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Cevik EC, Mamillapalli R, Taylor HS. Stem cells and female reproduction: endometrial physiology, disease and therapy. Stem Cells 2025; 43:sxaf016. [PMID: 40317260 DOI: 10.1093/stmcls/sxaf016] [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: 05/05/2024] [Accepted: 12/11/2024] [Indexed: 05/07/2025]
Abstract
The human endometrium, a dynamic tissue that undergoes cyclical shedding, repair, regeneration, and remodeling, relies on progenitor stem cells for replenishment. Bone marrow-derived mesenchymal stem cells (BM-MSCs) also may play a crucial role in the physiological process of endometrial regeneration, augmenting endometrial repair, supporting pregnancy, and thereby making a major contribution to reproduction. Notably, defective or inappropriate recruitment and engraftment of stem cells are implicated in various reproductive diseases, including endometriosis, highlighting the potential therapeutic avenues offered by stem cell-targeted interventions. Endometrial progenitor cells have shown promise in improving pregnancy outcomes and addressing infertility issues. Furthermore, BM-MSCs demonstrate the potential to reverse pathologies, including Asherman's syndrome and thin endometrium, offering novel approaches to treating infertility, implantation failure, and recurrent pregnancy loss. Mobilization of endogenous stem cells to areas of pathology through chemoattractants also presents a promising strategy for targeted therapy. Finally, endometrium-derived mesenchymal stem cells, characterized by their multipotent nature and ease of collection through minimally invasive techniques, hold promise in a wide range of reproductive and non-reproductive pathologies, including diabetes, kidney disease, Parkinson's disease, or cardiac disorders. As the best of our knowledge of stem cell biology continues to grow, the incorporation of stem cell-based therapies into clinical practice presents significant potential to transform reproductive medicine and enhance patient outcomes.
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Affiliation(s)
- E Cansu Cevik
- Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06520, United States
| | - Ramanaiah Mamillapalli
- Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06520, United States
| | - Hugh S Taylor
- Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06520, United States
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Rahnama M, Ghasemzadeh N, Latifi Z, Kheradmand F, Koukia FA, Khan S, Golchin A. Menstrual blood and endometrial mesenchymal stem/stromal cells: A frontier in regenerative medicine and cancer therapy. Eur J Pharmacol 2025; 1000:177726. [PMID: 40350020 DOI: 10.1016/j.ejphar.2025.177726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 05/08/2025] [Accepted: 05/09/2025] [Indexed: 05/14/2025]
Abstract
The acquisition of suitable stem cell sources is a significant issue in regenerative medicine. There has been considerable interest in utilizing mesenchymal stem cells (MSCs) derived from endometrial and menstrual blood as a promising resource of MSCs, owing to their unique biochemical properties and prospective use in clinical therapies. This population of stem cells has distinct characteristics in terms of immunophenotype, proliferation rate, and differentiation capacity. A notable characteristic of these stem cells is their capacity to develop into mesodermal lineages, highlighting their regenerative capability. Moreover, the presence of certain surface markers facilitates the augmentation of clonogenic endometrial MSCs. Their distinctive characteristics, along with their swift multiplication ability, underscore their significant promise for therapeutic applicability in regenerative medicine and cell-based treatments. Current investigations are examining possible usage of diverse stem cell resources in the treatment of inflammatory diseases and perhaps intractable illnesses like Parkinson's disease, utilizing their immunomodulatory properties. This review aims to analyze stem cell-related research that has utilized endometrial and menstrual blood-derived MSCs (enMSCs and MenSCs) with a special focus on their clinical application. We will explore the existing evidence about the therapeutic potential for these stem cells across many medical diseases and address the obstacles and prospective trajectories in this domain. Additionally, we will study the unique properties of enMSCs and MenSCs that make them promising candidates for regenerative medicine.
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Affiliation(s)
- Maryam Rahnama
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Navid Ghasemzadeh
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Zeinab Latifi
- Department of Biochemistry, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Kheradmand
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Fariba Abbasi Koukia
- Department of Pathology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Sharun Khan
- Graduate Institute of Medicine, Yuan Ze University, Taoyuan 32003, Taiwan
| | - Ali Golchin
- Department of Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran; Independent Researcher, Urmia, Iran.
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Sadiasa A, Werkmeister JA, Gurung S, Gargett CE. Steps towards the clinical application of endometrial and menstrual fluid mesenchymal stem cells for the treatment of gynecological disorders. Expert Opin Biol Ther 2025; 25:285-307. [PMID: 39925343 DOI: 10.1080/14712598.2025.2465826] [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: 10/29/2024] [Revised: 01/28/2025] [Accepted: 02/07/2025] [Indexed: 02/11/2025]
Abstract
INTRODUCTION The human endometrium is a highly regenerative tissue that contains mesenchymal stem/stromal cells (MSCs). These MSCs are sourced via office-based biopsies and menstrual fluid, providing a less invasive and readily available option for cell-based therapies. This review provides an update on endometrial-derived MSCs as a treatment option for gynecological diseases. AREAS COVERED This narrative review covers the characterization and therapeutic mechanisms of endometrium biopsy-derived MSCs (eMSCs) and menstrual fluid-derived mesenchymal stromal cells (MenSCs), highlighting similarities and differences. It also covers studies of their application in preclinical animal models and in clinical trials as potential cell-based therapies for gynecological diseases. EXPERT OPINION eMSCs and MenSCs from a homologous tissue source have the potential to promote regenerative activity as a treatment for gynecological diseases. Both eMSCs and MenSCs demonstrate therapeutic benefits through their paracrine activity in tissue regeneration, immunomodulation, angiogenesis, and mitigating fibrosis. Further research is essential to establish standardized isolation and characterization protocols, particularly for heterogeneous MenSCs, and to fully understand their mechanisms of action. Implementing SUSD2 magnetic bead sorting for purifying eMSCs from endometrial tissues and menstrual fluid is crucial for their use in future cell-based therapies. Optimization of production, storage, and delivery methods will maximize their therapeutic effectiveness.
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Affiliation(s)
- Alexander Sadiasa
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Jerome A Werkmeister
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Shanti Gurung
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
| | - Caroline E Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
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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.
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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.
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Ma Y, Qian J, Xu X, Wei C, Wang M, Zhang P, Chen S, Zhang L, Zhang Y, Wang Y, Xu W, Liu M, Lin X. Engraftment of self-renewing endometrial epithelial organoids promotes endometrial regeneration by differentiating into functional glands in rats. Front Bioeng Biotechnol 2024; 12:1449955. [PMID: 39723128 PMCID: PMC11668608 DOI: 10.3389/fbioe.2024.1449955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 11/18/2024] [Indexed: 12/28/2024] Open
Abstract
Introduction Extensive trauma frequently disrupts endometrial regeneration by diminishing endometrial stem cells/progenitor cells, affecting female fertility. While bone marrow mesenchymal stem cell (BMSC) transplantation has been suggested as an approach to address endometrial injury, it comes with certain limitations. Recent advancements in endometrial epithelial organoids (EEOs) have displayed encouraging potential for endometrial regeneration. Therefore, this study aims to explore whether EEOs surpass BMSCs in their ability to repair injured endometrium and to examine whether the restoration process involves the integration of EEOs into the endometrial tissue of the recipient. Methods We developed rat EEOs (rEEOs) mimicking the features of the rat endometrium. Subsequently, we created a rat model of endometrial injury to compare the effects of rEEOs and rat BMSCs (rBMSCs) on endometrial regeneration and reproductive recovery. Bulk RNA-sequencing analysis was conducted to further investigate the capacity of rEEOs for endometrial regeneration and to identify discrepancies between rEEOs and rBMSCs. Additionally, to track the fate of the transplanted cells in vivo, we transplanted green fluorescent protein (GFP) -labelled rEEOs or red fluorescent protein (RFP) -labelled rBMSCs. Results In a rat model of endometrial injury, we observed that fertility recovery in rats transplanted with rEEOs was more comparable to that of normal rats than in those treated with rBMSC. rEEOs possess a high concentration of endometrial epithelial stem/progenitor cells and secrete vascular endothelial growth factor (VEGF)-A to promote endometrial neovascularization. Significantly, we observed that cells from GFP-labelled rEEOs could integrate and differentiate into functional glands within the injured endometrium of recipient rats. Discussion EEOs offer a transformative approach to address the challenges of endometrial trauma. Their remarkable regenerative potential holds promise for the restoration of damaged endometrium. As we venture into the future, the concept of utilizing patient-specific EEOs for transplantation emerges as a tantalizing prospect. However, the EEOs in our experiments were mainly cultured in Matrigel, which has barriers to clinical translation as a biomaterial, a new biomaterial to be explored. Secondly, our experiments have been successful only in rat models, and more efforts need to be made before clinical translation.
