{"paper_id":"09d9bc8e-95d9-4a42-8157-22c006f5a9d4","body_text":"Kong et al. Stem Cell Res Ther          (2021) 12:474  \nhttps://doi.org/10.1186/s13287-021-02526-z\nREVIEW\nEndometrial stem/progenitor cells \nand their roles in immunity, clinical application, \nand endometriosis\nYue Kong1,2, Yang Shao1,2, Chunxia Ren3* and Gong Yang1,2,4*  \nAbstract \nEndometrial stem/progenitor cells have been proved to exist in periodically regenerated female endometrium and \ncan be divided into three categories: endometrial epithelial stem/progenitor cells,  CD140b+CD146+ or  SUSD2+ endo-\nmetrial mesenchymal stem cells (eMSCs), and side population cells (SPs). Endometrial stem/progenitor cells in the \nmenstruation blood are defined as menstrual stem cells (MenSCs). Due to their abundant sources, excellent prolifera-\ntion, and autotransplantation capabilities, MenSCs are ideal candidates for cell-based therapy in regenerative medi-\ncine, inflammation, and immune-related diseases. Endometrial stem/progenitor cells also participate in the occur-\nrence and development of endometriosis by entering the pelvic cavity from retrograde menstruation and becoming \noverreactive under certain conditions to form new glands and stroma through clonal expansion. Additionally, the \nlimited bone marrow mesenchymal stem cells (BMDSCs) in blood circulation can be recruited and infiltrated into the \nlesion sites, leading to the establishment of deep invasive endometriosis. On the other hand, cell derived from endo-\nmetriosis may also enter the blood circulation to form circulating endometrial cells (CECs) with stem cell-like prop-\nerties, and to migrate and implant into distant tissues. In this manuscript, by reviewing the available literature, we \noutlined the characteristics of endometrial stem/progenitor cells and summarized their roles in immunoregulation, \nregenerative medicine, and endometriosis, through which to provide some novel therapeutic strategies for reproduc-\ntive and cancerous diseases.\nKeywords: Stem cells, Endometriosis, Human endometrium, Immunology\n© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco \nmmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nIntroduction\nEndometrium can be divided into shallow and deep lay -\ners based on the structure. The shallow layer is called \nfunctional layer that experiences periodic changes of \nproliferation, secretion, and shedding under the regula -\ntion of hormones. The deep layer is named as basal layer. \nThe basal layer owns strong proliferation and repair \nabilities without falling off during the menstrual period \nbut generates new functional layers. The periodic endo -\nmetrial regeneration implies the presence of stem/\nprogenitor cells in the endometrium. Gargett et  al. first \nrevealed the existence of adult stem/progenitor cells in \nendometrium by identification of  rare clonogenic cells \nor colony-forming units (CFUs) from purified single-cell \nsuspensions of hysterectomy tissues in 2004 [1]. Since \nthen, the study of endometrial stem/progenitor cells has \nbeen highly developed. At present, based on cell types \nand identification techniques, endometrial stem/pro -\ngenitor cell population is defined as  CD140b+CD146+ \nor  SUSD2+ endometrium-derived mesenchymal stem \nOpen Access\n*Correspondence:  renchunxia2018@shutcm.edu.cn; yanggong@fudan.edu.\ncn\n1 Cancer Institute, Fudan University Shanghai Cancer Center, \nShanghai 200032, China\n3 Center for Reproductive Medicine, Shuguang Hospital Affiliated \nto Shanghai University of Traditional Chinese Medicine, Shanghai 200120, \nChina\nFull list of author information is available at the end of the article\n\nPage 2 of 16Kong et al. Stem Cell Res Ther          (2021) 12:474 \ncells (eMSCs), endometrial epithelial stem/progenitor \ncells, and side population cells (SPs) [2–4], whereas those \nderived from menstrual blood are called menstrual stem \ncells (MenSCs).