), identified distinct luminal and glandular progenitor cell (PC) populations, and defined glandular and luminal epithelium (LE) cell differentiation trajectories. Neonatal DES exposure disrupted uterine epithelial cell differentiation, resulting in a failure to generate an EpSC population or distinguishable glandular and luminal progenitors or mature cells. Instead, the DES-exposed epithelial cells were characterized by a single proliferating PC population and widespread activation of Wnt/β-catenin signaling. The underlying endometrial stromal cells had dramatic increases in inflammatory signaling pathways and oxidative stress. Together, these changes activated phosphoinositide 3-kinase/AKT serine-threonine kinase signaling and malignant transformation of cells that were marked by phospho-AKT and the cancer-associated protein olfactomedin 4. Here, we defined a mechanistic pathway from developmental exposure to an endocrine disrupting chemical to the development of adult-onset cancer. These findings provide an explanation for how human cancers, which are often associated with abnormal activation of PI3K/AKT signaling, could result from exposure to environmental insults during development.
Collapse
Affiliation(s)
- Elizabeth Padilla-Banks
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
| | - Wendy N. Jefferson
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
| | - Brian N. Papas
- Integrative Bioinformatics, Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
| | - Alisa A. Suen
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
| | - Xin Xu
- Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
| | - Diana V. Carreon
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
| | - Cynthia J. Willson
- Inotiv-RTP, Research Triangle Park, North Carolina, United States of America
| | - Erin M. Quist
- Experimental Pathology Laboratories, Research Triangle Park, North Carolina, United States of America
| | - Carmen J. Williams
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, United States of America
| |
Collapse
|
|
15
|
Marla S, Mortlock S, Yoon S, Crawford J, Andersen S, Mueller MD, McKinnon B, Nguyen Q, Montgomery GW. Global Analysis of Transcription Start Sites and Enhancers in Endometrial Stromal Cells and Differences Associated with Endometriosis. Cells 2023; 12:1736. [PMID: 37443771 PMCID: PMC10340717 DOI: 10.3390/cells12131736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/20/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
Identifying tissue-specific molecular signatures of active regulatory elements is critical to understanding gene regulatory mechanisms. In this study, transcription start sites (TSS) and enhancers were identified using Cap analysis of gene expression (CAGE) across endometrial stromal cell (ESC) samples obtained from women with (n = 4) and without endometriosis (n = 4). ESC TSSs and enhancers were compared to those reported in other tissue and cell types in FANTOM5 and were integrated with RNA-seq and ATAC-seq data from the same samples for regulatory activity and network analyses. CAGE tag count differences between women with and without endometriosis were statistically tested and tags within close proximity to genetic variants associated with endometriosis risk were identified. Over 90% of tag clusters mapping to promoters were observed in cells and tissues in FANTOM5. However, some potential cell-type-specific promoters and enhancers were also observed. Regions of open chromatin identified using ATAC-seq provided further evidence of the active transcriptional regions identified by CAGE. Despite the small sample number, there was evidence of differences associated with endometriosis at 210 consensus clusters, including IGFBP5, CALD1 and OXTR. ESC TSSs were also located within loci associated with endometriosis risk from genome-wide association studies. This study provides novel evidence of transcriptional differences in endometrial stromal cells associated with endometriosis and provides a valuable cell-type specific resource of active TSSs and enhancers in endometrial stromal cells.
Collapse
Affiliation(s)
- Sushma Marla
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; (S.M.); (S.M.); (B.M.); (Q.N.)
| | - Sally Mortlock
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; (S.M.); (S.M.); (B.M.); (Q.N.)
| | - Sohye Yoon
- The Genome Innovation Hub, The University of Queensland, Brisbane, QLD 4072, Australia; (S.Y.); (J.C.); (S.A.)
| | - Joanna Crawford
- The Genome Innovation Hub, The University of Queensland, Brisbane, QLD 4072, Australia; (S.Y.); (J.C.); (S.A.)
| | - Stacey Andersen
- The Genome Innovation Hub, The University of Queensland, Brisbane, QLD 4072, Australia; (S.Y.); (J.C.); (S.A.)
| | - Michael D. Mueller
- Department of Gynecology and Gynecological Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Berne, Switzerland;
| | - Brett McKinnon
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; (S.M.); (S.M.); (B.M.); (Q.N.)
- Department of Gynecology and Gynecological Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Berne, Switzerland;
| | - Quan Nguyen
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; (S.M.); (S.M.); (B.M.); (Q.N.)
| | - Grant W. Montgomery
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; (S.M.); (S.M.); (B.M.); (Q.N.)
- The Genome Innovation Hub, The University of Queensland, Brisbane, QLD 4072, Australia; (S.Y.); (J.C.); (S.A.)
| |
Collapse
|
|
16
|
Tabeeva G, Silachev D, Vishnyakova P, Asaturova A, Fatkhudinov T, Smetnik A, Dumanovskaya M. The Therapeutic Potential of Multipotent Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Endometrial Regeneration. Int J Mol Sci 2023; 24:ijms24119431. [PMID: 37298382 DOI: 10.3390/ijms24119431] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Disruption of endometrial regeneration, fibrosis formation, and intrauterine adhesions underlie the development of "thin" endometrium and/or Asherman's syndrome (AS) and are a common cause of infertility and a high risk for adverse obstetric outcomes. The methods used (surgical adhesiolysis, anti-adhesive agents, and hormonal therapy) do not allow restoration of the regenerative properties of the endometrium. The experience gained today with cell therapy using multipotent mesenchymal stromal cells (MMSCs) proves their high regenerative and proliferative properties in tissue damage. Their contribution to regenerative processes is still poorly understood. One of these mechanisms is based on the paracrine effects of MMSCs associated with the stimulation of cells of the microenvironment by secreting extracellular vesicles (EVs) into the extracellular space. EVs, whose source is MMSCs, are able to stimulate progenitor cells and stem cells in damaged tissues and exert cytoprotective, antiapoptotic, and angiogenic effects. This review described the regulatory mechanisms of endometrial regeneration, pathological conditions associated with a decrease in endometrial regeneration, and it presented the available data from studies on the effect of MMSCs and their EVs on endometrial repair processes, and the involvement of EVs in human reproductive processes at the level of implantation and embryogenesis.
Collapse
Affiliation(s)
- Gyuzyal Tabeeva
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
| | - Denis Silachev
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Polina Vishnyakova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Alexandra Asaturova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
| | - Timur Fatkhudinov
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia (RUDN University), 117198 Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution Petrovsky National Research Centre of Surgery, 117418 Moscow, Russia
| | - Antonina Smetnik
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
| | - Madina Dumanovskaya
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
| |
Collapse
|
|
17
|
A re-appraisal of mesenchymal-epithelial transition (MET) in endometrial epithelial remodeling. Cell Tissue Res 2023; 391:393-408. [PMID: 36401092 PMCID: PMC9889438 DOI: 10.1007/s00441-022-03711-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 11/08/2022] [Indexed: 11/21/2022]
Abstract
Mesenchymal-epithelial transition (MET) is a mechanism of endometrial epithelial regeneration. It is also implicated in adenocarcinoma and endometriosis. Little is known about this process in normal uterine physiology. Previously, using pregnancy and menses-like mouse models, MET occurred only as an epithelial damage/repair mechanism. Here, we hypothesized that MET also occurs in other physiological endometrial remodeling events, outside of damage/repair, such as during the estrous cycle and adenogenesis (gland development). To investigate this, Amhr2-Cre-YFP/GFP mesenchyme-specific reporter mice were used to track the fate of mesenchymal-derived (MD) cells. Using EpCAM (epithelial marker), EpCAM+YFP+ MD-epithelial cells were identified in all stages of the estrous cycle except diestrus, in both postpartum and virgin mice. EpCAM+YFP+ MD-epithelial cells comprised up to 80% of the epithelia during estrogen-dominant proestrus and significantly declined to indistinguishable from control uteri in diestrus, suggesting MET is hormonally regulated. MD-epithelial cells were also identified during postnatal epithelial remodeling. MET occurred immediately after birth at postnatal day (P) 0.5 with EpCAM+GFP+ cells ranging from negligible (0.21%) to 82% of the epithelia. EpCAM+GFP+ MD-epithelial cells declined during initiation of adenogenesis (P8, avg. 1.75%) and then increased during gland morphogenesis (P14, avg. 10%). MD-epithelial cells expressed markers in common with non-MD-epithelial cells (e.g., EpCAM, FOXA2, ESR1, PGR). However, MD-epithelial cells were differentially regulated postnatally and in adults, suggesting a functional distinction in the two populations. We conclude that MET occurs not only as an epithelial damage/repair mechanism but also during other epithelial remodeling events, which to our knowledge has not been demonstrated in other tissues.
Collapse
|
|
18
|
Signaling Pathways Regulating Human Cervical Ripening in Preterm and Term Delivery. Cells 2022; 11:cells11223690. [PMID: 36429118 PMCID: PMC9688647 DOI: 10.3390/cells11223690] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/13/2022] [Accepted: 11/18/2022] [Indexed: 11/22/2022] Open
Abstract
At the end of gestation, the cervical tissue changes profoundly. As a result of these changes, the uterine cervix becomes soft and vulnerable to dilation. The process occurring in the cervical tissue can be described as cervical ripening. The ripening is a process derivative of enzymatic breakdown and inflammatory response. Therefore, it is apparent that cervical remodeling is a derivative of the reactions mediated by multiple factors such as hormones, prostaglandins, nitric oxide, and inflammatory cytokines. However, despite the research carried out over the years, the cellular pathways responsible for regulating this process are still poorly understood. A comprehensive understanding of the entire process of cervical ripening seems crucial in the context of labor induction. Greater knowledge could provide us with the means to help women who suffer from dysfunctional labor. The overall objective of this review is to present the current understanding of cervical ripening in terms of molecular regulation and cell signaling.