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Affiliation(s)
- Yana Ma
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China
| | - Jingjing Qian
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Obstetrics and Gynecology, Yuyao People’s Hospital of Zhejiang Province, Ningbo, China
| | - Xin Xu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China
| | - Cheng Wei
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China
| | - Minyuan Wang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Gynecology, Wenling First People’s Hospital of Zhejiang Province, Taizhou, China
| | - Peipei Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Obstetrics and Gynecology, Tiantai People’s Hospital of Zhejiang Province, Taizhou, China
| | - Sijia Chen
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China
| | - Lingyan Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China
| | - Yanling Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China
| | - Yanpeng Wang
- Center for Reproductive Medicine, Department of Gynecology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
| | - Wenzhi Xu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China
| | - Mengying Liu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China
| | - Xiaona Lin
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China
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Wang J, Zhan H, Wang Y, Zhao L, Huang Y, Wu R. Current advances in understanding endometrial epithelial cell biology and therapeutic applications for intrauterine adhesion. Stem Cell Res Ther 2024; 15:379. [PMID: 39456113 PMCID: PMC11515228 DOI: 10.1186/s13287-024-03989-6] [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: 04/25/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
The human endometrium is a highly regenerative tissue capable of undergoing scarless repair during the menstruation and postpartum phases. This process is mediated by endometrial adult stem/progenitor cells. During the healing of endometrial injuries, swift reepithelization results in the rapid covering of the wound surface and facilitates subsequent endometrial restoration. The involvement of endogenous endometrial epithelial stem cells, stromal cells, and bone marrow-derived cells in the regeneration of the endometrial epithelium has been a subject of prolonged debate. Increasing evidence suggests that the regeneration of the endometrial epithelium mainly relies on epithelial stem cells rather than stromal cells and bone marrow-derived cells. Currently, no consensus has been established on the identity of epithelial stem cells in the epithelial compartment. Several markers, including stage-specific embryonic antigen-1 (SSEA-1), sex-determining region Y-box 9 (SOX9), neural-cadherin (N-cadherin), leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5), CD44, axis inhibition protein 2 (Axin2), and aldehyde dehydrogenase 1A1 (ALDH1A1), have been suggested as potential candidate markers for endometrial epithelial stem cells. The identification of endometrial epithelial stem cells contributes to our understanding of endometrial regeneration and offers new therapeutic insights into diseases characterized by regenerative defects in the endometrium, such as intrauterine adhesion. This review explores different perspectives on the origins of human and mouse endometrial epithelial cells. It summarizes the potential markers, locations, and hierarchies of epithelial stem cells in both human and mouse endometrium. It also discusses epithelial cell-based treatments for intrauterine adhesion, hoping to inspire further research and clinical application of endometrial epithelial stem cells.
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Affiliation(s)
- Jia Wang
- Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China
- Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou, People's Republic of China
| | - Hong Zhan
- Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China
- Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou, People's Republic of China
| | - Yinfeng Wang
- Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China
- Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou, People's Republic of China
| | - Li Zhao
- Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China
- Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou, People's Republic of China
| | - Yunke Huang
- Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China
- Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou, People's Republic of China
| | - Ruijin Wu
- Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China.
- Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou, People's Republic of China.
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, People's Republic of China.
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Abstract
The uterine lining (endometrium) regenerates repeatedly over the life span as part of its normal physiology. Substantial portions of the endometrium are shed during childbirth (parturition) and, in some species, menstruation, but the tissue is rapidly rebuilt without scarring, rendering it a powerful model of regeneration in mammals. Nonetheless, following some assaults, including medical procedures and infections, the endometrium fails to regenerate and instead forms scars that may interfere with normal endometrial function and contribute to infertility. Thus, the endometrium provides an exceptional platform to answer a central question of regenerative medicine: Why do some systems regenerate while others scar? Here, we review our current understanding of diverse endometrial disruption events in humans, nonhuman primates, and rodents, and the associated mechanisms of regenerative success and failure. Elucidating the determinants of these disparate repair processes promises insights into fundamental mechanisms of mammalian regeneration with substantial implications for reproductive health.
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Affiliation(s)
- Claire J Ang
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA;
- Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA
| | - Taylor D Skokan
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA;
| | - Kara L McKinley
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA;
- Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
- Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts, USA
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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; 24:9431. [PMID: 37298382 PMCID: PMC10253661 DOI: 10.3390/ijms24119431] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [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.
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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; (P.V.); (A.A.); (A.S.); (M.D.)
| | - 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; (P.V.); (A.A.); (A.S.); (M.D.)
- 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; (P.V.); (A.A.); (A.S.); (M.D.)
| | - 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; (P.V.); (A.A.); (A.S.); (M.D.)
| | - 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; (P.V.); (A.A.); (A.S.); (M.D.)
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Bi-potential hPSC-derived Müllerian duct-like cells for full-thickness and functional endometrium regeneration. NPJ Regen Med 2022; 7:68. [DOI: 10.1038/s41536-022-00263-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 11/07/2022] [Indexed: 11/24/2022] Open
Abstract
AbstractStem cell-based tissue regeneration strategies are promising treatments for severe endometrial injuries. However, there are few appropriate seed cells for regenerating a full-thickness endometrium, which mainly consists of epithelia and stroma. Müllerian ducts in female embryonic development develop into endometrial epithelia and stroma. Hence, we first generated human pluripotent stem cells (hPSC)-derived Müllerian duct-like cells (MDLCs) using a defined and effective protocol. The MDLCs are bi-potent, can gradually differentiate into endometrial epithelial and stromal cells, and reconstitute full-thickness endometrium in vitro and in vivo. Furthermore, MDLCs showed the in situ repair capabilities of reconstructing endometrial structure and recovering pregnancy function in full-thickness endometrial injury rats, and their differentiation fate was revealed by single-cell RNA sequencing (scRNA-seq). Our study provides a strategy for hPSC differentiation into endometrial lineages and an alternative seed cell for injured endometrial regeneration.
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Persaud K, Zhao Q, Owusu-Akyaw A, Rameshwar P, Goldsmith LT, Morelli SS. Expression of glucocorticoid and androgen receptors in bone marrow-derived hematopoietic and nonhematopoietic murine endometrial cells. F&S SCIENCE 2022; 3:255-268. [PMID: 35717521 DOI: 10.1016/j.xfss.2022.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 04/18/2022] [Accepted: 04/28/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE To determine whether bone marrow (BM)-derived cells engrafting the murine endometrium express the glucocorticoid receptor (GR) and androgen receptor (AR). Recent data demonstrate that BM is a long-term source of multiple hematopoietic and nonhematopoietic endometrial cell types. Important roles for glucocorticoids and androgens in regulating endometrial functions, including decidualization and early embryo attachment/invasion, have very recently emerged. Whether endometrial cells of BM origin express glucocorticoid or ARs has not been previously studied. DESIGN Animal study. SETTING Basic science laboratory. ANIMAL(S) Wild-type C57BL/6J male mice expressing enhanced green fluorescent protein (GFP) and syngeneic wild-type C57BL/6J female mice aged 6-9 weeks. INTERVENTION(S) Murine bone marrow transplant. MAIN OUTCOME MEASURE(S) Bone marrow cells were harvested from adult wild-type C57BL/6 mice and subjected to flow cytometry to identify the percentage of hematopoietic and nonhematopoietic cells expressing GR or AR. Uterine tissue sections from lethally irradiated syngeneic adult female C57BL/6 mice that had been recipients of BM transplants from adult male transgenic donor mice ubiquitously expressing GFP were studied. Immunohistochemistry was performed in the uterine tissue sections of the recipient mice at 5, 9, and 12 months after transplant using specific anti-GR, anti-AR, anti-GFP, anti-CD45 (pan leukocyte marker), and anti-F4/80 (murine macrophage marker) primary antibodies. Confocal laser microscopy was used to localize and quantitate BM-derived (GFP+) cell types in the endometrial stromal and epithelial compartments and determine whether BM-derived cell types in the murine endometrium express GR or AR. RESULT(S) Hematopoietic cells comprised 93.6%-96.6% of all cells in the BM, of which 98.1% ± 0.2% expressed GR and 92.2% ± 4.4% expressed AR. Nonhematopoietic cells comprised 0.4%-1.3% of BM, of which 52.8% ± 5.9% expressed GR and 48.9% ± 3.4% expressed AR. After BM transplant, the proportion of cells originating from BM in the endometrial stromal compartment increased over time, reaching 13.5% ± 2.3% at 12 months after transplant. In the epithelial compartments, <1% of the cells were of BM origin at 12 months after transplant. Most (60%-72%) GR+ and/or AR+ BM-derived cells in the stroma were hematopoietic (CD45+) cells, of which 37%-51% were macrophages. Nonetheless, 28%-33% of GR+ cells, and 28%-40% of AR+ BM-derived cells, were nonhematopoietic (CD45-) stromal cells of BM origin. CONCLUSION(S) A substantial number of BM-derived cells express GR and AR, suggesting a role for these cells in both glucocorticoid-regulated and androgen-regulated endometrial functions, such as proliferation and/or decidualization.
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Affiliation(s)
- Kavitha Persaud
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers New Jersey Medical School, Newark, New Jersey.
| | - Qingshi Zhao
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers New Jersey Medical School, Newark, New Jersey
| | - Amma Owusu-Akyaw
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers New Jersey Medical School, Newark, New Jersey
| | - Pranela Rameshwar
- Department of Medicine, Hematology/Oncology, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey
| | - Laura T Goldsmith
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers New Jersey Medical School, Newark, New Jersey
| | - Sara S Morelli
- Department of Obstetrics, Gynecology and Reproductive Health, Rutgers New Jersey Medical School, Newark, New Jersey
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11
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Ludke A, Hatta K, Yao A, Li RK. Uterus: A Unique Stem Cell Reservoir Able to Support Cardiac Repair via Crosstalk among Uterus, Heart, and Bone Marrow. Cells 2022; 11:cells11142182. [PMID: 35883625 PMCID: PMC9324611 DOI: 10.3390/cells11142182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/09/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022] Open
Abstract
Clinical evidence suggests that the prevalence of cardiac disease is lower in premenopausal women compared to postmenopausal women and men. Although multiple factors contribute to this difference, uterine stem cells may be a major factor, as a high abundance of these cells are present in the uterus. Uterine-derived stem cells have been reported in several studies as being able to contribute to cardiac neovascularization after injury. However, our studies uniquely show the presence of an “utero-cardiac axis”, in which uterine stem cells are able to home to cardiac tissue to promote tissue repair. Additionally, we raise the possibility of a triangular relationship among the bone marrow, uterus, and heart. In this review, we discuss the exchange of stem cells across different organs, focusing on the relationship that exists between the heart, uterus, and bone marrow. We present increasing evidence for the existence of an utero-cardiac axis, in which the uterus serves as a reservoir for cardiac reparative stem cells, similar to the bone marrow. These cells, in turn, are able to migrate to the heart in response to injury to promote healing.