\nEndometriosis is defined as the growth and infiltra -\ntion of endometrial tissue (glands and stroma) outside \nthe uterine cavity with  the typical symptom of periodic \nbleeding, which causes infertility, pain, nodules, and \nmasses [5]. A most widely accepted hypothesis for the \npathogenesis of endometriosis first proposed by Sampson \net al. in 1927 is that the endometrial glandular epithelium \nand stromal cells flow within the menstrual blood and \nenter the pelvic cavity through the fallopian tubes. These \ncells may invade, grow and spread in the ovary and the \nadjacent pelvic peritoneum tissues, to eventually form \nthe  pelvic endometriosis [6]. This theory is called ret -\nrograde menstruation (RM), but it still cannot explain \nwhy only 6–10% of the reproductive age women with \nRM develop into endometriosis [7]. The concept of stem \ncells may well explain the low incidence of endometriosis \nin patients with RM because the abnormal endometrial \nstem/progenitor cells  from just a few patients enter the \npelvic cavity to cause endometriotic lesions [2, 8–11].\nIn this review, we collected the recent advances in \nthe identification and characterization of adult stem/\nprogenitor cells in female endometrium and   summa -\nrized the cell-based therapy and immunoregulation of \nendometrial stem/progenitor cells. We also outlined the \nsignaling pathways and molecular mechanisms involved \nin endometrial stem/progenitor cell populations. The \nphysiological/pathological roles of bone marrow-derived \nand endogenous stem/progenitor cells in endometriosis \nare also analyzed. Finally, we proposed that MenSCs are \nthe most promising candidates for the  stem cell-based \ntherapy. The investigation of the molecular mechanisms \nof stem/progenitor cells in the development of endome -\ntriosis may provide  some novel strategies for molecular \ntherapy of reproductive and cancerous diseases.\nMultiple populations of stem/progenitor cells \nin endometrium\nCD140b+CD146+ eMSCs\nThe  CD146+CD140b+ population is located \nat the perivascular region in both functional and basal lay-\ners and can differentiate into osteogenic, myogenic, adi -\npogenic, and chondrogenic lineages, as well as fibroblasts \nand smooth muscle cells [12–14] (Fig.  1). Mesenchymal \nstem cell (MSC) markers CD29, CD44, CD73, CD90, \nCD105, but not endothelial or hemopoietic markers \nCD31, CD34, and CD45, are expressed in this population \nFig. 1 Schematic diagram illustrates the localization of endometrial stem/progenitor cells and the hypothesis that stem cells in RM, BMDSCs and \nCECs may be involved in the development of endometriosis.  CD140b+CD146+ eMSCs are located perivascularly in both the functionalis and basalis. \n SUSD2+ eMSCs are also perivascular cells. Epithelial progenitor cells are a subset of SSEA-1+ cells located at the bottom of basalis, and may form \nindividual colonies. Endometrial SPs are composed of heterogeneous populations, including endothelial cells and  CD140b+CD146+ eMSCs. \nEndometrial stem/progenitor cells in RM may be the cellular source of primary endometriotic lesions. Abnormal endometrial stem/progenitor cells \nin RM enter the pelvic cavity and invade the mesothelium. On one hand, endometriotic cells secrete cytokines (such as CXCL12) to attract limited \nBMDSCs in blood circulation and implant them in the ectopic lesions. On the other hand, endometriotic cells enter the