Collapse
|
|
19
|
Impact of Oxidative Stress on Molecular Mechanisms of Cervical Ripening in Pregnant Women. Int J Mol Sci 2022; 23:ijms232112780. [PMID: 36361572 PMCID: PMC9657514 DOI: 10.3390/ijms232112780] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/13/2022] [Accepted: 10/21/2022] [Indexed: 11/29/2022] Open
Abstract
Uterine cervix is one of the essential factors in labor and maintaining the proper course of pregnancy. During the last days of gestation, the cervix undergoes extensive changes manifested by transformation from a tight and rigid to one that is soft and able to dilate. These changes can be summarized as “cervical ripening”. Changes in the cervical tissue can be referred to as remodeling of the extracellular matrix. The entire process is the result of a close relationship between biochemical and molecular pathways, which is strictly controlled by inflammatory and endocrine factors. When the production of reactive oxygen species exceeds the antioxidant capacity, oxidative stress occurs. A physiologic increase of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is observed through pregnancy. ROS play important roles as second messengers in many intracellular signaling cascades contributing to the course of gestation. This review considers their involvement in the cervical ripening process, emphasizing the molecular and biochemical pathways and the clinical implications.
Collapse
|
|
20
|
Khan KN, Fujishita A, Mori T. Pathogenesis of Human Adenomyosis: Current Understanding and Its Association with Infertility. J Clin Med 2022; 11:4057. [PMID: 35887822 PMCID: PMC9316454 DOI: 10.3390/jcm11144057] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/22/2022] [Accepted: 07/11/2022] [Indexed: 12/10/2022] Open
Abstract
The aim of this review article was to summarize our current understanding on the etiologies and pathogenesis of human adenomyosis and to clarify the relative association between adenomyosis and infertility. The exact pathogenesis of adenomyosis is still elusive. Among different reported concepts, direction invagination of gland cells from the basalis endometrium deep into myometrium is the most widely accepted opinion on the development of adenomyosis. According to this concept, endometrial epithelial cells and changed fibroblasts, abnormally found in the myometrium in response to repeated tissue injury and/or disruption at the endometrium-myometrium interface (EMI), elicit hyperplasia and hypertrophy of the surrounding smooth muscle cells. In this review, a comprehensive review was performed with a literature search using PubMed for all publications in English and Japanese (abstract in English), related to adenomyosis and infertility, from inception to April 2021. As an estrogen-regulated factor, hepatocyte growth factor (HGF) exhibits multiple functions in endometriosis, a disease commonly believed to arise from the functionalis endometrium. As a mechanistic basis of gland invagination, we investigated the role of HGF, either alone or in combination with estrogen, in the occurrence of epithelial-mesenchymal transition (EMT) in adenomyosis. Aside from microtrauma at the EMI, metaplasia of displaced Müllerian remnants, differentiation of endometrial stem/progenitor cells within the myometrium and somatic mutation of some target genes have been put forward to explain how adenomyosis develops. In addition, the possible role of microRNAs in adenomyosis is also discussed. Besides our knowledge on the conventional classification (focal and diffuse), two recently proposed classifications (intrinsic and extrinsic) of adenomyosis and the biological differences between them have been described. Although the mechanistic basis is unclear, the influence of adenomyosis on fertility outcome is important, especially considering the recent tendency to delay pregnancy among women. Besides other proposed mechanisms, a recent transmission election microscopic (TEM) study indicated that microvilli damage and an axonemal alteration in the apical endometria of human adenomyosis, in response to endometrial inflammation, may be involved in negative fertility outcomes. We present a critical analysis of the literature data concerning the mechanistic basis of infertility in women with adenomyosis and its impact on fertility outcome.
Collapse
Affiliation(s)
- Khaleque N. Khan
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan;
| | - Akira Fujishita
- Department of Gynecology, Saiseikai Nagasaki Hospital, Nagasaki 850-0003, Japan;
| | - Taisuke Mori
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan;
| |
Collapse
|
|
21
|
Lenz J, Konecna P, Tichy F, Machacova D, Fiala L, Hurnik P, Kyllar M. Unique expression patterns of the embryonal stem cell marker SOX2 and hormone receptors suggest the existence of a subpopulation of epithelial stem/progenitor cells in porcine and bovine endometrium. Vet Med Sci 2022; 8:1489-1501. [PMID: 35561288 PMCID: PMC9297784 DOI: 10.1002/vms3.802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND There are currently insufficient data on the population of endometrial epithelial stem/progenitor cells in farm animals. OBJECTIVES With the aim of identifying a potential population of epithelial stem/progenitor cells in the porcine and bovine endometrium, this study immunohistochemically examined the expression patterns of the oestrogen and progesterone receptors, as well as that of the embryonal stem cell marker SOX2. METHODS A total of 24 endometrial tissue samples obtained from cycling pigs (n = 12) and cows (n = 12) were included in our study. Each endometrium was divided into basal, middle and luminal portions. The percentage of marker-positive cells and the intensity of the immunoreaction in each portion of the endometrium were determined. RESULTS Inverse expression patterns of SOX2 and progesterone receptors were found in both animal species throughout the oestrous cycle. Strong diffuse SOX2 expression was detected in the basal portions of the glands, while a significant decrease in positivity and a weak immunoreaction were found in the luminal two thirds of the glandular epithelium. Strong progesterone receptor expression was observed in at least 90% of glandular cells in the middle and luminal portions, whereas weak staining and significant decrease in positivity were detected in the basal portions of the glands. One oestrogen receptor expression pattern resembled that of progesterone receptors. CONCLUSION The inverse expression patterns of SOX2 and hormone (especially progesterone) receptors suggest that endometrial epithelial stem/progenitor cells represent a subset of cells that reside in the basal portions of the endometrial glands in both the bovine and porcine endometrium.
Collapse
Affiliation(s)
- Jiri Lenz
- Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Brno, Czech Republic.,Department of Pathology, Znojmo Hospital, Znojmo, Czech Republic.,Cytohisto s.r.o., Břeclav, Czech Republic
| | - Petra Konecna
- Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Brno, Czech Republic
| | - Frantisek Tichy
- Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Brno, Czech Republic
| | - Dominika Machacova
- Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Brno, Czech Republic
| | - Ludek Fiala
- Cytohisto s.r.o., Břeclav, Czech Republic.,Department of Sexology, Psychiatric Clinic, Faculty of Medicine, Charles University Pilsen, Pilsen, Czech Republic.,Institute of Sexology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic
| | | | - Michal Kyllar
- Department of Pathobiology, Institute of Morphology, University of Veterinary Medicine Vienna, Vienna, Austria
| |
Collapse
|
|
22
|
Tang S, Cope DI, Vasquez YM, Monsivais D. BMP/SMAD1/5 Signaling in the Endometrial Epithelium Is Essential for Receptivity and Early Pregnancy. Endocrinology 2022; 163:6564025. [PMID: 35383354 PMCID: PMC9049119 DOI: 10.1210/endocr/bqac043] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Indexed: 11/19/2022]
Abstract
The biological processes that control endometrial receptivity and embryo implantation are critical for the successful outcome of pregnancy. The endometrium is the complex inner lining of the uterine wall that is under the cyclical control of estrogen and progesterone and is a site of intimate contact between mother and blastocyst. The bone morphogenetic signaling (BMP) pathway is a highly conserved signaling pathway that controls key cellular processes throughout pregnancy and exerts intracellular effects via the SMAD1/5 transcription factors. To delineate the endometrial compartment-specific roles of BMP signaling, we generated mice with epithelial-specific conditional deletion of SMAD1/5 using Lactoferrin-icre (Smad1flox/flox;Smad5flox/flox;Lactoferrin-cre, "Smad1/5 cKO"). Histological analysis of the reproductive tracts showed that Smad1/5 cKO mice were developmentally normal and displayed no defects in glandular morphology. In fertility analyses, single SMAD1 or SMAD5 deletion had no effect on fertility; however, double-conditional deletion of SMAD1 and SMAD5 resulted in severe subfertility. Timed mating analyses revealed endometrial receptivity defects in the Smad1/5 cKO mice beginning at 3.5 days post coitum (dpc) that perturbed embryo implantation at 4.5 dpc, as demonstrated by the detection of unattached blastocysts in the uterus, decreased COX2 expression, and FOXO1 cytoplasmic mislocalization. We also found that defects that arose during peri-implantation adversely affected embryonic and decidual development at 5.5 and 6.5 dpc. Thus, uterine epithelial BMP/SMAD1/5 signaling is essential during early pregnancy and SMAD1/5 epithelial-specific deletion has detrimental effects on stromal cell decidualization and pregnancy development.