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Affiliation(s)
- Ana Ludke
- Division of Cardiovascular Surgery, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; (A.L.); (K.H.); (A.Y.)
| | - Kota Hatta
- Division of Cardiovascular Surgery, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; (A.L.); (K.H.); (A.Y.)
| | - Alina Yao
- Division of Cardiovascular Surgery, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; (A.L.); (K.H.); (A.Y.)
| | - Ren-Ke Li
- Division of Cardiovascular Surgery, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; (A.L.); (K.H.); (A.Y.)
- Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada
- Correspondence: ; Tel.: +1-416-581-7492
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12
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Trophic and immunomodulatory effects of adipose tissue derived stem cells in a preclinical murine model of endometriosis. Sci Rep 2022; 12:8031. [PMID: 35577867 PMCID: PMC9110373 DOI: 10.1038/s41598-022-11891-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 04/25/2022] [Indexed: 11/24/2022] Open
Abstract
Endometriosis, which exhibits enigmatic pathological features such as stromal fibrosis and proliferation of ectopic epithelial cells, is known as a refractory disease. Mesenchymal stem cells modulate the fibrosis in stromal tissues through their trophic and immunomodulatory properties. To investigate the potential of stem cells in treating endometriosis, we examined the secondary morphology and molecular alterations in endometriosis-like lesions after the administration of adipose tissue-derived stem cells (ASCs) to an experimental murine model of endometriosis. The infused ASCs were found integrated in the endometriosis-like lesions. Accompanied by the suppression of stromal fibrosis and proliferation of endometriotic epithelial cells, the infusion of ASCs with stemness potential (early passage of ASCs) suppressed the growth of endometriosis-like lesions and inhibited the expression of pro-inflammatory and pro-fibrotic cytokines, whereas no significant attenuation of endometriosis-like lesions occurred after the infusion of ASCs without stemness potential (late passage of ASCs). Accordingly, the trophic and immunomodulatory properties of ASCs may regulate fibrosis in endometriosis-like lesions, suggesting that regenerative medicine could be recognized as an innovative treatment for patients with endometriosis through the accumulation of evidence of preclinical efficacy.
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13
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Jain V, Chodankar RR, Maybin JA, Critchley HOD. Uterine bleeding: how understanding endometrial physiology underpins menstrual health. Nat Rev Endocrinol 2022; 18:290-308. [PMID: 35136207 PMCID: PMC9098793 DOI: 10.1038/s41574-021-00629-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/21/2021] [Indexed: 12/16/2022]
Abstract
Menstruation is a physiological process that is typically uncomplicated. However, up to one third of women globally will be affected by abnormal uterine bleeding (AUB) at some point in their reproductive years. Menstruation (that is, endometrial shedding) is a fine balance between proliferation, decidualization, inflammation, hypoxia, apoptosis, haemostasis, vasoconstriction and, finally, repair and regeneration. An imbalance in any one of these processes can lead to the abnormal endometrial phenotype of AUB. Poor menstrual health has a negative impact on a person's physical, mental, social, emotional and financial well-being. On a global scale, iron deficiency and iron deficiency anaemia are closely linked with AUB, and are often under-reported and under-recognized. The International Federation of Gynecology and Obstetrics have produced standardized terminology and a classification system for the causes of AUB. This standardization will facilitate future research endeavours, diagnosis and clinical management. In a field where no new medications have been developed for over 20 years, emerging technologies are paving the way for a deeper understanding of the biology of the endometrium in health and disease, as well as opening up novel diagnostic and management avenues.
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Affiliation(s)
- Varsha Jain
- MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
| | - Rohan R Chodankar
- MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
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14
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Singh P, Metkari S, Bhartiya D. Additional evidence to support OCT-4 positive VSELs and EnSCs as the elusive tissue-resident stem/progenitor cells in adult mice uterus. Stem Cell Res Ther 2022; 13:60. [PMID: 35123545 PMCID: PMC8818151 DOI: 10.1186/s13287-022-02703-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/04/2022] [Indexed: 01/27/2023] Open
Abstract
OBJECTIVE True identity and specific set of markers to enrich endometrial stem cells still remains elusive. Present study was undertaken to further substantiate that very small embryonic-like stem cells (VSELs) are the true and elusive stem cells in adult mice endometrium. METHODS This was achieved by undertaking three sets of experiments. Firstly, SSEA-1+ and Oct-4 + positive VSELs, sorted from GFP mice, were transplanted into the uterine horns of wild-type Swiss mice and GFP uptake was studied within the same estrus cycle. Secondly, uterine lumen was scratched surgically and OCT-4 expressing stem/progenitor cells were studied at the site of injury after 24-72 h. Thirdly, OCT-4 expression was studied in the endometrium and myometrium of adult mice after neonatal exposure to estradiol (20 µg/pup/day on days 5-7 after birth). RESULTS GFP + ve VSELs expressing SSEA-1 and Oct-4 engrafted and differentiated into the epithelial cells lining the lumen as well as the glands during the estrus stage when maximum remodeling occurs. Mechanical scratching activated tissue-resident, nuclear OCT-4 positive VSELs and slightly bigger 'progenitors' endometrial stem cells (EnSCs, cytoplasmic OCT-4) which underwent clonal expansion and further differentiated into luminal and glandular epithelial cells. Neonatal exposure to endocrine disruption resulted in increased numbers of OCT-4 positive VSELs/EnSCs in adult endometrium. DISCUSSION Results support the presence of functionally active VSELs in adult endometrium. VSELs self-renew and give rise to EnSCs that further differentiate into epithelial cells under normal physiological conditions. Also, VSELs are vulnerable to endocrine insults. To conclude VSELs are true and elusive uterine stem cells that maintain life-long uterine homeostasis and their dysregulation may result in various pathologies.
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Affiliation(s)
- Pushpa Singh
- Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India
| | - Siddhanath Metkari
- Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India
| | - Deepa Bhartiya
- Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India.
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15
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Cousins FL, Filby CE, Gargett CE. Endometrial Stem/Progenitor Cells–Their Role in Endometrial Repair and Regeneration. FRONTIERS IN REPRODUCTIVE HEALTH 2022; 3:811537. [PMID: 36304009 PMCID: PMC9580754 DOI: 10.3389/frph.2021.811537] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/23/2021] [Indexed: 12/12/2022] Open
Abstract
The human endometrium is a remarkable tissue, undergoing ~450 cycles of proliferation, differentiation, shedding (menstruation), repair, and regeneration over a woman's reproductive lifespan. Post-menstrual repair is an extremely rapid and scar-free process, with re-epithelialization of the luminal epithelium completed within 48 h of initiation of shedding. Following menstruation, the functionalis grows from the residual basalis layer during the proliferative phase under the influence of rising circulating estrogen levels. The regenerative capacity of the endometrium is attributed to stem/progenitor cells which reside in both the epithelial and stromal cell compartments of the basalis layer. Finding a definitive marker for endometrial epithelial progenitors (eEPCs) has proven difficult. A number of different markers have been suggested as putative progenitor markers including, N-cadherin, SSEA-1, AXIN2, SOX-9 and ALDH1A1, some of which show functional stem cell activity in in vitro assays. Each marker has a unique location(s) in the glandular epithelium, which has led to the suggestion that a differentiation hierarchy exists, from the base of epithelial glands in the basalis to the luminal epithelium lining the functionalis, where epithelial cells express different combinations of markers as they differentiate and move up the gland into the functionalis away from the basalis niche. Perivascular endometrial mesenchymal stem cells (eMSCs) can be identified by co-expression of PDGFRβ and CD146 or by a single marker, SUSD2. This review will detail the known endometrial stem/progenitor markers; their identity, location and known interactions and hierarchy across the menstrual cycle, in particular post-menstrual repair and estrogen-driven regeneration, as well as their possible contributions to menstruation-related disorders such as endometriosis and regeneration-related disorder Asherman's syndrome. We will also highlight new techniques that allow for a greater understanding of stem/progenitor cells' role in repair and regeneration, including 3D organoids, 3D slice cultures and gene sequencing at the single cell level. Since mouse models are commonly used to study menstruation, repair and regeneration we will also detail the mouse stem/progenitor markers that have been investigated in vivo.
