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      Human menstrual blood: a renewable and sustainable source of stem cells for regenerative medicine

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          Abstract

          Stem cells (SCs) play an important role in autologous and even allogenic applications. Menstrual blood discharge has been identified as a valuable source of SCs which are referred to as menstrual blood-derived stem cells (MenSCs). Compared to SCs from bone marrow and adipose tissues, MenSCs come from body discharge and obtaining them is non-invasive to the body, they are easy to collect, and there are no ethical concerns. There is, hence, a growing interest in the functions of MenSCs and their potential applications in regenerative medicine. This review presents recent progress in research into MenSCs and their potential application. Clinical indications of using MenSCs for various regenerative medicine applications are emphasized, and future research is recommended to accelerate clinical applications of MenSCs.

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          Modulating the stem cell niche for tissue regeneration.

          The field of regenerative medicine holds considerable promise for treating diseases that are currently intractable. Although many researchers are adopting the strategy of cell transplantation for tissue repair, an alternative approach to therapy is to manipulate the stem cell microenvironment, or niche, to facilitate repair by endogenous stem cells. The niche is highly dynamic, with multiple opportunities for intervention. These include administration of small molecules, biologics or biomaterials that target specific aspects of the niche, such as cell-cell and cell-extracellular matrix interactions, to stimulate expansion or differentiation of stem cells, or to cause reversion of differentiated cells to stem cells. Nevertheless, there are several challenges in targeting the niche therapeutically, not least that of achieving specificity of delivery and responses. We envisage that successful treatments in regenerative medicine will involve different combinations of factors to target stem cells and niche cells, applied at different times to effect recovery according to the dynamics of stem cell-niche interactions.
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            Endometrial regenerative cells: A novel stem cell population

            Angiogenesis is a critical component of the proliferative endometrial phase of the menstrual cycle. Thus, we hypothesized that a stem cell-like population exist and can be isolated from menstrual blood. Mononuclear cells collected from the menstrual blood contained a subpopulation of adherent cells which could be maintained in tissue culture for >68 doublings and retained expression of the markers CD9, CD29, CD41a, CD44, CD59, CD73, CD90 and CD105, without karyotypic abnormalities. Proliferative rate of the cells was significantly higher than control umbilical cord derived mesenchymal stem cells, with doubling occurring every 19.4 hours. These cells, which we termed "Endometrial Regenerative Cells" (ERC) were capable of differentiating into 9 lineages: cardiomyocytic, respiratory epithelial, neurocytic, myocytic, endothelial, pancreatic, hepatic, adipocytic, and osteogenic. Additionally, ERC produced MMP3, MMP10, GM-CSF, angiopoietin-2 and PDGF-BB at 10–100,000 fold higher levels than two control cord blood derived mesenchymal stem cell lines. Given the ease of extraction and pluripotency of this cell population, we propose ERC as a novel alternative to current stem cells sources.
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              Endometrial stem/progenitor cells: the first 10 years

              BACKGROUND The existence of stem/progenitor cells in the endometrium was postulated many years ago, but the first functional evidence was only published in 2004. The identification of rare epithelial and stromal populations of clonogenic cells in human endometrium has opened an active area of research on endometrial stem/progenitor cells in the subsequent 10 years. METHODS The published literature was searched using the PubMed database with the search terms ‘endometrial stem cells and menstrual blood stem cells' until December 2014. RESULTS Endometrial epithelial stem/progenitor cells have been identified as clonogenic cells in human and as label-retaining or CD44+ cells in mouse endometrium, but their characterization has been modest. In contrast, endometrial mesenchymal stem/stromal cells (MSCs) have been well characterized and show similar properties to bone marrow MSCs. Specific markers for their enrichment have been identified, CD146+PDGFRβ+ (platelet-derived growth factor receptor beta) and SUSD2+ (sushi domain containing-2), which detected their perivascular location and likely pericyte identity in endometrial basalis and functionalis vessels. Transcriptomics and secretomics of SUSD2+ cells confirm their perivascular phenotype. Stromal fibroblasts cultured from endometrial tissue or menstrual blood also have some MSC characteristics and demonstrate broad multilineage differentiation potential for mesodermal, endodermal and ectodermal lineages, indicating their plasticity. Side population (SP) cells are a mixed population, although predominantly vascular cells, which exhibit adult stem cell properties, including tissue reconstitution. There is some evidence that bone marrow cells contribute a small population of endometrial epithelial and stromal cells. The discovery of specific markers for endometrial stem/progenitor cells has enabled the examination of their role in endometrial proliferative disorders, including endometriosis, adenomyosis and Asherman's syndrome. Endometrial MSCs (eMSCs) and menstrual blood stromal fibroblasts are an attractive source of MSCs for regenerative medicine because of their relative ease of acquisition with minimal morbidity. Their homologous and non-homologous use as autologous and allogeneic cells for therapeutic purposes is currently being assessed in preclinical animal models of pelvic organ prolapse and phase I/II clinical trials for cardiac failure. eMSCs and stromal fibroblasts also exhibit non-stem cell-associated immunomodulatory and anti-inflammatory properties, further emphasizing their desirable properties for cell-based therapies. CONCLUSIONS Much has been learnt about endometrial stem/progenitor cells in the 10 years since their discovery, although several unresolved issues remain. These include rationalizing the terminology and diagnostic characteristics used for distinguishing perivascular stem/progenitor cells from stromal fibroblasts, which also have considerable differentiation potential. The hierarchical relationship between clonogenic epithelial progenitor cells, endometrial and decidual SP cells, CD146+PDGFR-β+ and SUSD2+ cells and menstrual blood stromal fibroblasts still needs to be resolved. Developing more genetic animal models for investigating the role of endometrial stem/progenitor cells in endometrial disorders is required, as well as elucidating which bone marrow cells contribute to endometrial tissue. Deep sequencing and epigenetic profiling of enriched populations of endometrial stem/progenitor cells and their differentiated progeny at the population and single-cell level will shed new light on the regulation and function of endometrial stem/progenitor cells.
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                Author and article information

                Contributors
                haining_lv@163.com
                yalihu@nju.edu.cn
                zhanfeng.cui@eng.ox.ac.uk
                huidong.jia@eng.ox.ac.uk
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                1757-6512
                21 November 2018
                21 November 2018
                2018
                : 9
                : 325
                Affiliations
                [1 ]ISNI 0000 0004 1800 1685, GRID grid.428392.6, Department of Obstetrics and Gynecology, , Nanjing Drum Tower Hospital, Graduate School of Peking Union Medical College, ; 321 Zhongshan Road, Nanjing, China
                [2 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Tissue Engineering Group, Institute of Biomedical Engineering, Department of Engineering Science, , University of Oxford, ; ORCRB, Roosevelt Drive, Headington, Oxford, OX3 7DQ UK
                Author information
                http://orcid.org/0000-0001-5216-2421
                Article
                1067
                10.1186/s13287-018-1067-y
                6249727
                30463587
                d5345adc-68da-4b79-9ba3-3a070eb10240
                © The Author(s). 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100011176, Peking Union Medical College;
                Award ID: 3332018186
                Funded by: Jiangsu Provincial Key Medical Center
                Award ID: YXZXB2016004
                Award Recipient :
                Funded by: Key Research and Development program of Jiangsu province 
                Award ID: BE2016612
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Molecular medicine
                menstrual blood,menstrual blood-derived stem cells,regenerative medicine

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