Collapse
Affiliation(s)
- Suni Tang
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA
- Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Dominique I Cope
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA
- Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yasmin M Vasquez
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA
- Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Diana Monsivais
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA
- Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA
- Correspondence: Diana Monsivais, PhD, Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Smith S217, Houston, TX 77030, USA.
| |
Collapse
|
|
23
|
Brucker SY, Hentrich T, Schulze-Hentrich JM, Pietzsch M, Wajngarten N, Singh AR, Rall K, Koch A. Endometrial organoids derived from Mayer-Rokitansky-Küster-Hauser syndrome patients provide insights into disease-causing pathways. Dis Model Mech 2022; 15:dmm049379. [PMID: 35394036 PMCID: PMC9118093 DOI: 10.1242/dmm.049379] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 03/31/2022] [Indexed: 12/13/2022] Open
Abstract
The uterus is responsible for the nourishment and mechanical protection of the developing embryo and fetus and is an essential part in mammalian reproduction. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by agenesis of the uterus and upper part of the vagina in females with normal ovarian function. Although heavily studied, the cause of the disease is still enigmatic. Current research in the field of MRKH mainly focuses on DNA-sequencing efforts and, so far, has been unable to decipher the nature and heterogeneity of the disease, thereby holding back scientific and clinical progress. Here, we developed long-term expandable organoid cultures from endometrium found in uterine rudiment horns of MRKH patients. Phenotypically, they share great similarity with healthy control organoids and are surprisingly fully hormone responsive. Transcriptome analyses, however, identified an array of dysregulated genes that point to potentially disease-causing pathways altered during the development of the female reproductive tract. We consider the endometrial organoid cultures to be a powerful research tool that promise to enable an array of studies into the pathogenic origins of MRKH syndrome and possible treatment opportunities to improve patient quality of life.
Collapse
Affiliation(s)
- Sara Y. Brucker
- Department of Women's Health, University of Tübingen, 72076 Tübingen, Germany
- Rare Disease Center Tübingen, University of Tübingen, 72076 Tübingen, Germany
| | - Thomas Hentrich
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany
| | - Julia M. Schulze-Hentrich
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany
- Institute for Bioinformatics and Medical Informatics (IBMI), University of Tübingen, 72076 Tübingen, Germany
| | - Martin Pietzsch
- Department of Women's Health, University of Tübingen, 72076 Tübingen, Germany
| | - Noel Wajngarten
- Research Institute for Women's Health, University of Tübingen, 72076 Tübingen, Germany
| | - Anjali Ralhan Singh
- Research Institute for Women's Health, University of Tübingen, 72076 Tübingen, Germany
| | - Katharina Rall
- Department of Women's Health, University of Tübingen, 72076 Tübingen, Germany
- Rare Disease Center Tübingen, University of Tübingen, 72076 Tübingen, Germany
| | - André Koch
- Research Institute for Women's Health, University of Tübingen, 72076 Tübingen, Germany
| |
Collapse
|
|
24
|
Influence of Genotype on Endometrial Angiogenesis during Early Pregnancy in Piau and Commercial Line Gilts. Animals (Basel) 2022; 12:ani12050553. [PMID: 35268121 PMCID: PMC8908842 DOI: 10.3390/ani12050553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 02/04/2022] [Accepted: 02/16/2022] [Indexed: 11/17/2022] Open
Abstract
This study aimed to evaluate the endometrial angiogenesis of pregnant commercial line and Piau gilts during early pregnancy. We used 27 gilts, divided into three groups according to the type of mating: Commercial (n = 9), commercial line females mated with commercial line males; Cross-mated (n = 9), Piau females mated with commercial line males; and Piau (n = 9), Piau females mated with Piau males. Each group was divided into three subgroups based on gestational age at the time of slaughter (7, 15, and 30 days of pregnancy). Immediately after slaughter, endometrial samples were obtained for histological evaluation and for analysis of the relative transcript abundance (RTA) of angiogenesis-related genes (HIF1α, FGF9, ANG1, TEK, VEGFA, ANGPT1, and ANGPT2). The number of endometrial glands was similar among groups but decreased with gestational age (p < 0.05). Piau females showed a higher number of blood vessels (p < 0.05) at 7 and 15 days of pregnancy, but no differences were observed among groups at 30 days, suggesting an influence of the male genotype on the pattern of uterine vascularization. There were no differences among groups for RTA of the FGF9, HIF1α, TEK, VEGFA, ANGPT1, and ANGPT2 genes. The HIF1α-gene RTA was higher at 7 and 15 days of pregnancy; for TEK and ANGPT1, the RTA was higher at 15 days of pregnancy; and the RTA of VEGFA and ANGPT2 genes were higher at 30 days of pregnancy. The ANG1 RTA was similar for pregnancies in the commercial and Piau groups but was higher (p < 0.05) at 15 days in the Cross-mated group, suggesting an interaction between genotypes. Overall, the pattern found for the RTA of angiogenesis-related genes was similar among the groups in this study, although some phenotypic differences could be noted, such as the highest number of blood vessels being found during early pregnancy of Piau gilts. The results of the gene RTA when crossed with phenotypic data led to conclusions that are conflicting with those reported in the literature. However, noteworthy is that angiogenesis is a complex process in which the balance between stimulatory and inhibitory factors may be related to time.
Collapse
|
|
25
|
Lin Y, Dong S, Ye X, Liu J, Li J, Zhang Y, Tu M, Wang S, Ying Y, Chen R, Wang F, Ni F, Chen J, Du B, Zhang D. Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels. Stem Cell Res Ther 2022; 13:66. [PMID: 35135594 PMCID: PMC8822809 DOI: 10.1186/s13287-022-02717-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 01/04/2022] [Indexed: 12/22/2022] Open
Abstract
Background Thin endometrium is a primary cause of defective endometrial receptivity, resulting in infertility or recurrent miscarriage. Much effort has been devoted toward regenerating thin endometrium by stem cell-based therapies. The human placenta-derived mesenchymal stem cells (HP-MSCs) are emerging alternative sources of MSCs with various advantages. To maximize their retention inside the uterus, we loaded HP-MSCs with cross-linked hyaluronic acid hydrogel (HA hydrogel) to investigate their therapeutic efficacy and possible underlying mechanisms.
Methods Ethanol was injected into the mice uterus to establish the endometrium-injured model. The retention time of HP-MSCs and HA hydrogel was detected by in vivo imaging, while the distribution of HP-MSCs was detected by immunofluorescence staining. Functional restoration of the uterus was assessed by testing embryo implantation rates. The endometrial morphological alteration was observed by H&E staining, Masson staining, and immunohistochemistry. In vitro studies were further conducted using EdU, transwell, tube formation, and western blot assays. Results Instilled HP-MSCs with HA hydrogel (HP-MSCs-HA) exhibited a prolonged retention time in mouse uteri than normal HP-MSCs. In vivo studies showed that the HP-MSCs-HA could significantly increase the gland number and endometrial thickness (P < 0.001, P < 0.05), decrease fibrous area (P < 0.0001), and promote the proliferation and angiogenesis of endometrial cells (as indicated by Ki67 and VEGF, P < 0.05, P < 0.05, respectively) in mice injured endometrium. HP-MSCs-HA could also significantly improve the embryo implantation rate (P < 0.01) compared with the ethanol group. Further mechanistic study showed the paracrine effects of HP-MSCs. They could not only promote the proliferation and migration of human endometrial stromal cells via the JNK/Erk1/2-Stat3-VEGF pathway but also facilitate the proliferation of glandular cells via Jak2-Stat5 and c-Fos-VEGF pathway. In turn, the increased VEGF in the endometrium promoted the angiogenesis of endothelial cells. Conclusion Our study suggested the potential therapeutic effects and the underlying mechanisms of HP-MSCs-HA on treating thin endometrium. HA hydrogel could be a preferable delivery method for HP-MSCs, and the strategy represents a promising therapeutic approach against endometrial injury in clinical settings. Graphical abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02717-2.
Collapse
Affiliation(s)
- Yifeng Lin
- Key Laboratory of Women's Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Shunni Dong
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Xiaohang Ye
- Key Laboratory of Women's Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Juan Liu
- Key Laboratory of Women's Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Jiaqun Li
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Yanye Zhang
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Mixue Tu
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Siwen Wang
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Yanyun Ying
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Ruixue Chen
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Feixia Wang
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Feida Ni
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Jianpeng Chen
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Binyang Du
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China.
| | - Dan Zhang
- Key Laboratory of Women's Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China. .,Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China.
| |
Collapse
|
|
26
|
Machado DA, Ontiveros AE, Behringer RR. Mammalian uterine morphogenesis and variations. Curr Top Dev Biol 2022; 148:51-77. [DOI: 10.1016/bs.ctdb.2021.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
|
27
|
Gao X, Yao X, Li X, Liang Y, Liu Z, Wang Z, Li K, Li Y, Zhang G, Wang F. Roles of WNT6 in Sheep Endometrial Epithelial Cell Cycle Progression and Uterine Glands Organogenesis. Vet Sci 2021; 8:vetsci8120316. [PMID: 34941843 PMCID: PMC8708052 DOI: 10.3390/vetsci8120316] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/22/2021] [Accepted: 12/04/2021] [Indexed: 11/22/2022] Open
Abstract
The uterus, as part of the female reproductive tract, is essential for embryo survival and in the maintenance of multiple pregnancies in domestic animals. This study was conducted to investigate the effects of WNT6 on Hu sheep endometrial epithelial cells (EECs) and uterine glands (UGs) in Hu sheep, with high prolificacy rates. In the present study, Hu sheep with different fecundity, over three consecutive pregnancies, were divided into two groups: high prolificacy rate group (HP, litter size = 3) and low prolificacy rate group (LP, litter size = 1). A comparative analysis of the endometrial morphology was performed by immunofluorescence. RNA-seq was used to analyze the gene’s expression in endometrium of HP and LP Hu sheep, providing a candidate gene, which was investigated in EECs and organoid culture. Firstly, higher density of UGs was found in the HP Hu sheep groups (p < 0.05). The RNA-seq data revealed the importance of the WNT signaling pathway and WNT6 gene in Hu sheep endometrium. Functionally, WNT6 could promote the cell cycle progression of EECs via WNT/β-catenin signal and enhance UGs organogenesis. Taken together, WNT6 is a crucial regulator for sheep endometrial development; this finding may offer a new insight into understanding the regulatory mechanism of sheep prolificacy.