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Affiliation(s)
- Fiona L. Cousins
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynecology, Monash University, Clayton, VIC, Australia
- *Correspondence: Fiona L. Cousins
| | - Caitlin E. Filby
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynecology, Monash University, Clayton, VIC, Australia
| | - Caroline E. Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynecology, Monash University, Clayton, VIC, Australia
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16
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Tal R, Kisa J, Abuwala N, Kliman HJ, Shaikh S, Chen AY, Lyu F, Taylor HS. Bone marrow-derived progenitor cells contribute to remodeling of the postpartum uterus. Stem Cells 2021; 39:1489-1505. [PMID: 34224633 PMCID: PMC9313624 DOI: 10.1002/stem.3431] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 06/18/2021] [Indexed: 11/11/2022]
Abstract
Endometrial stem/progenitor cells play a role in postpartum uterine tissue regeneration, but the underlying mechanisms are poorly understood. While circulating bone marrow (BM)-derived cells (BMDCs) contribute to nonhematopoietic endometrial cells, the contribution of BMDCs to postpartum uterus remodeling is unknown. We investigated the contribution of BMDCs to the postpartum uterus using 5-fluorouracil-based nongonadotoxic BM transplant from green fluorescent protein (GFP) donors into wild-type C57BL/6J female mice. Flow cytometry showed an influx of GFP+ cells to the uterus immediately postpartum accounting for 28.7% of total uterine cells, followed by a rapid decrease to prepregnancy levels. The majority of uterine GFP+ cells were CD45+ leukocytes, and the proportion of nonhematopoietic CD45-GFP+ cells peaked on postpartum day (PPD) 1 (17.5%). Immunofluorescence colocalization of GFP with CD45 pan-leukocyte and F4/80 macrophage markers corroborated these findings. GFP+ cells were found mostly in subepithelial stromal location. Importantly, GFP+ cytokeratin-positive epithelial cells were found within the luminal epithelium exclusively on PPD1, demonstrating direct contribution to postpartum re-epithelialization. A subset (3.2%) of GFP+ cells were CD31+CD45- endothelial cells, and found integrated within blood vessel endothelium. Notably, BM-derived GFP+ cells demonstrated preferential proliferation (PCNA+) and apoptosis (TUNEL+) on PPD1 vs resident GFP- cells, suggesting an active role for BMDCs in rapid tissue turnover. Moreover, GFP+ cells gradually acquired cell senescence together with decreased proliferation throughout the postpartum. In conclusion, BM-derived progenitors were found to have a novel nonhematopoietic cellular contribution to postpartum uterus remodeling. This contribution may have an important functional role in physiological as well as pathological postpartum endometrial regeneration.
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Affiliation(s)
- Reshef Tal
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - Jacqueline Kisa
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - Nafeesa Abuwala
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - Harvey J Kliman
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - Shafiq Shaikh
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - Alice Y Chen
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - Fang Lyu
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
| | - Hugh S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
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17
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Advancements in endometrial epithelial stem cell research. SCIENCE CHINA-LIFE SCIENCES 2021; 65:215-218. [PMID: 34586574 DOI: 10.1007/s11427-021-1988-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 07/21/2021] [Indexed: 10/20/2022]
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18
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Wang Z, Yang M, Mao L, Wang X, Wang S, Cui G, Hou Z, Yang M, Cui L, Bai W. Efficacy and safety of autologous platelet-rich fibrin for the treatment of infertility with intrauterine adhesions. J Obstet Gynaecol Res 2021; 47:3883-3894. [PMID: 34482587 DOI: 10.1111/jog.14964] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 07/05/2021] [Accepted: 07/22/2021] [Indexed: 12/26/2022]
Abstract
AIM To evaluate the efficacy and safety of autologous platelet-rich fibrin (PRF) for the treatment of infertility with intrauterine adhesions. METHODS Forty patients who suffered from infertility with intrauterine adhesions (IUAs) were enrolled in this prospective trial from October 2018 to December 2019. They were randomly divided into a PRF group and a control group. Both groups underwent transcervical resection of adhesions (TCRA) during the follicular phase. PRF group: PRF prepared from autologous venous blood was placed in the uterine cavity after TCRA and after the first menstrual re-fluid; control group: no PRF insertion. After the second menstrual re-fluid, both groups underwent hysteroscopy to reevaluate adhesion severity. Pregnancy rate, intrauterine adhesion score, menstrual volume and duration, and endometrial thickness were assessed and adverse events were recorded. RESULTS (1) PRF group pregnancy rate was significantly higher than the control group (55.0% vs. 20.0%). Mean follow-up time was (17.63 ± 2.33) months. All patients fell pregnant naturally. Four (PRF) and one (control) patients delivered live births without placental complications. (2) Intrauterine adhesion scores decreased compared with treatment-before. (3) In the pictorial blood loss assessment chart, score and menstrual duration during the 3rd menstrual cycle showed significant improvements for both groups. (4) Endometrial thickness also showed an increasing trend, and subendometrial bloodflow improved. (5) No treatment-related serious adverse events were noted. CONCLUSION Placing PRF into the uterine cavity of infertility patients with IUAs following TCRA is a safe and effective therapeutic method.
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Affiliation(s)
- Zijun Wang
- Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Mukun Yang
- Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Lele Mao
- Department of Obstetrics and Gynecology, Xiehe Hospital, Tongji Medical University, Wuhan, China
| | - Xiaoxue Wang
- Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Shuowen Wang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China
| | - Guangxia Cui
- Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Zhaoxi Hou
- Department of Obstetrics and Gynecology, Beijing Haidian Maternal and Child Health Hospital, Beijing, China
| | - Min Yang
- Department of Ultrasonography, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Lei Cui
- Department of Plastic Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Wenpei Bai
- Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
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19
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Abstract
Uniquely among adult tissues, the human endometrium undergoes cyclical shedding, scar-free repair and regeneration during a woman's reproductive life. Therefore, it presents an outstanding model for study of such processes. This Review examines what is known of endometrial repair and regeneration following menstruation and parturition, including comparisons with wound repair and the influence of menstrual fluid components. We also discuss the contribution of endometrial stem/progenitor cells to endometrial regeneration, including the importance of the stem cell niche and stem cell-derived extracellular vesicles. Finally, we comment on the value of endometrial epithelial organoids to extend our understanding of endometrial development and regeneration, as well as therapeutic applications.
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Affiliation(s)
- Lois A Salamonsen
- Centre for Reproductive Health, Clayton, Victoria 3168, Australia.,Department of Molecular and Translational Science, Clayton, Victoria 3168, Australia
| | - Jennifer C Hutchison
- Centre for Reproductive Health, Clayton, Victoria 3168, Australia.,Department of Molecular and Translational Science, Clayton, Victoria 3168, Australia
| | - Caroline E Gargett
- Ritchie Centre, Hudson Institute of Medical Research, 25-31 Wright St, Clayton, Victoria 3168, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria 3168, Australia
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20
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Lv Q, Wang L, Luo X, Chen X. Adult stem cells in endometrial regeneration: Molecular insights and clinical applications. Mol Reprod Dev 2021; 88:379-394. [PMID: 34014590 PMCID: PMC8362170 DOI: 10.1002/mrd.23476] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 03/23/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023]
Abstract
Endometrial damage is an important cause of female reproductive problems, manifested as menstrual abnormalities, infertility, recurrent pregnancy loss, and other complications. These conditions are collectively termed "Asherman syndrome" (AS) and are typically associated with recurrent induced pregnancy terminations, repeated diagnostic curettage and intrauterine infections. Cancer treatment also has unexpected detrimental side effects on endometrial function in survivors independently of ovarian effects. Endometrial stem cells act in the regeneration of the endometrium and in repair through direct differentiation or paracrine effects. Nonendometrial adult stem cells, such as bone marrow-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells, with autologous and allogenic applications, can also repair injured endometrial tissue in animal models of AS and in human studies. However, there remains a lack of research on the repair of the damaged endometrium after the reversal of tumors, especially endometrial cancers. Here, we review the biological mechanisms of endometrial regeneration, and research progress and challenges for adult stem cell therapy for damaged endometrium, and discuss the potential applications of their use for endometrial repair after cancer remission, especially in endometrial cancers. Successful application of such cells will improve reproductive parameters in patients with AS or cancer. Significance: The endometrium is the fertile ground for embryos, but damage to the endometrium will greatly impair female fertility. Adult stem cells combined with tissue engineering scaffold materials or not have made great progress in repairing the injured endometrium due to benign lesions. However, due to the lack of research on the repair of the damaged endometrium caused by malignant tumors or tumor therapies, the safety and effectiveness of such stem cell-based therapies need to be further explored. This review focuses on the molecular insights and clinical application potential of adult stem cells in endometrial regeneration and discusses the possible challenges or difficulties that need to be overcome in stem cell-based therapies for tumor survivors. The development of adult stem cell-related new programs will help repair damaged endometrium safely and effectively and meet fertility needs in tumor survivors.
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Affiliation(s)
- Qiaoying Lv
- Department of GynecologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Lulu Wang
- Department of GynecologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Xuezhen Luo
- Department of GynecologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
| | - Xiaojun Chen
- Department of GynecologyObstetrics and Gynecology Hospital of Fudan UniversityShanghaiChina
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21
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Jiang X, Li X, Fei X, Shen J, Chen J, Guo M, Li Y. Endometrial membrane organoids from human embryonic stem cell combined with the 3D Matrigel for endometrium regeneration in asherman syndrome. Bioact Mater 2021; 6:3935-3946. [PMID: 33937593 PMCID: PMC8079828 DOI: 10.1016/j.bioactmat.2021.04.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 03/29/2021] [Accepted: 04/04/2021] [Indexed: 12/18/2022] Open
Abstract
Asherman's syndrome (AS), a leading cause of uterine infertility worldwide, is characterized by scarring of the uterine surfaces lacking endometrial epithelial cells, which prevents endometrial regeneration. Current research on cell therapy for AS focuses on mesenchymal and adult stem cells from the endometrium. However, insufficient number, lack of purity, and rapid senescence of endometrial epithelial progenitor cells (EEPCs) during experimental processes restrict their use in cell therapies. In this study, we induced human embryonic stem cells-9 (H9-ESC) into EEPCs by optimizing the induction factors from the definitive endoderm. EEPCs, which act as endometrial epithelial cells, accompanied by human endometrial stromal cells provide a niche environment for the development of endometrial membrane organoids (EMOs) in an in vitro 3D culture model. To investigate the function of EMOs, we transplanted tissue-engineered constructs with EMOs into an in vivo rat AS model. The implantation of EMOs into the damaged endometrium facilitates endometrial regeneration and angiogenesis. Implanting EMOs developed from human embryonic stem cells into the endometrium might prove useful for "endometrial re-engineering" in the treatment of Asherman's syndrome.