blood circulation to cause \ndistant infiltration\n\nPage 3 of 16\nKong et al. Stem Cell Res Ther          (2021) 12:474 \n \n[15] (Table  1). The percentage and clonal capacity of \n CD140b+CD146+ cells are constant at different stages of \nthe menstrual cycle (menstrual, proliferative, and secre -\ntory  phases). However, compared with the secretory \nstage,  CD140b+CD146+ cells from the menstrual endo -\nmetrium experience more rounds of  the self-renewal, \nsuggesting that  CD140b+CD146+ cells may be activated \nduring menstruation to promote the periodic regenera -\ntion of the endometrium. More  CD140b+CD146+ cells \ncan be detected in the deeper portion of the endome -\ntrium than in the superficial layer, but their clonogenic \nand self-renewal activities remain similarly [16]. Gene \nexpression profiling revealed that 1518 and 762 genes are \ndifferentially and significantly expressed between \n CD140b+CD146+ cells and endothelial cells, or between \n CD140b+CD146+ cells and stromal fibroblasts, respec -\ntively [13]. In addition,   CD140b+CD146+ cells highly \nexpress genes involved in angiogenesis, steroid hormone/\nhypoxia responses, immunomodulation, inflammation, \ncell communication, and proteolysis/inhibition, and \ndisplay  the increased expression of Notch, IGF, TGF-\nβ, Hedgehog, and G protein-coupled receptor signal -\ning  molecules compared with  CD140b+CD146− cells \n[13]. Co-culture of endometrial cells (epithelial or stro -\nmal) derived from menstruation with  CD140b+CD146+ \neMSCs enhances the cloning and self-renewal activi -\nties of  CD140b+CD146+ eMSCs. Co-culture of \n CD140b+CD146+ cells with the  endometrial niche cell \nconditioned media containing the high levels of interleu -\nkin 6, C-X-C motif ligand 1 (CXCL1) and CXCL5 may \nincrease the proliferation and self-renewal abilities of \n CD140b+CD146+ eMSCs [17].\nCD146+ cells derived from human endometrium can \nform colony-forming units [18] and differentiate into \nadipocytes, osteoblasts, neural progenitors, and glial-\nlike cells [19, 20] (Table  1). With the help of the col -\nlagen–matrigel scaffold on the top of the myometrial \nsmooth muscle cells, human endometrial  CD146+ cells \nmay generate endometrial gland-like structures in  vitro \n[21] and express all recognized markers of MSCs, includ -\ning CD10, CD13, CD44, CD73, CD90, and CD105 \n[20] (Table  1). Cysteine-rich angiogenesis inducer 61 \n(CYR61), also called CCN family member 1, is highly \nexpressed in endothelial cells and smooth muscle cells \n[22] and may play an important role in angiogenesis and \ntissue repair [23, 24]. Compared with  CD146+CYR61−, \n CD146+CYR61+ cells can stimulate angiogenesis. The \nrat  endometrium transplanted with  CD146+CYR61+ \ncells  appear with higher blood vessel density than that \ntransplanted with  CD146+ or  CD146+CYR61−  cells. \nIn addition, endometrial injury rats transplanted with \n CD146+CYR61+ cells appear with higher pregnancy rate \nthan control group [20].\nTable 1 Surface marker phenotype and in vitro/in vivo differentiation of human endometrial stem cells\nMenSCs menstrual stem cells, SPs side population cells, eMSCs endometrial mesenchymal stem cells\nCell type Positive marker Negative marker In vitro and in vivo \ndifferentiation\nReferences\nMenSCs CD73, CD90, CD105, CD13, \nCD44, CD29, CD9, CD44, \nCD41a, CD59\nCD19, CD34, CD45, CD117, \nCD130, HLA-DR\nAdipocytes, osteocytes, \ncardiomyocytes, neurocytes, \nrespiratory epithelial cells, \nendothelial cells, myocytes, \nhepatic cells, pancreatic cells, \nand germ-like cell\n[42, 43]\nEndometrial SPs of epithelial \norigin\nCD9, CD90, CD105, CD73, CD45, \nCD34, CD31, CD133, stro-1\nCD9, CD13 