Collapse
Affiliation(s)
- Xiaoxiao Gao
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (X.G.); (X.Y.); (X.L.); (Y.L.); (Z.L.); (Z.W.); (K.L.); (Y.L.); (G.Z.)
- Hu Sheep Academy, Nanjing Agricultural University, Nanjing 210095, China
| | - Xiaolei Yao
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (X.G.); (X.Y.); (X.L.); (Y.L.); (Z.L.); (Z.W.); (K.L.); (Y.L.); (G.Z.)
- Hu Sheep Academy, Nanjing Agricultural University, Nanjing 210095, China
| | - Xiaodan Li
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (X.G.); (X.Y.); (X.L.); (Y.L.); (Z.L.); (Z.W.); (K.L.); (Y.L.); (G.Z.)
- Hu Sheep Academy, Nanjing Agricultural University, Nanjing 210095, China
| | - Yaxu Liang
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (X.G.); (X.Y.); (X.L.); (Y.L.); (Z.L.); (Z.W.); (K.L.); (Y.L.); (G.Z.)
- Hu Sheep Academy, Nanjing Agricultural University, Nanjing 210095, China
| | - Zifei Liu
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (X.G.); (X.Y.); (X.L.); (Y.L.); (Z.L.); (Z.W.); (K.L.); (Y.L.); (G.Z.)
- Hu Sheep Academy, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhibo Wang
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (X.G.); (X.Y.); (X.L.); (Y.L.); (Z.L.); (Z.W.); (K.L.); (Y.L.); (G.Z.)
- Hu Sheep Academy, Nanjing Agricultural University, Nanjing 210095, China
| | - Kang Li
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (X.G.); (X.Y.); (X.L.); (Y.L.); (Z.L.); (Z.W.); (K.L.); (Y.L.); (G.Z.)
- Hu Sheep Academy, Nanjing Agricultural University, Nanjing 210095, China
| | - Yingqi Li
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (X.G.); (X.Y.); (X.L.); (Y.L.); (Z.L.); (Z.W.); (K.L.); (Y.L.); (G.Z.)
- Hu Sheep Academy, Nanjing Agricultural University, Nanjing 210095, China
| | - Guomin Zhang
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (X.G.); (X.Y.); (X.L.); (Y.L.); (Z.L.); (Z.W.); (K.L.); (Y.L.); (G.Z.)
- Hu Sheep Academy, Nanjing Agricultural University, Nanjing 210095, China
| | - Feng Wang
- Jiangsu Livestock Embryo Engineering Laboratory, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (X.G.); (X.Y.); (X.L.); (Y.L.); (Z.L.); (Z.W.); (K.L.); (Y.L.); (G.Z.)
- Hu Sheep Academy, Nanjing Agricultural University, Nanjing 210095, China
- Correspondence: ; Tel.: +86-025-84395381
| |
Collapse
|
|
28
|
Akthar I, Marey MA, Kim Y, Shimada M, Suarez SS, Miyamoto A. Sperm interaction with the uterine innate immune system: toll-like receptor 2 (TLR2) is a main sensor in cattle. Reprod Fertil Dev 2021; 34:139-148. [PMID: 35231265 DOI: 10.1071/rd21265] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
During the passage through the female reproductive tract, sperm interact with various compartments and their immune systems. The immune system that protects the female against pathogens also could destroy sperm or prevent them from reaching the site of fertilisation. In particular, the uterine innate immune response is crucial from the perspectives of both the sperm and the uterus. Following insemination, sperm immediately start to trigger inflammation in the uterus by entering uterine glands and activating an innate immune response. In cattle, the activation occurs mainly via TLR2 signalling, if not the only one, between sperm and the uterine epithelium lining the glands. This acute immune response is manifested as the upregulation of mRNA expression of IL8, TNFA, IL1B , and PGES . As a consequence, many sperm are trapped by polymorphonuclear neutrophils, the first and major component of innate immunity. The sperm-induced uterine innate immune responses apparently serve to clear the uterus of excess sperm and, importantly, prepare the endometrium for implantation. Pathophysiological conditions in the uterus seriously disrupt this phenomenon, and thus could directly decrease fertility.
Collapse
Affiliation(s)
- Ihshan Akthar
- Global Agromedicine Research Center (GAMRC), Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan
| | - Mohamed A Marey
- Global Agromedicine Research Center (GAMRC), Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan; and Department of Theriogenology, Faculty of Veterinary Medicine, Damanhur University, Behera, Egypt
| | - Yejin Kim
- Global Agromedicine Research Center (GAMRC), Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan
| | - Masayuki Shimada
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Susan S Suarez
- Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Akio Miyamoto
- Global Agromedicine Research Center (GAMRC), Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan
| |
Collapse
|
|
29
|
Regulation of uterine function during estrous cycle, anestrus phase and pregnancy by steroids in red deer (Cervus elaphus L.). Sci Rep 2021; 11:20109. [PMID: 34635709 PMCID: PMC8505504 DOI: 10.1038/s41598-021-99601-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 09/21/2021] [Indexed: 11/08/2022] Open
Abstract
Steroid synthesis and production in ruminant uterus is not obvious, especially in seasonally reproduced. We compared steroid production by investigating enzymes involved in red deer uterine steroid metabolism in reproductive seasons. Blood and uteri (endometrium and myometrium) were collected post mortem from hinds on 4th day (N = 8), 13th day of the cycle (N = 8), anestrus (N = 8) and pregnancy (N = 8). The expression of cytochrome P450 aromatase (P450), 3 -beta-hydroxysteroid dehydrogenase (3β-HSD), 17 -beta-hydroxysteroid dehydrogenase (17β-HSD), aldo-keto reductase family 1 C1 (AKR1C1), estrogen receptor alpha (ERα), and progesterone receptors (PRs), were analyzed using real-time-PCR and Western Blotting. Plasma samples were assayed for 17-beta-estradiol (E2), progesterone (P4), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T4) concentrations by EIA. Hinds at the beginning of the estrous cycle, mainly in endometrium, were characterized by a high mRNA expression of 3β-HSD, AKR1C1, PRs and ERα, contrary to the expression in myometrium during pregnancy (P < 0.05). For P4, E2, and FSH, concentration was the highest during the 13th day of the estrous cycle (P < 0.05). Uterine steroid production and output in hinds as a representative seasonally reproduced ruminant occurred mainly during the estrous cycle and sustained in anestrus.
Collapse
|
|
30
|
Mesenchymal Stem Cells in Preclinical Infertility Cytotherapy: A Retrospective Review. Stem Cells Int 2021; 2021:8882368. [PMID: 34054970 PMCID: PMC8143877 DOI: 10.1155/2021/8882368] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 04/06/2021] [Accepted: 05/07/2021] [Indexed: 12/11/2022] Open
Abstract
Infertility is a global reproductive disorder which is caused by a variety of complex diseases. Infertility affects the individual, family, and community through physical, psychological, social and economic consequences. The results from recent preclinical studies regarding stem cell-based therapies are promising. Stem cell-based therapies cast a new hope for infertility treatment as a replacement or regeneration strategy. The main features and application prospects of mesenchymal stem cells in the future of infertility should be understood by clinicians. Mesenchymal stem cells (MSCs) are multipotent stem cells with abundant source, active proliferation, and multidirectional differentiation potential. MSCs play a role through cell homing, secretion of active factors, and participation in immune regulation. Another advantage is that, compared with embryonic stem cells, there are fewer ethical factors involved in the application of MSCs. However, a number of questions remain to be answered prior to safe and effective clinical application. In this review, we summarized the recent status of MSCs in the application of the diseases related to or may cause to infertility and suggest a possible direction for future cytotherapy to infertility.