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Affiliation(s)
- Xiuxiu Jiang
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
| | - Xingmiao Li
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
| | - Xiangwei Fei
- Key Laboratory of Women′s Reproductive Health Research of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
| | - Jiajie Shen
- Key Laboratory of Women′s Reproductive Health Research of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
| | - Jianhua Chen
- Department of Pathology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
| | - Meijun Guo
- Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
| | - Yangyang Li
- Key Laboratory of Women′s Reproductive Health Research of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, 310006, China
- Corresponding author.
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22
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Cousins FL, Pandoy R, Jin S, Gargett CE. The Elusive Endometrial Epithelial Stem/Progenitor Cells. Front Cell Dev Biol 2021; 9:640319. [PMID: 33898428 PMCID: PMC8063057 DOI: 10.3389/fcell.2021.640319] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/22/2021] [Indexed: 12/20/2022] Open
Abstract
The human endometrium undergoes approximately 450 cycles of proliferation, differentiation, shedding and regeneration over a woman's reproductive lifetime. The regenerative capacity of the endometrium is attributed to stem/progenitor cells residing in the basalis layer of the tissue. Mesenchymal stem cells have been extensively studied in the endometrium, whereas endometrial epithelial stem/progenitor cells have remained more elusive. This review details the discovery of human and mouse endometrial epithelial stem/progenitor cells. It highlights recent significant developments identifying putative markers of these epithelial stem/progenitor cells that reveal their in vivo identity, location in both human and mouse endometrium, raising common but also different viewpoints. The review also outlines the techniques used to identify epithelial stem/progenitor cells, specifically in vitro functional assays and in vivo lineage tracing. We will also discuss their known interactions and hierarchy and known roles in endometrial dynamics across the menstrual or estrous cycle including re-epithelialization at menses and regeneration of the tissue during the proliferative phase. We also detail their potential role in endometrial proliferative disorders such as endometriosis.
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Affiliation(s)
- Fiona L. Cousins
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynecology, Monash University, Clayton, VIC, Australia
| | - Ronald Pandoy
- Buck Institute for Research on Aging, Novato, CA, United States
| | - Shiying Jin
- Buck Institute for Research on Aging, Novato, CA, United States
| | - Caroline E. Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Obstetrics and Gynecology, Monash University, Clayton, VIC, Australia
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23
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de Miguel-Gómez L, López-Martínez S, Francés-Herrero E, Rodríguez-Eguren A, Pellicer A, Cervelló I. Stem Cells and the Endometrium: From the Discovery of Adult Stem Cells to Pre-Clinical Models. Cells 2021; 10:cells10030595. [PMID: 33800355 PMCID: PMC7998473 DOI: 10.3390/cells10030595] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/25/2021] [Accepted: 03/04/2021] [Indexed: 02/06/2023] Open
Abstract
Adult stem cells (ASCs) were long suspected to exist in the endometrium. Indeed, several types of endometrial ASCs were identified in rodents and humans through diverse isolation and characterization techniques. Putative stromal and epithelial stem cell niches were identified in murine models using label-retention techniques. In humans, functional methods (clonogenicity, long-term culture, and multi-lineage differentiation assays) and stem cell markers (CD146, SUSD2/W5C5, LGR5, NTPDase2, SSEA-1, or N-cadherin) facilitated the identification of three main types of endogenous endometrial ASCs: stromal, epithelial progenitor, and endothelial stem cells. Further, exogenous populations of stem cells derived from bone marrow may act as key effectors of the endometrial ASC niche. These findings are promoting the development of stem cell therapies for endometrial pathologies, with an evolution towards paracrine approaches. At the same time, promising therapeutic alternatives based on bioengineering have been proposed.
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Affiliation(s)
- Lucía de Miguel-Gómez
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain; (L.d.M.-G.); (S.L.-M.); (E.F.-H.); (A.R.-E.)
- Department of Pediatrics, Obstetrics, and Gynaecology, School of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Sara López-Martínez
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain; (L.d.M.-G.); (S.L.-M.); (E.F.-H.); (A.R.-E.)
| | - Emilio Francés-Herrero
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain; (L.d.M.-G.); (S.L.-M.); (E.F.-H.); (A.R.-E.)
- Department of Pediatrics, Obstetrics, and Gynaecology, School of Medicine, University of Valencia, 46010 Valencia, Spain;
| | - Adolfo Rodríguez-Eguren
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain; (L.d.M.-G.); (S.L.-M.); (E.F.-H.); (A.R.-E.)
| | - Antonio Pellicer
- Department of Pediatrics, Obstetrics, and Gynaecology, School of Medicine, University of Valencia, 46010 Valencia, Spain;
- IVIRMA Rome Parioli, 00197 Rome, Italy
| | - Irene Cervelló
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain; (L.d.M.-G.); (S.L.-M.); (E.F.-H.); (A.R.-E.)
- Correspondence: ; Tel.: +34-963-903-305
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Gao Y, Wu G, Xu Y, Zhao D, Zheng L. Stem Cell-Based Therapy for Asherman Syndrome: Promises and Challenges. Cell Transplant 2021; 30:9636897211020734. [PMID: 34105392 PMCID: PMC8193648 DOI: 10.1177/09636897211020734] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 02/23/2021] [Accepted: 05/05/2021] [Indexed: 12/20/2022] Open
Abstract
Asherman syndrome (AS) has an adverse effect on reproductive health and fertility by affecting endometrial regeneration. Stem cell-based therapies hold promise for future use in activating non-functional endometrium and reconstructing the endometrium in vivo. It has been postulated that various endometrial stem cells (EnSCs) are responsible for endometrial regeneration. Numerous studies have focused on bone marrow-derived stem cells (BMDSCs), which may provide new ideas for repairing endometrial lesions and reconstructing the endometrium. Other sources of stem cells, such as menstrual blood, umbilical cord, and amniotic membrane, have also attracted much attention as candidates for transplantation in AS. This review discusses the features and specific biomarkers among four types of resident endometrial stem cells, applications of four different sources of exogenous stem cells in AS, and development of stem cell therapy using biomaterials and exosomes.
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Affiliation(s)
- Yiyin Gao
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Guijie Wu
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Ying Xu
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Donghai Zhao
- Department of Pathology, Jilin Medical University, Jilin, Jilin, China
| | - Lianwen Zheng
- Reproductive Medical Center, Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China
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25
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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.
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26
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Pluripotent Stem (VSELs) and Progenitor (EnSCs) Cells Exist in Adult Mouse Uterus and Show Cyclic Changes Across Estrus Cycle. Reprod Sci 2020; 28:278-290. [PMID: 32710237 DOI: 10.1007/s43032-020-00250-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/11/2020] [Accepted: 06/30/2020] [Indexed: 12/19/2022]
Abstract
We have earlier reported pluripotent, very small embryonic-like stem cells (VSELs) and slightly bigger endometrial stem cells (EnSCs) in adult mouse uterus and their regulation by gonadotropin and steroid hormones. VSELs can differentiate into cells of all three lineages in vitro; however, they neither expand readily in vitro nor compliment a developing embryo. In the present study, a robust protocol is described to enrich uterine stem/progenitor cells along with their characterization and variation across estrus cycle. After enzymatic digestion of adult mouse uterus, single-cell suspension obtained was spun at 1000 rpm (250 g) to pellet majority of cells. Stem cells remain buoyant at this speed and were pelleted by spinning supernatant at 3000 rpm (1000 g). Spherical, darkly stained VSELs (2-6 μm) with high nucleo-cytoplasmic ratio and EnSCs (> 6 μm) expressed OCT-4, NANOG, SSEA-1, SCA-1, and c-KIT. OCT-4-positive cells co-expressed SSEA-1, ERα, ERβ, PR, and FSHR. Transcripts specific for pluripotent state (Oct-4, Oct-4a, Sox-2, Nanog), primordial germ cells (Stella, Fragilis), and receptors for pituitary and steroid hormones (ERα, ERβ, PR, FSHR 1 and 3) were studied by RT-PCR in 3000 rpm pellet. Cell pellet collected at 3000 rpm showed 10-fold enrichment of VSELs (2-6 μm, viable cells with surface phenotype of LIN-CD45-SCA-1+) by flow cytometry and upregulation of pluripotent transcripts by qRT-PCR compared with 1000 rpm pellet. VSELs were maximal during estrus and metestrus phases of estrus cycle. To conclude, VSELs/EnSCs can be enriched from adult uterus using the strategy described here, vary in numbers across estrus cycle, and are vulnerable to endocrine disruption as they express steroid receptors.
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27
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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.
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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.