Adipocytes, osteocytes [96, 97]\nEndometrial SPs from the stro-\nmal compartment\nVimentin, CD90, CD73, CD45, \nCD34, CD31, CD133, stro-1\nCD9, CD13, CD105, ERα, PR Adipocytes, osteocytes [97]\nSUSD2+ eMSCs CD29, CD44, CD73, CD90, \nCD105, CD117, CD140b, \nCD146, and STRO-1, NTP-\nDase2\nCD31, CD45 Adipocytes, osteocytes, \nchondrocytes, myocytes, \nendothelial cells\n[12]\nCD140b+CD146+ eMSCs CD29, CD44, CD73, CD90, \nCD105, CD140b, CD146\nCD31, CD34, CD45 Osteocytes, myocytes, adipo-\ncytes, chondrocytes, fibro-\nblasts and smooth muscle cell\n[12, 14, 15]\nCD146+ cells CD10, CD13, CD44, CD73, CD90, \nand CD105\nCD31, CD34, CD45, CD56, \nCD144, CD9\nAdipocytes, osteoblasts, and \nneuron-like cells, glial-like cells\n[19, 21]\nEpithelial stem/progenitor cells N-cadherin, SSEA-1, Axin 2 Entire complement of glandular \nlineages, endometrial orga-\nnoids\n[104, 107, 150]\n\nPage 4 of 16Kong et al. Stem Cell Res Ther          (2021) 12:474 \nSUSD2+ eMSCs\nSUSD2, a novel marker of eMSCs, is proved particu -\nlarly effective in the  selection of eMSCs [12].  SUSD2+ \ncells reside predominantly in a perivascular location in \nboth basal and functional layers of endometrium (Fig.  1). \n SUSD2+ cells can differentiate into adipocytes, osteo -\ncytes, chondrocytes, myocytes, endothelial cells in  vitro \nand produce endometrial stromal-like tissues in  vivo \n(Table  1). Freshly isolated  SUSD2+ cells express MSC \nmarkers including CD29, CD44, CD73, CD90, CD105, \nCD117, CD140b, CD146, and STRO-1 (Table 1).  SUSD2+ \ncells also express nucleoside triphosphate diphosphohy -\ndrolase 2 (NTPDase2), a membrane-expressed enzyme \nexisting in mesenchymal-derived cells, such as pericytes \nin different tissues and stem cells in adult neurogenic \nregions [25, 26]. The expression level and localization of \nNTPDase2 remain unchanged throughout the menstrual \ncycle, indicating that the enzyme can be used as a cell \nmarker to improve the separation of eMSCs for regenera-\ntive medicine treatment [27].\nSUSD2+ eMSC seems to be affected by pregnancy \nand obesity, but not by aging. In the undifferenti -\nated state,  SUSD2+-derived cells produce lower levels \nof various chemokines and inflammatory regulators \nthan  SUSD2− cells. However, this is switched after \ndecidualization  because these  SUSD2+ cells are turned \ninto the main source  to produce chemokines and \ncytokines including chemokine (C–C motif) ligand 7, \nand the  leukemia inhibitory factor [28].  SUSD2+ cells \noriginated from myometrium and uterine fibroids are \nfeatured as MSCs and can also be induced into decidua \n[29]. Perivascular  SUSD2+ cells isolated from postmen -\nopausal endometrium also display the characteristics of \nMSCs, regardless whether the patients receive estrogen \npretreatment for the regeneration of endometrium [30]. \nHowever, adipocytes may adversely affect endometrial \nstem cells. Compared with that in  women with nor -\nmal body mass index (BMI), the proportion and cloning \nefficiency of  SUSD2+ cells in the endometrium of obese \nwomen are significantly reduced [31].\nSignaling pathways involved in  SUSD2+ eMSCs\nIn recent years, scientists have gradually paid the atten -\ntion to the clinical application of endometrial stem cells. \nThe  in vitro expansion and stemness maintenance  of \neMSCs  are a major challenge for the current clinical \ntreatment. Studies have found that A83-01, a TGF-β \nreceptor inhibitor, can maintain  SUSD2+ eMSCs pro -\nliferation, clonogenicity, and function   through the \nFig. 2 GnRH, TGF-β, and SHH affect the multiple functions of eMSCs, such as proliferation, differentiation, aging, and migration. GnRH