Collapse
|
|
31
|
de Barros JWF, Villela E Silva P, da Silva GV, da Silva KP, Borges CDS, Mueller A, Valencise L, Pupo AS, Kempinas WDG. Rosuvastatin exposure in female Wistar rats alters uterine contractility and do not show evident (anti)estrogenic effects. Drug Chem Toxicol 2021; 45:2233-2245. [PMID: 33934680 DOI: 10.1080/01480545.2021.1919139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Statins are 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor drugs that lead to serum-cholesterol-lowering effects. Rosuvastatin, a third-generation statin, has shown better results in reducing cholesterol concentrations when compared to other widely prescribed statins. Recent studies by our group reported that rosuvastatin impairs reproductive function in rats possibly by disrupting the reproductive-endocrine axis. In this study, we evaluated whether rosuvastatin presents estrogenic or antiestrogenic effects, by an in vivo uterotrophic assay in rats, and investigated the direct effect of this drug upon rat uterine tissue contractility both in non-gravid and gravid periods. Rosuvastatin exposure in vivo at doses of 0 (control), 3, and 10 mg/kg/d was not associated with estrogenic or antiestrogenic effects on uterine tissue. However, in vivo (doses of 0, 3, and 10 mg/kg/d) and ex vivo (concentrations of 0, 1, 10, and 100 µg/mL) exposures to this drug were related to alterations in uterine basal contraction pattern. Furthermore, in vivo and ex vivo rosuvastatin exposures potentially modulate the action of uterine contraction inducers carbachol, norepinephrine, and prostaglandin E2. Thus, rosuvastatin can affect uterine physiology not necessarily by an endocrine mechanism related to the estrogen signaling, but possibly by its pleiotropic effects, with indirect tissue and cellular interactions, since in vivo and ex vivo exposures of uterine fragments to rosuvastatin presented different responses in uterine contractile parameters, which require further studies upon the precise mechanism of action of this drug in female reproductive function.
Collapse
Affiliation(s)
- Jorge Willian Franco de Barros
- Department of Structural and Functional Biology, Institute of Biosciences, Laboratory of Reproductive and Developmental Biology and Toxicology, São Paulo State University (UNESP), Botucatu, Brazil
| | - Patrícia Villela E Silva
- Department of Structural and Functional Biology, Institute of Biosciences, Laboratory of Reproductive and Developmental Biology and Toxicology, São Paulo State University (UNESP), Botucatu, Brazil
| | - Gustavo Venâncio da Silva
- Department of Structural and Functional Biology, Institute of Biosciences, Laboratory of Reproductive and Developmental Biology and Toxicology, São Paulo State University (UNESP), Botucatu, Brazil
| | - Katiussia Pinho da Silva
- Department of Biophysics and Pharmacology, São Paulo State University (Unesp), Institute of Biosciences, Botucatu, Brazil
| | - Cibele Dos Santos Borges
- Department of Structural and Functional Biology, Institute of Biosciences, Laboratory of Reproductive and Developmental Biology and Toxicology, São Paulo State University (UNESP), Botucatu, Brazil
| | - André Mueller
- Department of Biophysics and Pharmacology, São Paulo State University (Unesp), Institute of Biosciences, Botucatu, Brazil
| | - Lethícia Valencise
- Department of Structural and Functional Biology, Institute of Biosciences, Laboratory of Reproductive and Developmental Biology and Toxicology, São Paulo State University (UNESP), Botucatu, Brazil
| | - André Sampaio Pupo
- Department of Biophysics and Pharmacology, São Paulo State University (Unesp), Institute of Biosciences, Botucatu, Brazil
| | - Wilma De Grava Kempinas
- Department of Structural and Functional Biology, Institute of Biosciences, Laboratory of Reproductive and Developmental Biology and Toxicology, São Paulo State University (UNESP), Botucatu, Brazil
| |
Collapse
|
|
32
|
A Detailed Study in Adenomyosis and Endometriosis: Evaluation of the Rate of Coexistence Between Uterine Adenomyosis and DIE According to Imaging and Histopathology Findings. Reprod Sci 2021; 28:2387-2397. [PMID: 33725313 DOI: 10.1007/s43032-021-00527-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 03/01/2021] [Indexed: 01/11/2023]
Abstract
The current study was designed to evaluate the relationship between adenomyosis and its subtypes with endometriotic lesions (ovarian endometrioma (OMAs) and posterior deep infiltrative endometriosis (DIE)), to examine the probability of existence of a common cause of these mysterious diseases, and to evaluate the accuracy, sensitivity, and specificity of both transvaginal ultrasonography (TVS) and MRI in diagnosis of adenomyotic uterus. In this retrospective cross-sectional study, we selected 154 women with coexistence of endometriosis and adenomyosis according to their imaging, intraoperative, or pathological findings who were nominated for laparoscopic surgery. Eighty-six patients with just DIE resection without LH (laparoscopic hysterectomy) (group 1), and 68 patients with LH + DIE resection (group 2). The accuracy, sensitivity, and specificity of ultrasonographic and MRI findings for diagnosing adenomyosis were 72.1%, 77.6%, 40.0% and 49.2%, 41.5%, 90.0% respectively. So, TVS is a more sensitive diagnostic tool for diagnosing adenomyosis. However, MRI was more specific than TVS in the diagnosis of diffuse adenomyosis especially with simultaneous presence of uterine leiomyoma. Regarding the association of different types of adenomyosis (focal and diffuse) with different endometriosis lesions (OMA and posterior compartment DIE), we just found diffuse type of adenomyosis more frequent in the absence of rectal and rectovaginal septum (RVS) DIE (p ≤ 0.05). In addition to the questionable different nature of rectal and RVS DIE lesion, there is no relationship between adenomyosis subtypes and endometriotic lesions.
Collapse
|
|
33
|
Uterine Stem Cells and Benign Gynecological Disorders: Role in Pathobiology and Therapeutic Implications. Stem Cell Rev Rep 2020; 17:803-820. [PMID: 33155150 DOI: 10.1007/s12015-020-10075-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2020] [Indexed: 12/15/2022]
Abstract
Stem cells in the endometrium and myometrium possess an immense regenerative potential which is necessary to maintain the menstrual cycle and support pregnancy. These cells, as well as bone marrow stem cells, have also been implicated in the development of common benign gynecological disorders including leiomyomas, endometriosis and adenomyosis. Current evidence suggests the conversion of uterine stem cells to tumor initiating stem cells in leiomyomas, endometriosis stem cells, and adenomyosis stem cells, acquiring genetic and epigenetic alterations for the progression of each benign condition. In this comprehensive review, we aim to summarize the progress that has been made to characterize the involvement of stem cells in the pathogenesis of benign gynecologic conditions which, despite their enormous burden, are not yet fully understood. We focus on the stem cell characteristics and aberrations that contribute to the development of benign gynecological disorders and the possible clinical implications of what is known so far. Lastly, we discuss the role of uterine stem cells in the setting of regenerative medicine, particularly in the treatment of Asherman syndrome.Graphical abstract.
Collapse
|
|
34
|
Di Simone N, Santamaria Ortiz A, Specchia M, Tersigni C, Villa P, Gasbarrini A, Scambia G, D’Ippolito S. Recent Insights on the Maternal Microbiota: Impact on Pregnancy Outcomes. Front Immunol 2020; 11:528202. [PMID: 33193302 PMCID: PMC7645041 DOI: 10.3389/fimmu.2020.528202] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 08/27/2020] [Indexed: 12/20/2022] Open
Abstract
Hormonal changes during and after pregnancy are linked with modifications in the maternal microbiota. We describe the importance of the maternal microbiota in pregnancy and examine whether changes in maternal microbiotic composition at different body sites (gut, vagina, endometrium) are associated with pregnancy complications. We analyze the likely interactions between microbiota and the immune system. During pregnancy, the gastrointestinal (gut) microbiota undergoes profound changes that lead to an increase in lactic acid-producing bacteria and a reduction in butyrate-producing bacteria. The meaning of such changes needs clarification. Additionally, several studies have indicated a possible involvement of the maternal gut microbiota in autoimmune and lifelong diseases. The human vagina has its own microbiota, and changes in vaginal microbiota are related to several pregnancy-related complications. Recent studies show reduced lactobacilli, increased bacterial diversity, and low vaginal levels of beta-defensin 2 in women with preterm births. In contrast, early and healthy pregnancies are characterized by low diversity and low numbers of bacterial communities dominated by Lactobacillus. These observations suggest that early vaginal cultures that show an absence of Lactobacillus and polymicrobial vaginal colonization are risk factors for preterm birth. The endometrium is not a sterile site. Resident endometrial microbiota has only been defined recently. However, questions remain regarding the main components of the endometrial microbiota and their impact on the reproductive tract concerning both fertility and pregnancy outcomes. A classification based on endometrial bacterial patterns could help develop a microbiota-based diagnosis as well as personalized therapies for the prevention of obstetric complications and personalized treatments through nutritional, microbiotic, or pharmaceutical interventions.
Collapse
Affiliation(s)
- Nicoletta Di Simone
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | | | - Monia Specchia
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Chiara Tersigni
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Paola Villa
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Antonio Gasbarrini
- Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Giovanni Scambia
- Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Silvia D’Ippolito
- Dipartimento di Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| |
Collapse
|
|
35
|
Yin M, Zhou HJ, Lin C, Long L, Yang X, Zhang H, Taylor H, Min W. CD34 +KLF4 + Stromal Stem Cells Contribute to Endometrial Regeneration and Repair. Cell Rep 2020; 27:2709-2724.e3. [PMID: 31141693 PMCID: PMC6548470 DOI: 10.1016/j.celrep.2019.04.088] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 03/01/2019] [Accepted: 04/16/2019] [Indexed: 12/22/2022] Open
Abstract
The regenerative capacity of the human endometrium requires a population of local stem cells. However, the phenotypes, locations, and origin of these cells are still unknown. In a mouse menstruation model, uterine stromal SM22α+-derived CD34+KLF4+ stem cells are activated and integrate into the regeneration area, where they differentiate and incorporate into the endometrial epithelium; this process is correlated with enhanced protein SUMOylation in CD34+KLF4+ cells. Mice with a stromal SM22α-specific SENP1 deletion (SENP1smKO) exhibit accelerated endometrial repair in the regeneration model and develop spontaneous uterine hyperplasia. Mechanistic studies suggest that SENP1 deletion induces SUMOylation of ERα, which augments ERα transcriptional activity and proliferative signaling in SM22α+CD34+KLF4+ cells. These cells then transdifferentiate to the endometrial epithelium. Our study reveals that CD34+KLF4+ stromal-resident stem cells directly contribute to endometrial regeneration, which is regulated through SENP1-mediated ERα suppression. The regenerative capacity of the human endometrium requires a population of local stem cells. Here, Yin et al. show that uterine stromal SM22α+CD34+KLF4+ stem cells are activated by ERα SUMOylation and integrate into the regeneration area, where they differentiate and incorporate into the endometrial epithelium.