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28
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Bozorgmehr M, Gurung S, Darzi S, Nikoo S, Kazemnejad S, Zarnani AH, Gargett CE. Endometrial and Menstrual Blood Mesenchymal Stem/Stromal Cells: Biological Properties and Clinical Application. Front Cell Dev Biol 2020; 8:497. [PMID: 32742977 PMCID: PMC7364758 DOI: 10.3389/fcell.2020.00497] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 05/25/2020] [Indexed: 12/11/2022] Open
Abstract
A highly proliferative mesenchymal stem/stromal cell (MSC) population was recently discovered in the dynamic, cyclically regenerating human endometrium as clonogenic stromal cells that fulfilled the International Society for Cellular Therapy (ISCT) criteria. Specific surface markers enriching for clonogenic endometrial MSC (eMSC), CD140b and CD146 co-expression, and the single marker SUSD2, showed their perivascular identity in the endometrium, including the layer which sheds during menstruation. Indeed, cells with MSC properties have been identified in menstrual fluid and commonly termed menstrual blood stem/stromal cells (MenSC). MenSC are generally retrieved from menstrual fluid as plastic adherent cells, similar to bone marrow MSC (bmMSC). While eMSC and MenSC share several biological features with bmMSC, they also show some differences in immunophenotype, proliferation and differentiation capacities. Here we review the phenotype and functions of eMSC and MenSC, with a focus on recent studies. Similar to other MSC, eMSC and MenSC exert immunomodulatory and anti-inflammatory impacts on key cells of the innate and adaptive immune system. These include macrophages, T cells and NK cells, both in vitro and in small and large animal models. These properties suggest eMSC and MenSC as additional sources of MSC for cell therapies in regenerative medicine as well as immune-mediated disorders and inflammatory diseases. Their easy acquisition via an office-based biopsy or collected from menstrual effluent makes eMSC and MenSC attractive sources of MSC for clinical applications. In preparation for clinical translation, a serum-free culture protocol was established for eMSC which includes a small molecule TGFβ receptor inhibitor that prevents spontaneous differentiation, apoptosis, senescence, maintains the clonogenic SUSD2+ population and enhances their potency, suggesting potential for cell-therapies and regenerative medicine. However, standardization of MenSC isolation protocols and culture conditions are major issues requiring further research to maximize their potential for clinical application. Future research will also address crucial safety aspects of eMSC and MenSC to ensure these protocols produce cell products free from tumorigenicity and toxicity. Although a wealth of data on the biological properties of eMSC and MenSC has recently been published, it will be important to address their mechanism of action in preclinical models of human disease.
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Affiliation(s)
- Mahmood Bozorgmehr
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shanti Gurung
- Centre for Reproductive Health, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - Saeedeh Darzi
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Shohreh Nikoo
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Somaieh Kazemnejad
- Nanobitechnology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Amir-Hassan Zarnani
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Caroline E. Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
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29
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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: 50] [Impact Index Per Article: 10.0] [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.
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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
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30
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Yilmaz BD, Bulun SE. Endometriosis and nuclear receptors. Hum Reprod Update 2020; 25:473-485. [PMID: 30809650 DOI: 10.1093/humupd/dmz005] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 12/03/2018] [Accepted: 02/22/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Endometriosis is recognized as a steroid-dependent disorder; however, the precise roles of nuclear receptors (NRs) in steroid responsiveness and other signaling pathways are not well understood. OBJECTIVE AND RATIONALE Over the past several years, a number of paradigm-shifting breakthroughs have occurred in the area of NRs in endometriosis. We review and clarify new information regarding the mechanisms responsible for: (i) excessive estrogen biosynthesis, (ii) estrogen-dependent inflammation, (iii) defective differentiation due to progesterone resistance and (iv) enhanced survival due to deficient retinoid production and action in endometriosis. We emphasize the roles of the relevant NRs critical for these pathological processes in endometriosis. SEARCH METHODS We conducted a comprehensive search using PubMed for human, animal and cellular studies published until 2018 in the following areas: endometriosis; the steroid and orphan NRs, estrogen receptors alpha (ESR1) and beta (ESR2), progesterone receptor (PGR), steroidogenic factor-1 (NR5A1) and chicken ovalbumin upstream promoter-transcription factor II (NR2F2); and retinoids. OUTCOMES Four distinct abnormalities in the intracavitary endometrium and extra-uterine endometriotic tissue underlie endometriosis progression: dysregulated differentiation of endometrial mesenchymal cells, abnormal epigenetic marks, inflammation activated by excess estrogen and the development of progesterone resistance. Endometriotic stromal cells compose the bulk of the lesions and demonstrate widespread epigenetic abnormalities. Endometriotic stromal cells also display a wide range of abnormal NR expression. The orphan NRs NR5A1 and NR2F2 compete to regulate steroid-synthesizing genes in endometriotic stromal cells; NR5A1 dominance gives rise to excessive estrogen formation. Endometriotic stromal cells show an abnormally low ESR1:ESR2 ratio due to excessive levels of ESR2, which mediates an estrogen-driven inflammatory process and prostaglandin formation. These cells are also deficient in PGR, leading to progesterone resistance and defective retinoid synthesis. The pattern of NR expression, involving low ESR1 and PGR and high ESR2, is reminiscent of uterine leiomyoma stem cells. This led us to speculate that endometriotic stromal cells may display stem cell characteristics found in other uterine tissues. The biologic consequences of these abnormalities in endometriotic tissue include intense inflammation, defective differentiation and enhanced survival. WIDER IMPLICATIONS Steroid- and other NR-related abnormalities exert genome-wide biologic effects via interaction with defective epigenetic programming and enhance inflammation in endometriotic stromal cells. New synthetic ligands, targeting PGR, retinoic acid receptors and ESR2, may offer novel treatment options.
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Affiliation(s)
- Bahar D Yilmaz
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, 250 E. Superior Street, Chicago, IL, USA
| | - Serdar E Bulun
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, 250 E. Superior Street, Chicago, IL, USA
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31
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Santamaria X, Liu JH, Aghajanova L, Isaacson K, Movilla P, Fernandez H, Capmas P, Donnez J, Simón C. Should we consider alternative therapies to operative hysteroscopy for the treatment of Asherman syndrome? Fertil Steril 2020; 113:511-521. [PMID: 32111470 DOI: 10.1016/j.fertnstert.2020.01.022] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 01/20/2020] [Indexed: 12/30/2022]
Affiliation(s)
| | - James H Liu
- Department of Obstetrics and Gynecology, University Hospitals Cleveland, Cleveland, Ohio; Department of Reproductive Biology, Case Western Reserve University, Cleveland, Ohio
| | - Lusine Aghajanova
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Stanford School of Medicine, Stanford, California
| | - Keith Isaacson
- Department of Minimally Invasive Gynecologic Surgery, Newton Wellesley Hospital, Newton, Massachusetts
| | - Peter Movilla
- Department of Minimally Invasive Gynecologic Surgery, Newton Wellesley Hospital, Newton, Massachusetts
| | - Hervé Fernandez
- Department of Gynecology and Obstetrics, AP-HP, GHU-Sud, Hospital Bicêtre, Le Kremlin Bicêtre, France; Faculty of medicine, University Paris-Sud Saclay, Le Kremlin Bicêtre, France; INSERM U1018, Centre of Research in Epidemiology and Population Health (CESP), Le Kremlin Bicêtre, France
| | - Perrine Capmas
- Department of Gynecology and Obstetrics, AP-HP, GHU-Sud, Hospital Bicêtre, Le Kremlin Bicêtre, France; Faculty of medicine, University Paris-Sud Saclay, Le Kremlin Bicêtre, France; INSERM U1018, Centre of Research in Epidemiology and Population Health (CESP), Le Kremlin Bicêtre, France
| | - Jacques Donnez
- Société de Recherche pour l'Infertilité (SRI), Brussels, Belgium
| | - Carlos Simón
- Department of Obstetrics & Gynecology, Valencia University & INCLIVA, Valencia, Spain; Department of Obstetrics & Gynecology, BIDMC Harvard University, Boston, Massachusetts; Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas.
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32
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Lv CX, Duan H, Wang S, Gan L, Xu Q. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Promote Proliferation of Allogeneic Endometrial Stromal Cells. Reprod Sci 2020; 27:1372-1381. [PMID: 32006246 DOI: 10.1007/s43032-020-00165-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 12/01/2019] [Indexed: 12/13/2022]
Abstract
Umbilical cord mesenchymal stem cells (UCMSCs) have been proposed as an ideal source for cell-based therapy to promote endometrial repair and regeneration. Furthermore, increasing evidence has indicated that UCMSC-derived exosomes (UCMSC-exos) act as important paracrine mediators to recapitulate the features of MSCs and may play a vital role in this process. UCMSCs and human endometrial stromal cells (ESCs) were isolated and characterized. ESCs were cocultured with UCMSCs and further assessed by flow cytometry and EdU incorporation assays. UCMSC-exos were extracted by differential ultracentrifugation and identified by western blots, transmission electron microscopy, and nanoparticle tracking analysis. The internalization of UCMSC-exos by ESCs was observed under a confocal microscope. ESCs were treated with UCMSC-exos at different concentrations and for different durations, with cell viability evaluated by CCK-8 assays. The cell cycle analysis showed that the percentage of ESCs in S phase significantly increased after coculture with UCMSCs, whereas it significantly decreased after inhibition of UCMSC-exo secretions. EdU incorporation assays also showed a similar trend. The isolated UCMSC-exos had a typical cup-shaped morphology with a monolayer membrane, expressed the specific exosomal markers Alix, CD63, and TSG101 and were approximately 60 to 200 nm in diameter. The PKH26-labeled UCMSC-exos were incorporated into ESCs. Moreover, UCMSC-exos enhanced the cell growth and viability of ESCs in a dose-dependent manner, and the effects occurred in a short period of time. UCMSC-exos promote the proliferation of ESCs in a dose-dependent manner; thus, they could be used as a potential treatment to promote endometrial repair.