inhibits \nthe multiple beneficial functions of eMSCs, such as proliferation, differentiation, and migration, through the PI3K/AKT signaling. The activation \nof Akt signaling attenuates the GnRH-induced adverse effects on multiple stem cell functions. TGF-β inhibits the proliferation, differentiation, \nand colony-forming efficiency of  SUSD2+ eMSCs. A83-01, TGF-β receptor inhibitor, can maintain the clonogenicity of  SUSD2+ eMSCs, promote \nproliferation, prevent cell apoptosis, and maintain eMSC function. Exogenous SHH therapy could significantly alleviate various aging-related \ndeclines in multiple eMSC functions through the inhibition of SERPINB2 expression\n\nPage 5 of 16\nKong et al. Stem Cell Res Ther          (2021) 12:474 \n \ninhibition of TGF-βR signaling [32, 33] (Fig.  2). The \nexpression of genes associated with anti-inflammatory \nresponse, angiogenesis, cell migration and proliferation \ncan be promoted by A83-01 in  SUSD2+ eMSCs [34].\nLong-term GnRH exposure of eMSCs may be respon -\nsible for the relatively low rate of in  vitro fertilization \n(IVF) positive pregnancy outcomes. Unlike terminally \ndifferentiated fibroblasts,  SUSD2+ eMSCs express \nabundant GnRH receptors. GnRH inhibits the multiple \nbeneficial functions of eMSCs, such as proliferation, \ndifferentiation and migration, through the  PI3K/Akt \nsignaling pathway [35] (Fig. 2 ).\nThe Sonic hedgehog (SHH) signaling typically func -\ntions in morphogenesis during  the embryonic devel -\nopment [36]. In addition, the decreased SHH signal \nintegrity of local eMSCs may be a potential factor for \nthe decreased regeneration of ageing endometrium. \nThe activity of SHH is decreased significantly with age -\ning, but the exogenous SHH therapy may significantly \nalleviate the  various ageing-associated declines. SER -\nPINB2 is a major regulator for the SHH signal trans -\nduction during senescence, whereas  the senescence of \nstem cells may enhance the expression of SERPINB2, \nwhich in turn mediates the role of SHH to attenuate the \nsenescence-induced dysfunction of eMSCs [37] (Fig. 2 ).\nSUSD2+ eMSCs in immunity and tissue engineering\nMesenchymal stem cells (MSCs) from other tissues, such \nas bone marrow, umbilical cord, and adipose tissues, \ninhibit the proliferation of T cells, B cells, natural killer \ncells (NK), and dendritic cells (DCs) to induce cell cycle \narrest through the  mechanisms associated with IL-10, \nprostaglandin E2, TGF-β1, and regulatory T cells (Tregs) \n[38]. Although  SUSD2+ eMSCs inhibit the  mitogen-\ninduced lymphocyte proliferation in a dose-dependent \nmanner, blocking  of the mouse IL-10 receptors or  the \nprostaglandin production dose not inhibit lymphocyte \nproliferation. Despite the reduction of Tregs, endome -\ntrial  SUSD2+ cells continue to inhibit lymphocyte prolif -\neration in the presence of TGF-β receptor inhibitors [39]. \nTherefore, the inhibition of  the mitogen-induced lym -\nphocyte proliferation by  SUSD2+ cells occurs through \nan  uncertain mechanism different from that of MSCs \nfrom other tissues (Fig.  3A). Moreover, the  systemic \nFig. 3 Roles of  SUSD2+ eMSCs and MenSCs in immunity. A TGF-β promotes the differentiation of Tregs that inhibit T-lymphocyte proliferation. \nA83-01 increases the T-lymphocyte proliferation through the inhibition of the TGF-β signaling-dependent Treg differentiation, but  SUSD2+ eMSCs \ncontinue to inhibit the lymphocyte proliferation via an uncertain mechanism independent of the TGF-β signaling from that of MSC from other \ntissues. B MenSCs inhibit the phenotypic differentiation of human peripheral blood monocytes into immature and mature DCs. MenSCs can