Collapse
Affiliation(s)
- Mingzhu Yin
- Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad St., New Haven, CT 06520, USA
| | - Huanjiao Jenny Zhou
- Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad St., New Haven, CT 06520, USA
| | - Caixia Lin
- Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Lingli Long
- Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Xiaolei Yang
- Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Haifeng Zhang
- Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad St., New Haven, CT 06520, USA
| | - Hugh Taylor
- Department of Comparative Medicine and Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Wang Min
- Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad St., New Haven, CT 06520, USA.
| |
Collapse
|
|
36
|
Abudukeyoumu A, Li MQ, Xie F. Transforming growth factor-β1 in intrauterine adhesion. Am J Reprod Immunol 2020; 84:e13262. [PMID: 32379911 DOI: 10.1111/aji.13262] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/30/2020] [Accepted: 05/01/2020] [Indexed: 02/06/2023] Open
Abstract
Intrauterine adhesion (IUA), led by trauma to the basal layer, can prevent the endometrium from growing, resulting in complications in females, such as infertility and amenorrhea. Transforming growth factor-β1 (TGF-β1) plays a crucial role in inducing and promoting the differentiation and proliferation of mesenchymal cells, in the secretion of extracellular matrix-associated components, and is a major cytokine in initiating and terminating tissue repair downstream of the TGF-β/Smad signaling pathway. Some evidence supports that TGF-β1 is closely associated with the occurrence and development of IUA, and is regarded as an early risk factor of disease recurrence. Furthermore, the role of TGF-β1 has been demonstrated to be potentially regulated by a variety of cytokines, hormones, enzymes, and microRNAs. This review provides an overview of the expression, function, and regulation of TGF-β1 in IUA, with a brief discussion and perspectives on its future clinical implications on the diagnosis and treatment of IUA.
Collapse
Affiliation(s)
- Ayitila Abudukeyoumu
- Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.,Medical Center of Diagnosis and Treatment for Cervical Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Ming-Qing Li
- Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.,NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
| | - Feng Xie
- Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.,Medical Center of Diagnosis and Treatment for Cervical Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
| |
Collapse
|
|
37
|
Massimiani M, Lacconi V, La Civita F, Ticconi C, Rago R, Campagnolo L. Molecular Signaling Regulating Endometrium-Blastocyst Crosstalk. Int J Mol Sci 2019; 21:E23. [PMID: 31861484 PMCID: PMC6981505 DOI: 10.3390/ijms21010023] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 11/29/2019] [Accepted: 12/16/2019] [Indexed: 12/13/2022] Open
Abstract
Implantation of the embryo into the uterine endometrium is one of the most finely-regulated processes that leads to the establishment of a successful pregnancy. A plethora of factors are released in a time-specific fashion to synchronize the differentiation program of both the embryo and the endometrium. Indeed, blastocyst implantation in the uterus occurs in a limited time frame called the "window of implantation" (WOI), during which the maternal endometrium undergoes dramatic changes, collectively called "decidualization". Decidualization is guided not just by maternal factors (e.g., estrogen, progesterone, thyroid hormone), but also by molecules secreted by the embryo, such as chorionic gonadotropin (CG) and interleukin-1β (IL-1 β), just to cite few. Once reached the uterine cavity, the embryo orients correctly toward the uterine epithelium, interacts with specialized structures, called pinopodes, and begins the process of adhesion and invasion. All these events are guided by factors secreted by both the endometrium and the embryo, such as leukemia inhibitory factor (LIF), integrins and their ligands, adhesion molecules, Notch family members, and metalloproteinases and their inhibitors. The aim of this review is to give an overview of the factors and mechanisms regulating implantation, with a focus on those involved in the complex crosstalk between the blastocyst and the endometrium.
Collapse
Affiliation(s)
- Micol Massimiani
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (M.M.); (V.L.); (F.L.C.)
- Saint Camillus International University of Health Sciences, Via di Sant’Alessandro, 8, 00131 Rome, Italy
| | - Valentina Lacconi
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (M.M.); (V.L.); (F.L.C.)
| | - Fabio La Civita
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (M.M.); (V.L.); (F.L.C.)
| | - Carlo Ticconi
- Department of Surgical Sciences, Section of Gynecology and Obstetrics, University Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy;
| | - Rocco Rago
- Physiopathology of Reproduction and Andrology Unit, Sandro Pertini Hospital, Via dei Monti Tiburtini 385/389, 00157 Rome, Italy;
| | - Luisa Campagnolo
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (M.M.); (V.L.); (F.L.C.)
| |
Collapse
|
|
38
|
Seishima R, Leung C, Yada S, Murad KBA, Tan LT, Hajamohideen A, Tan SH, Itoh H, Murakami K, Ishida Y, Nakamizo S, Yoshikawa Y, Wong E, Barker N. Neonatal Wnt-dependent Lgr5 positive stem cells are essential for uterine gland development. Nat Commun 2019; 10:5378. [PMID: 31772170 PMCID: PMC6879518 DOI: 10.1038/s41467-019-13363-3] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 11/05/2019] [Indexed: 12/21/2022] Open
Abstract
Wnt signaling is critical for directing epithelial gland development within the uterine lining to ensure successful gestation in adults. Wnt-dependent, Lgr5-expressing stem/progenitor cells are essential for the development of glandular epithelia in the intestine and stomach, but their existence in the developing reproductive tract has not been investigated. Here, we employ Lgr5-2A-EGFP/CreERT2/DTR mouse models to identify Lgr5-expressing cells in the developing uterus and to evaluate their stem cell identity and function. Lgr5 is broadly expressed in the uterine epithelium during embryogenesis, but becomes largely restricted to the tips of developing glands after birth. In-vivo lineage tracing/ablation/organoid culture assays identify these gland-resident Lgr5high cells as Wnt-dependent stem cells responsible for uterine gland development. Adjacent Lgr5neg epithelial cells within the neonatal glands function as essential niche components to support the function of Lgr5high stem cells ex-vivo. These findings constitute a major advance in our understanding of uterine development and lay the foundations for investigating potential contributions of Lgr5+ stem/progenitor cells to uterine disorders. Uterine gland development is essential for successful embryo implantation, decidua formation and placental development. Here the authors demonstrate that neonatal Wnt-dependent Lgr5 expressing stem/progenitor cells at the tips of developing glands are indispensable for uterine gland development.
Collapse
Affiliation(s)
- Ryo Seishima
- A*STAR Institute of Medical Biology, Singapore, 138648, Singapore
| | - Carly Leung
- A*STAR Institute of Medical Biology, Singapore, 138648, Singapore
| | - Swathi Yada
- A*STAR Institute of Medical Biology, Singapore, 138648, Singapore
| | | | - Liang Thing Tan
- A*STAR Institute of Medical Biology, Singapore, 138648, Singapore
| | | | - Si Hui Tan
- A*STAR Institute of Medical Biology, Singapore, 138648, Singapore
| | - Hideki Itoh
- A*STAR Skin Research Institute of Singapore, Singapore, 138648, Singapore
| | - Kazuhiro Murakami
- Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
| | - Yoshihiro Ishida
- Department of Dermatology, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, 606-8501, Japan
| | - Satoshi Nakamizo
- A*STAR Skin Research Institute of Singapore, Singapore, 138648, Singapore
| | - Yusuke Yoshikawa
- A*STAR Institute of Medical Biology, Singapore, 138648, Singapore
| | - Esther Wong
- A*STAR Institute of Medical Biology, Singapore, 138648, Singapore
| | - Nick Barker
- A*STAR Institute of Medical Biology, Singapore, 138648, Singapore. .,Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. .,School of Biological Sciences, Nanyang Technological University, Singapore, 308232, Singapore.
| |
Collapse
|
|
39
|
Kelleher AM, DeMayo FJ, Spencer TE. Uterine Glands: Developmental Biology and Functional Roles in Pregnancy. Endocr Rev 2019; 40:1424-1445. [PMID: 31074826 PMCID: PMC6749889 DOI: 10.1210/er.2018-00281] [Citation(s) in RCA: 126] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 04/15/2019] [Indexed: 12/18/2022]
Abstract
All mammalian uteri contain glands in the endometrium that develop only or primarily after birth. Gland development or adenogenesis in the postnatal uterus is intrinsically regulated by proliferation, cell-cell interactions, growth factors and their inhibitors, as well as transcription factors, including forkhead box A2 (FOXA2) and estrogen receptor α (ESR1). Extrinsic factors regulating adenogenesis originate from other organs, including the ovary, pituitary, and mammary gland. The infertility and recurrent pregnancy loss observed in uterine gland knockout sheep and mouse models support a primary role for secretions and products of the glands in pregnancy success. Recent studies in mice revealed that uterine glandular epithelia govern postimplantation pregnancy establishment through effects on stromal cell decidualization and placental development. In humans, uterine glands and, by inference, their secretions and products are hypothesized to be critical for blastocyst survival and implantation as well as embryo and placental development during the first trimester before the onset of fetal-maternal circulation. A variety of hormones and other factors from the ovary, placenta, and stromal cells impact secretory function of the uterine glands during pregnancy. This review summarizes new information related to the developmental biology of uterine glands and discusses novel perspectives on their functional roles in pregnancy establishment and success.