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Affiliation(s)
- Cheng-Xiao Lv
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Hua Duan
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People's Republic of China.
| | - Sha Wang
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Lu Gan
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Qian Xu
- Department of Minimally Invasive Gynecologic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, People's Republic of China
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33
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Tal R, Shaikh S, Pallavi P, Tal A, López-Giráldez F, Lyu F, Fang YY, Chinchanikar S, Liu Y, Kliman HJ, Alderman M, Pluchino N, Kayani J, Mamillapalli R, Krause DS, Taylor HS. Adult bone marrow progenitors become decidual cells and contribute to embryo implantation and pregnancy. PLoS Biol 2019; 17:e3000421. [PMID: 31513564 PMCID: PMC6742226 DOI: 10.1371/journal.pbio.3000421] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 08/09/2019] [Indexed: 12/22/2022] Open
Abstract
Decidua is a transient uterine tissue shared by mammals with hemochorial placenta and is essential for pregnancy. The decidua is infiltrated by many immune cells promoting pregnancy. Adult bone marrow (BM)-derived cells (BMDCs) differentiate into rare populations of nonhematopoietic endometrial cells in the uterus. However, whether adult BMDCs become nonhematopoietic decidual cells and contribute functionally to pregnancy is unknown. Here, we show that pregnancy mobilizes mesenchymal stem cells (MSCs) to the circulation and that pregnancy induces considerable adult BMDCs recruitment to decidua, where some differentiate into nonhematopoietic prolactin-expressing decidual cells. To explore the functional importance of nonhematopoietic BMDCs to pregnancy, we used Homeobox a11 (Hoxa11)-deficient mice, having endometrial stromal-specific defects precluding decidualization and successful pregnancy. Hoxa11 expression in BM is restricted to nonhematopoietic cells. BM transplant (BMT) from wild-type (WT) to Hoxa11-/- mice results in stromal expansion, gland formation, and marked decidualization otherwise absent in Hoxa11-/- mice. Moreover, in Hoxa11+/- mice, which have increased pregnancy losses, BMT from WT donors leads to normalized uterine expression of numerous decidualization-related genes and rescue of pregnancy loss. Collectively, these findings reveal that adult BMDCs have a previously unrecognized nonhematopoietic physiologic contribution to decidual stroma, thereby playing important roles in decidualization and pregnancy.
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Affiliation(s)
- Reshef Tal
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Shafiq Shaikh
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Pallavi Pallavi
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Aya Tal
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Francesc López-Giráldez
- Yale Center for Genome Analysis (YCGA), Yale University, New Haven, Connecticut, United States of America
| | - Fang Lyu
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Yuan-Yuan Fang
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Shruti Chinchanikar
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Ying Liu
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Harvey J. Kliman
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Myles Alderman
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Nicola Pluchino
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Jehanzeb Kayani
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Ramanaiah Mamillapalli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Diane S. Krause
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America
| | - Hugh S. Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, United States of America
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Santamaria X, Mas A, Cervelló I, Taylor H, Simon C. Uterine stem cells: from basic research to advanced cell therapies. Hum Reprod Update 2019; 24:673-693. [PMID: 30239705 DOI: 10.1093/humupd/dmy028] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 08/04/2018] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Stem cell research in the endometrium and myometrium from animal models and humans has led to the identification of endometrial/myometrial stem cells and their niches. This basic knowledge is beginning to be translated to clinical use for incurable uterine pathologies. Additionally, the implication of bone marrow-derived stem cells (BMDSCs) in uterine physiology has opened the field for the exploration of an exogenous and autologous source of stem cells. OBJECTIVE AND RATIONALE In this review, we outline the progress of endometrial and myometrial stem/progenitor cells in both human and mouse models from their characterization to their clinical application, indicating roles in Asherman syndrome, atrophic endometrium and tissue engineering, among others. SEARCH METHODS A comprehensive search of PubMed and Google Scholar up to December 2017 was conducted to identify peer-reviewed literature related to the contribution of bone marrow, endometrial and myometrial stem cells to potential physiological regeneration as well as their implications in pathologies of the human uterus. OUTCOMES The discovery and main characteristics of stem cells in the murine and human endometrium and myometrium are presented together with the relevance of their niches and cross-regulation. The current state of advanced stem cell therapy using BMDSCs in the treatment of Asherman syndrome and atrophic endometrium is analyzed. In the myometrium, the understanding of genetic and epigenetic defects that result in the development of tumor-initiating cells in the myometrial stem niche and thus contribute to the growth of uterine leiomyoma is also presented. Finally, recent advances in tissue engineering based on the creation of novel three-dimensional scaffolds or decellularisation open up new perspectives for the field of uterine transplantation. WIDER IMPLICATIONS More than a decade after their discovery, the knowledge of uterine stem cells and their niches is crystalising into novel therapeutic approaches aiming to treat with cells those conditions that cannot be cured with drugs, particularly the currently incurable uterine pathologies. Additional work and improvements are needed, but the basis has been formed for this therapeutic application of uterine cells.
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Affiliation(s)
- Xavier Santamaria
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Reproductive Medicine Department, IVI Barcelona, Barcelona, Spain.,Department of Obstetrics and Gynecology, Biomedical Research Group in Gynecology, Vall Hebron Institut de Recerca, Barcelona, Spain
| | - Aymara Mas
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Department of Obstetrics and Gynecology, Reproductive Medicine Research Group, La Fe Health Research Institute, Valencia, Spain
| | - Irene Cervelló
- Department of Obstetrics and Gynecology, Fundación Instituto Valenciano de Infertilidad (FIVI), and Instituto Universitario IVI/INCLIVA, Valencia, Spain
| | - Hugh Taylor
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Carlos Simon
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Department of Pediatrics, Obstetrics, and Gynecology, Valencia University and INCLIVA, Valencia, Spain.,Department of Obstetrics and Gynecology, Stanford University, Stanford, CA, USA
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Santamaria X, Mas A, Cervelló I, Taylor HS, Simon C. Reply: Bone marrow-derived endometrial cells: what you see is what you get. Hum Reprod Update 2019; 25:274-275. [PMID: 30601981 DOI: 10.1093/humupd/dmy042] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Indexed: 11/13/2022] Open
Affiliation(s)
- Xavier Santamaria
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Reproductive Medicine Department, IVI Barcelona, Barcelona, Spain.,Department of Obstetrics and Gynecology, Biomedical Research Group in Gynecology, Vall Hebron Institut de Recerca, Barcelona, Spain
| | - Aymara Mas
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Department of Obstetrics and Gynecology, Reproductive Medicine Research Group, La Fe Health Research Institute, Valencia, Spain
| | - Irene Cervelló
- Department of Obstetrics and Gynecology, Fundación Instituto Valenciano de Infertilidad (FIVI), and Instituto Universitario IVI/INCLIVA, Valencia, Spain
| | - Hugh S Taylor
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Carlos Simon
- Reproductive Medicine Department, Igenomix Academy, Paterna (Valencia), Spain.,Department of Pediatrics, Obstetrics, and Gynecology, Valencia University and INCLIVA, Valencia, Spain.,Department of Obstetrics and Gynecology, Stanford University, Stanford, CA, USA
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36
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Deane JA, Ong Y, Cousins FL, Gargett CE. Bone marrow-derived endometrial cells: transdifferentiation or misidentification? Hum Reprod Update 2019; 25:272-274. [DOI: 10.1093/humupd/dmy041] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Accepted: 11/24/2018] [Indexed: 01/29/2023] Open
Affiliation(s)
- J A Deane
- The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, VIC, Australia
| | - Y Ong
- The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, VIC, Australia
| | - F L Cousins
- The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, VIC, Australia
| | - C E Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, VIC, Australia
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37
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Zhu X, Péault B, Yan G, Sun H, Hu Y, Ding L. Stem Cells and Endometrial Regeneration: From Basic Research to Clinical Trial. Curr Stem Cell Res Ther 2019; 14:293-304. [PMID: 30516114 DOI: 10.2174/1574888x14666181205120110] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 10/30/2018] [Accepted: 10/31/2018] [Indexed: 12/14/2022]
Abstract
Monthly changes in the endometrial cycle indicate the presence of endometrial stem cells. In recent years, various stem cells that exist in the endometrium have been identified and characterized. Additionally, many studies have shown that Bone Marrow Mesenchymal Stem Cells (BM-MSCs) provide an alternative source for regenerating the endometrium and repairing endometrial injury. This review discusses the origin of endometrial stem cells, the characteristics and main biomarkers among five types of putative endometrial stem cells, applications of endometrium-derived stem cells and menstrual blood-derived stem cells, the association between BM-MSCs and endometrial stem cells, and progress in repairing endometrial injury.
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Affiliation(s)
- Xinxin Zhu
- Center for Reproductive Medicine, Drum Tower Clinic Medical College of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Bruno Péault
- MRC Center for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, United Kingdom
| | - Guijun Yan
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Haixiang Sun
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Yali Hu
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Lijun Ding
- Center for Reproductive Medicine, Drum Tower Clinic Medical College of Nanjing Medical University, Nanjing 210029, Jiangsu, China
- MRC Center for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, United Kingdom
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
- Clinical Center for Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
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Lee YJ, Yi KW. Bone marrow-derived stem cells contribute to regeneration of the endometrium. Clin Exp Reprod Med 2018; 45:149-153. [PMID: 30538944 PMCID: PMC6277671 DOI: 10.5653/cerm.2018.45.4.149] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 10/24/2018] [Accepted: 11/07/2018] [Indexed: 12/22/2022] Open
Abstract
Stem cells are undifferentiated cells capable of self-renewal and differentiation into various cell lineages. Stem cells are responsible for the development of organs and regeneration of damaged tissues. The highly regenerative nature of the human endometrium during reproductive age suggests that stem cells play a critical role in endometrial physiology. Bone marrow-derived cells migrate to the uterus and participate in the healing and restoration of functionally or structurally damaged endometrium. This review summarizes recent research into the potential therapeutic effects of bone marrow-derived stem cells in conditions involving endometrial impairment.
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Affiliation(s)
- Youn Jeong Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Korea
| | - Kyong Wook Yi
- Department of Obstetrics and Gynecology, Korea University College of Medicine, Seoul, Korea
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Cousins FL, O DF, Ong YR, Breault DT, Deane JA, Gargett CE. Telomerase Reverse Transcriptase Expression in Mouse Endometrium During Reepithelialization and Regeneration in a Menses-Like Model. Stem Cells Dev 2018; 28:1-12. [PMID: 30358490 DOI: 10.1089/scd.2018.0133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The regenerative capacity of the endometrium has been attributed to resident stem/progenitor cells. A number of stem/progenitor markers have been reported for human endometrial stem/progenitor cells; however, the lack of convenient markers in the mouse has made experimental investigation into endometrial regeneration difficult. We recently identified endometrial epithelial, endothelial, and immune cells, which express a reporter for the stem/progenitor marker, mouse telomerase reverse transcriptase (mTert). In this study, we investigate the expression pattern of a green fluorescent protein (GFP) reporter for mTert promoter activity (mTert-GFP) in endometrial regeneration following a menses-like event. mTert-GFP expression marks subepithelial populations of T cells and mature macrophages and may play a role in immune cell regulated repair. Clusters of mTert-GFP-positive epithelial cells were identified close to areas of reepithelialization and possibly highlight a role for mTert in the repair and regeneration of the endometrial epithelium.
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Affiliation(s)
- Fiona L Cousins
- 1 The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Australia
- 2 Department of Obstetrics and Gynecology, School of Clinical Sciences at Monash Health, Monash University Faculty of Medicine, Clayton, Australia
| | - Dorien F O
- 1 The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Australia
| | - Yih Rue Ong
- 1 The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Australia
| | - David T Breault
- 3 Division of Endocrinology, Boston Children's Hospital, Harvard Stem Cell Institute, Boston, Massachusetts
| | - James A Deane
- 1 The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Australia
- 2 Department of Obstetrics and Gynecology, School of Clinical Sciences at Monash Health, Monash University Faculty of Medicine, Clayton, Australia
| | - Caroline E Gargett
- 1 The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Australia
- 2 Department of Obstetrics and Gynecology, School of Clinical Sciences at Monash Health, Monash University Faculty of Medicine, Clayton, Australia
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40
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Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions. Int J Mol Sci 2018; 19:ijms19103240. [PMID: 30347708 PMCID: PMC6214006 DOI: 10.3390/ijms19103240] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 09/07/2018] [Accepted: 10/10/2018] [Indexed: 02/07/2023] Open
Abstract
The human endometrium is a highly regenerative organ undergoing over 400 cycles of shedding and regeneration over a woman’s lifetime. Menstrual shedding and the subsequent repair of the functional layer of the endometrium is a process unique to humans and higher-order primates. This massive regenerative capacity is thought to have a stem cell basis, with human endometrial stromal stem cells having already been extensively studied. Studies on endometrial epithelial stem cells are sparse, and the current belief is that the endometrial epithelial stem cells reside in the terminal ends of the basalis glands at the endometrial/myometrial interface. Since almost all endometrial pathologies are thought to originate from aberrations in stem cells that regularly regenerate the functionalis layer, expansion of our current understanding of stem cells is necessary in order for curative treatment strategies to be developed. This review critically appraises the postulated markers in order to identify endometrial stem cells. It also examines the current evidence supporting the existence of epithelial stem cells in the human endometrium that are likely to be involved both in glandular regeneration and in the pathogenesis of endometrial proliferative diseases such as endometriosis and endometrial cancer.
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41
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James K, Bhartiya D, Ganguly R, Kaushik A, Gala K, Singh P, Metkari SM. Gonadotropin and steroid hormones regulate pluripotent very small embryonic-like stem cells in adult mouse uterine endometrium. J Ovarian Res 2018; 11:83. [PMID: 30241552 PMCID: PMC6148988 DOI: 10.1186/s13048-018-0454-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 09/03/2018] [Indexed: 12/25/2022] Open
Abstract
Background Very small embryonic-like stem cells (VSELs) exist in adult organs, express pluripotent markers and have the ability to differentiate into three germ layers in vitro. Testicular, ovarian and hematopoietic stem/progenitor cells express receptors for follicle stimulating (FSH) and ovarian hormones and are activated by them to undergo proliferation/differentiation. VSELs exist in mouse uterus and are regulated by physiological dose of estradiol (E) & progesterone (P) during endometrial growth, differentiation and regeneration/remodeling. In the present study, effects of daily administration of E (2 μg/day), P (1 mg/Kg/day) or FSH (5 IU/day) for 7 days on the endometrium and stem/progenitor cells was studied in bilaterally ovariectomized mice. Results E treatment resulted in hypertrophy whereas P resulted in hyperplasia and overcrowding of epithelial cells. FSH also directly stimulated the endometrial cells. Nuclear OCT-4A positive VSELs were visualized in ovariectomized (atrophied) endometrium and cytoplasmic OCT-4B positive epithelial, stromal and endothelial cells were observed after treatment. FSH treated uterine tissue showed presence of 4 alternately spliced FSHR isoforms by Western blotting. 3–5 μm VSELs with a surface phenotype of LIN-/CD45-/SCA-1+ were enumerated by flow cytometry and were found to express ER, PR, FSHR1 and FSHR3 by RT-PCR analysis. Differential effects of treatment were observed on pluripotent (Oct4A, Sox2, Nanog), progenitors (Oct-4, Sca-1), primordial germ cells (Stella, Fragilis) and proliferation (Pcna) specific transcripts by qRT-PCR analysis. FSH and P (rather than E) exerted profound, direct stimulatory effects on uterine VSELs. Asymmetric, symmetric divisions and clonal expansion of stem/progenitor cells was confirmed by co-expression of OCT-4 and NUMB. Conclusions Results confirm presence of VSELs and their regulation by circulatory hormones in mouse uterus. Stem cell activation was more prominent after P and FSH compared to E treatment. The results question whether epithelial cells proliferation is regulated by paracrine influence of stromal cells or due to direct action of hormones on stem cells. VSELs expressing nuclear OCT-4A are the most primitive and pluripotent stem cells, undergo asymmetric cell division to self-renew and differentiate into epithelial, stromal and endothelial cells with cytoplasmic OCT-4B. Role of follicle stimulating and steroid hormones on the stem cells needs to be studied in various uterine pathologies.
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Affiliation(s)
- Kreema James
- Stem Cell Biology Department, ICMR - National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India
| | - Deepa Bhartiya
- Stem Cell Biology Department, ICMR - National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India.
| | - Ranita Ganguly
- Stem Cell Biology Department, ICMR - National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India
| | - Ankita Kaushik
- Stem Cell Biology Department, ICMR - National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India
| | - Kavita Gala
- Stem Cell Biology Department, ICMR - National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India
| | - Pushpa Singh
- Stem Cell Biology Department, ICMR - National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India
| | - S M Metkari
- Stem Cell Biology Department, ICMR - National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India
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Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies. Int J Mol Sci 2018; 19:ijms19082385. [PMID: 30104541 PMCID: PMC6121292 DOI: 10.3390/ijms19082385] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 08/05/2018] [Accepted: 08/09/2018] [Indexed: 12/13/2022] Open
Abstract
Endometriosis is an estrogen-dependent inflammatory disease that affects up to 10% of women of reproductive age and accounts for up to 50% of female infertility cases. It has been highly associated with poorer outcomes of assisted reproductive technology (ART), including decreased oocyte retrieval, lower implantation, and pregnancy rates. A better understanding of the pathogenesis of endometriosis-associated infertility is crucial for improving infertility treatment outcomes. Current theories regarding how endometriosis reduces fertility include anatomical distortion, ovulatory dysfunction, and niche inflammation-associated peritoneal or implantation defects. This review will survey the latest evidence on the role of inflammatory niche in the peritoneal cavity, ovaries, and uterus of endometriosis patients. Nonhormone treatment strategies that target these inflammation processes are also included. Furthermore, mesenchymal stem cell-based therapies are highlighted for potential endometriosis treatment because of their immunomodulatory effects and tropism toward inflamed lesion foci. Potential applications of stem cell therapy in treatment of endometriosis-associated infertility in particular for safety and efficacy are discussed.
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Deane JA, Ong YR, Cousins FL, Gargett CE. In Reply to Letter to the Editor from Bhartiya: Transplantation of Whole Bone Marrow Indicates That Bone Marrow Very Small Embryonic-Like Cells Do Not Contribute to Endometrial Lineages. Stem Cells 2018; 36:809. [PMID: 29345012 DOI: 10.1002/stem.2784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 12/26/2017] [Indexed: 11/11/2022]
Affiliation(s)
- James A Deane
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Yih Rue Ong
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia
| | - Fiona L Cousins
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Caroline E Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
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44
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Bhartiya D. Being Pluripotent, Bone Marrow Very Small Embryonic-Like Stem Cells Rather Than Hematopoietic Stem Cells Have the Potential to Regenerate Other Adult Organs. Stem Cells 2018; 36:807-808. [PMID: 29345024 DOI: 10.1002/stem.2782] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 11/14/2017] [Accepted: 11/19/2017] [Indexed: 12/22/2022]
Affiliation(s)
- Deepa Bhartiya
- Stem Cell Biology Department, ICMR- National Institute for Research in Reproductive Health, Parel, Mumbai, Maharashtra, India
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