Collapse
Affiliation(s)
- Andrew M Kelleher
- Division of Animal Sciences, University of Missouri, Columbia, Missouri
| | - Francesco J DeMayo
- Reproductive and Developmental Biology Laboratory, National Institute on Environmental Health Sciences, Research Triangle Park, Durham, North Carolina
| | - Thomas E Spencer
- Division of Animal Sciences, University of Missouri, Columbia, Missouri.,Department of Obstetrics, Gynecology, and Women's Health, University of Missouri, Columbia, Missouri
| |
Collapse
|
|
40
|
Spencer TE, Kelleher AM, Bartol FF. Development and Function of Uterine Glands in Domestic Animals. Annu Rev Anim Biosci 2019; 7:125-147. [DOI: 10.1146/annurev-animal-020518-115321] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
All mammalian uteri contain glands that synthesize or transport and secrete substances into the uterine lumen. Uterine gland development, or adenogenesis, is uniquely a postnatal event in sheep and pigs and involves differentiation of glandular epithelium from luminal epithelium, followed by invagination and coiling morphogenesis throughout the stroma. Intrinsic transcription factors and extrinsic factors from the ovary and pituitary as well as the mammary gland (lactocrine) regulate uterine adenogenesis. Recurrent pregnancy loss is observed in the ovine uterine gland knockout sheep, providing unequivocal evidence that glands and their products are essential for fertility. Uterine gland hyperplasia and hypertrophy during pregnancy are controlled by sequential actions of hormones from the ovary and/or pituitary as well as the placenta. Gland-derived histotroph is transported by placental areolae for fetal growth. Increased knowledge of uterine gland biology is expected to improve pregnancy outcomes, as well as the health and productivity of mothers and their offspring.
Collapse
Affiliation(s)
- Thomas E. Spencer
- Division of Animal Sciences and Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, Missouri 65211, USA;,
| | - Andrew M. Kelleher
- Division of Animal Sciences and Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, Missouri 65211, USA;,
| | - Frank F. Bartol
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama 36849-5517, USA
| |
Collapse
|
|
41
|
D'Ippolito S, Di Nicuolo F, Pontecorvi A, Gratta M, Scambia G, Di Simone N. Endometrial microbes and microbiome: Recent insights on the inflammatory and immune "players" of the human endometrium. Am J Reprod Immunol 2018; 80:e13065. [PMID: 30375712 DOI: 10.1111/aji.13065] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 09/22/2018] [Accepted: 09/24/2018] [Indexed: 12/29/2022] Open
Abstract
In recent years, extended scientific works shed light on the important role played by the endometrium in early pregnancy. This review examines our current knowledge about the delicate balance between microbial and cellular immune agents at endometrial level: All of them might affect endometrial receptivity. In contrast to the classical thinking of human endometrium as a sterile tissue, several recent studies have drawn attention to a resident population of microorganisms, which reaches only a 30% of concordance with those of the cervical-vaginal flora. At present, the understanding of the microbiome in relation to human reproduction is in its infancy and further studies are needed to clarify the activity of endometrial microbiome and the possible effects of a "reproductive tract dysbiosis" on fertility. Moreover, in the human endometrium, there is a complex system works preventing the risk of infection as well as enabling, when pregnancy occurs, the acceptance of the blastocyst. In this way, the endometrium plays a central role in the uterine immune surveillance. A better understanding of the different agents that may affect endometrial receptivity would improve the diagnosis and treatment of obstetric complications related to defective implantation and placentation.
Collapse
Affiliation(s)
- Silvia D'Ippolito
- Dipartimento di Scienze della Salute della Donna e del Bambino, Area Salute Donna, Fondazione Policlinico Universitario A.Gemelli IRCCS, Rome, Italia.,Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica del Sacro Cuore, Rome, Italia
| | - Fiorella Di Nicuolo
- Dipartimento di Scienze della Salute della Donna e del Bambino, Area Salute Donna, Fondazione Policlinico Universitario A.Gemelli IRCCS, Rome, Italia.,Paolo VI International Scientific Institute, Università Cattolica del Sacro Cuore, Rome, Italia
| | - Alfredo Pontecorvi
- Paolo VI International Scientific Institute, Università Cattolica del Sacro Cuore, Rome, Italia.,Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Area Endocrino-Metabolica e Dermo-Reumatologica, Fondazione Policlinico Universitario A.Gemelli IRCCS, Rome, Italia.,Istituto di Patologia Medica, Università Cattolica del Sacro Cuore, Rome, Italia
| | - Matteo Gratta
- Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica del Sacro Cuore, Rome, Italia
| | - Giovanni Scambia
- Dipartimento di Scienze della Salute della Donna e del Bambino, Area Salute Donna, Fondazione Policlinico Universitario A.Gemelli IRCCS, Rome, Italia.,Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica del Sacro Cuore, Rome, Italia
| | - Nicoletta Di Simone
- Dipartimento di Scienze della Salute della Donna e del Bambino, Area Salute Donna, Fondazione Policlinico Universitario A.Gemelli IRCCS, Rome, Italia.,Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica del Sacro Cuore, Rome, Italia
| |
Collapse
|
|
42
|
Endometrial Stem Cells in Farm Animals: Potential Role in Uterine Physiology and Pathology. Bioengineering (Basel) 2018; 5:bioengineering5030075. [PMID: 30231577 PMCID: PMC6163755 DOI: 10.3390/bioengineering5030075] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 09/07/2018] [Accepted: 09/14/2018] [Indexed: 01/24/2023] Open
Abstract
The endometrium is an accessible source of mesenchymal stem cells. Most investigations of endometrial mesenchymal stem cells (eMSCs) have been conducted in humans. In animals, particularly in livestock, eMSC research is scarce. Such cells have been described in the bovine, ovine, caprine, porcine, and equine endometrium. Here we provide the state of the art of eMSCs in farm animals with a focus on the bovine species. In bovines, eMSCs have been identified during the phases of the estrous cycle, during which their functionality and the presence of eMSC-specific markers has been shown to change. Moreover, postpartum inflammation related to endometritis affects the presence and functionality of eMSCs, and prostaglandin E2 (PGE2) may be the mediator of such changes. We demonstrated that exposure to PGE2 in vitro modifies the transcriptomic profile of eMSCs, showing its potential role in the fate of stem cell activation, migration, and homing during pathological uterine inflammation in endometritis and in healthy puerperal endometrium. Farm animal research on eMSCs can be of great value in translational research for certain uterine pathologies and for immunomodulation of local responses to pathogens, hormones, and other substances. Further research is necessary in areas such as in vivo location of the niches and their immunomodulatory and anti-infective properties.
Collapse
|
|
43
|
Reusche N, Beineke A, Urhausen C, Beyerbach M, Schmicke M, Kramer S, Günzel-Apel A. Proliferative and apoptotic changes in the healthy canine endometrium and in cystic endometrial hyperplasia. Theriogenology 2018; 114:14-24. [DOI: 10.1016/j.theriogenology.2018.03.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 03/02/2018] [Accepted: 03/13/2018] [Indexed: 10/17/2022]
|
|
44
|
Vue Z, Gonzalez G, Stewart CA, Mehra S, Behringer RR. Volumetric imaging of the developing prepubertal mouse uterine epithelium using light sheet microscopy. Mol Reprod Dev 2018. [PMID: 29543367 DOI: 10.1002/mrd.22973] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Endometrial or uterine glands secrete substances essential for uterine receptivity to the embryo, implantation, conceptus survival, and growth. Adenogenesis is the process of gland formation within the stroma of the uterus. In the mouse, uterine gland formation initiates at postnatal day (P) 5. Uterine gland morphology is poorly understood because it is primarily based on two-dimensional (2D) histology. To more fully describe uterine gland morphogenesis, we generated three-dimensional (3D) models of postnatal uterine glands from P0 to P21, based on volumetric imaging using light sheet microscopy. At birth (P0), there were no glands. At P8, we found bud- and teardrop-shaped epithelial invaginations. By P11, the forming glands were elongated epithelial tubes. By P21, the elongated tubes had a sinuous morphology. These morphologies are homogeneously distributed along the anterior-posterior axis of the uterus. To facilitate uterine gland analyses, we propose a novel 3D staging system of uterine gland morphology during development in the prepubertal mouse. We define five uterine gland stages: Stage 1: bud; Stage 2: teardrop; Stage 3: elongated; Stage 4: sinuous; and Stage 5: primary branches. This staging system provides a standardized key to assess and quantify prepubertal uterine gland morphology that can be used for studies of uterine gland development and pathology. In addition, our studies suggest that gland formation initiation occurs during P8 and P11. However, between P11 and P21 gland formation initiation stops and all glands elongate and become sinuous. We also found that the mesometrial epithelium develops a unique morphology we term the uterine rail.
Collapse
Affiliation(s)
- Zer Vue
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas.,Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gabriel Gonzalez
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - C Allison Stewart
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shyamin Mehra
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Richard R Behringer
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas.,Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas
| |
Collapse
|
|
45
|
Stem cell therapy in Asherman syndrome and thin endometrium: Stem cell- based therapy. Biomed Pharmacother 2018; 102:333-343. [PMID: 29571018 DOI: 10.1016/j.biopha.2018.03.091] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 03/06/2018] [Accepted: 03/15/2018] [Indexed: 12/17/2022] Open
Abstract
The endometrium is one of the essential components of the uterus. The endometrium of human is a complex and dynamic tissue, which undergoes periods of growth and turn over during any menstrual cycle. Stem cells are initially undifferentiated cells that display a wide range of differentiation potential with no distinct morphological features. Stem cell therapy method recently has become a novel procedure for treatment of tissue injury and fibrosis in response to damage. Currently, there is massive interest in stem cells as a novel treatment method for regenerative medicine and more specifically for the regeneration of human endometrium disorder like Asherman syndrome (AS) and thin endometrium. AS also known as intrauterine adhesion (IUA) is a uterine disorder with the aberrant creation of adhesions within the uterus and/or cervix. Patients with IUA are significantly associated with menstrual abnormalities and suffer from pelvic pain. In addition, IUA might prevent implantation of the blastocyst, impair the blood supply to the uterus and early fetus, and finally result in the recurrent miscarriage or infertility in the AS patients. It has been evidenced that the transplantation of different stem cells with a diverse source in the endometrial zone had effects on endometrium such as declined the fibrotic area, an elevated number of glands, stimulated angiogenesis, the enhanced thickness of the endometrium, better formed tissue construction, protected gestation, and improved pregnancy rate. This study presents a summary of the investigations that indicate the key role of stem cell therapy in regeneration and renovation of defective parts.
Collapse
|
|
46
|
García-Solares J, Donnez J, Donnez O, Dolmans MM. Pathogenesis of uterine adenomyosis: invagination or metaplasia? Fertil Steril 2018; 109:371-379. [DOI: 10.1016/j.fertnstert.2017.12.030] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 12/20/2017] [Accepted: 12/26/2017] [Indexed: 12/14/2022]
|
|
47
|
Chambers JK, Shiga T, Takimoto H, Dohata A, Miwa Y, Nakayama H, Uchida K. Proliferative Lesions of the Endometrium of 50 Four-Toed Hedgehogs ( Atelerix albiventris). Vet Pathol 2018; 55:562-571. [PMID: 29448904 DOI: 10.1177/0300985818758467] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Uteri from 50 four-toed hedgehogs ( Atelerix albiventris) with clinical signs of uterine disease were histopathologically examined. Sixteen animals (32%) were diagnosed with endometrial hyperplasia, 7 animals (14%) were diagnosed with endometrial polyp, and 27 animals (54%) were diagnosed with endometrial neoplasia. The mean ages of the animals with endometrial hyperplasia, polyp, and neoplasia were 28.7 months, 29.4 months, and 25.2 months, respectively. The neoplasms were classified into 7 endometrial mixed tumors, 12 endometrial stromal nodules, and 8 endometrial stromal sarcomas. However, the endometrial stromal nodules and endometrial stromal sarcomas often developed within or were contiguous with an endometrial polyp or mixed tumor. Interestingly, the stromal tumors and the stromal components of the endometrial polyp and mixed tumor displayed extraendometrial differentiation (eg, into adipocytes, granular cells, smooth muscle cells, and osteoid tissue). The endometrial stromal sarcomas exhibited severe cellular atypia and invaded subendometrial tissue. Immunohistochemical examinations demonstrated that the stromal cells of the hyperplastic lesions as well as the neoplastic lesions were positive for CD10, the progesterone receptor, and Wilms tumor 1. The four-toed hedgehog develops unique uterine neoplasms that are mainly composed of endometrial stromal cells and probably arise from endometrial polyps and/or mixed tumors.
Collapse
Affiliation(s)
- James K Chambers
- 1 Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo, Japan
| | - Takanori Shiga
- 1 Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo, Japan
| | | | - Atsushi Dohata
- 1 Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo, Japan
| | | | - Hiroyuki Nakayama
- 1 Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo, Japan
| | - Kazuyuki Uchida
- 1 Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, the University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
48
|
Ding DC, Chu TY, Liu HW. Reciprocal crosstalk between endometrial carcinoma and mesenchymal stem cells via transforming growth factor-β/transforming growth factor receptor and C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4 aggravates malignant phenotypes. Oncotarget 2017; 8:115202-115214. [PMID: 29383153 PMCID: PMC5777765 DOI: 10.18632/oncotarget.23212] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 08/06/2017] [Indexed: 01/02/2023] Open
Abstract
Designated for cyclic shedding, the endometrial stroma is rich in endometrial mesenchymal stem cells (EMSCs) and may play an important role in the development of endometrial carcinoma (EC). This study characterized the crosstalk of EC cells with EMSCs and the resultant effects on malignant phenotypes. The cultured EMSCs expressed CD73, CD90, and CD105, but not CD14, CD19, CD34, CD45, or human leukocyte antigen—antigen D related markers. These EMSCs also showed osteogenic, adipogenic, and chondrogenic differentiation ability. Transforming growth factor (TGF)-β1 and C–X–C motif chemokine ligand 12 (CXCL12) secretion or expression were reciprocally enhanced in EC cells and EMSCs, as well as in their tissues. By acting on the receptors expressed in their mutual target cells, the interaction between TGF-β and CXCL12 results in the enhanced migration, invasion, tumorigenesis, and epithelial–mesenchymal transition of EC cells, which can be blocked by neutralizing the antibody of either CXCL12 or C–X–C chemokine receptor type 4. The study revealed unprecedented paracrine interactions between EC cells and EMSCs that resulted in the enhancement of transformation phenotypes. Thus, the blocking of TGF-β or CXCL12 signaling can be a therapeutic target for EC.
Collapse
Affiliation(s)
- Dah-Ching Ding
- Department of Obstetrics and Gynecology, Buddhist Tzu-Chi General Hospital, Hualien, Taiwan.,Institute of Medical Sciences, Tzu Chi University; Hualien, Taiwan
| | - Tang-Yuan Chu
- Department of Obstetrics and Gynecology, Buddhist Tzu-Chi General Hospital, Hualien, Taiwan.,Institute of Medical Sciences, Tzu Chi University; Hualien, Taiwan.,Cervical Cancer Prevention Center, Department of Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
| | - Hwan-Wun Liu
- Institute of Medical Sciences, Tzu Chi University; Hualien, Taiwan.,Department of Occupational Medicine, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
| |
Collapse
|
|
49
|
PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice. Cell Death Differ 2017; 24:2013-2021. [PMID: 28731465 DOI: 10.1038/cdd.2017.120] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 06/10/2017] [Accepted: 06/23/2017] [Indexed: 12/25/2022] Open
Abstract
Formation of secretary endometrial glands in the uterus known as adenogenesis is a typical process of branching morphogenesis involving dynamic epithelial growth and differentiation. Unsuccessful adenogenesis often leads to female infertility. However, it remains largely unexplored so far regarding the epigenetic machinery governing normal endometrial gland formation. Here, we demonstrated that PR-Set7, an epigenetic regulator for H4K20me1 modification, was extensively expressed in the postnatal uteri, and its conditional deletion resulted in a complete lack of endometrial glands and infertility in mice. Subsequent analysis revealed that uterine PR-Set7 deficiency abolishes the dynamic endometrial epithelial population growth during the short span of gland formation from postnatal days 3 to 9. This markedly reduced epithelial population growth in PR-Set7-null mutant uteri is well associated with DNA damage accumulation and massive apoptotic death in the epithelium, due to blockade of 53BP1 recruitment to DNA damage sites upon reduced levels of H4K20me1/2. Using PgrCre/+/Rosa26DTA/+ mouse line and postnatal progesterone injection mouse model, we further confirmed that an impaired epithelial cell population growth either by inducing epithelial death in the diphtheria toxin-A (DTA)-mouse model or attenuating epithelial growth upon postnatal progesterone treatment similarly hampers uterine adenogenesis. Collectively, we establish here a novel 'epithelial population growth threshold' model for successful gland development. Besides further shedding light on the regulatory machinery governing uterine gland formation, our findings raise a safety concern on progesterone supplementation to prevent preterm birth in women bearing a female fetus, as exogenous progesterone may hamper uterine adenogenesis via attenuating epithelial population growth.
Collapse
|
|
50
|
Laganà AS, Vitale SG, Salmeri FM, Triolo O, Ban Frangež H, Vrtačnik-Bokal E, Stojanovska L, Apostolopoulos V, Granese R, Sofo V. Unus pro omnibus, omnes pro uno: A novel, evidence-based, unifying theory for the pathogenesis of endometriosis. Med Hypotheses 2017; 103:10-20. [DOI: 10.1016/j.mehy.2017.03.032] [Citation(s) in RCA: 131] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2016] [Accepted: 03/21/2017] [Indexed: 01/17/2023]
|