also \naffect the proliferation of monocytes in a dose-dependent manner. In vivo studies, after the intravenous injection of MenSCs, the proportion \nof  CD4+ and  CD8+ T cells in spleen was significantly down-regulated and the percentage of  CD4+CD25+Foxp3+ regulatory T cells (Treg) and \nBreg  (CD19+IL‐10+) in spleen was significantly up-regulated. The serum levels of IL-1β, IL-6, and TNF-α in mice receiving MenSCs transplantation \nare lower, but the expression level of IL-10 is higher. CXCL12 secreted by MenSCs also increases the percentage of Treg, Breg, and M2 cells. \nMenSC-derived exosomes can resolve inflammation through the induction of the M1-M2 macrophages polarization. MenSCs treatment may inhibit \nthe proliferation of B cells to reduce  the production of IgM and IgG antibodies\n\nPage 6 of 16Kong et al. Stem Cell Res Ther          (2021) 12:474 \nadministration of endometrial  SUSD2+ cells dose not \ninhibit  the swelling of the T cell-mediated skin inflam -\nmation. Although endometrial  SUSD2+ cells can alter \nthe immune response, their immunoregulatory pool may \nnot be sufficient to suppress the certain T cell-mediated \ninflammatory events [39].\nAnimal studies demonstrate that  SUSD2+ eMSCs can \nalso modify immune responses to the  implanted mesh \n[39]. Seeding of eMCSs in  scaffolds can promote the \nformation and reconstruction of neo-tissues [40, 41]. \nThe eMSCs alter the growth of collagen and organiza -\ntion around the mesh filaments of the scaffold  to affect \nthe physiologically relevant tensile properties of the \nscaffold-tissue complex. The stiffness of scaffolds seeded \nwith eMSCs on initial stretching can be significantly \nalleviated. In addition,  the scaffold is an appropriate \nplatform for eMSCs delivery, proliferation, and differen -\ntiation, with  the better biocompatibility and the capac -\nity to regenerate neo-tissues, which may be a promising \napplication in the clinical mesh repair of pelvic organ \nprolapse (POP) to reduce the excessive scar tissue forma-\ntion induced by foreign body reactions and to relieve the \nin vivo poor mechanical compliance.\nMenstrual stem cells\nMenstrual stem cells (MenSCs) were first identified \nfrom menstrual blood in 2007, which can effectively \npropagate for over 68 population doublings with normal \nkaryotype [42]. MenSCs express markers CD29, CD9, \nCD13, CD44, CD41a, CD73, CD59, CD90, and CD105 \nbut not CD19, CD34, CD45, CD117, CD130, or HLA-DR \n[42, 43] (Table  1). MenSCs partially (over 50%) express \nthe pluripotency marker SSEA-4, but not Oct-4. Men -\nSCs can differentiate into adipocytic [44], osteogenic \n[45], cardiomyocytic [46], and  neurocytic  lineages [47], \nas well as  respiratory epithelial, endothelial, myocytic, \nhepatic [48], germ-like [49, 50], and pancreatic cells [42, \n51] (Table  1). Replacement of  fetal bovine serum with \nhuman platelet derivatives can promote the differen -\ntiation of MenSCs into osteoblasts [52]. The mitotically \ninactivated MenSCs are ideal feeder cells for the human \nembryonic stem cell lines C612 and C910 [43].\nMenSCs in regenerative medicine and tissue engineering\nMenSCs population is one of the clinically accessible \nsources of stem cells with great potential in regenera -\ntive medicine. MenSCs are abundant in sources with \nexcellent proliferation and autotransplantation capa -\nbilities and can be collected regularly and noninvasively. \nIn addition, MenSCs have a higher proliferation ability \nthan that of BMSCs [53]. Most importantly, any signifi -\ncant side effects including acute, subchronic, or chronic \npoisoning, infection, tumorigenesis, or endometrio -\nsis has not been reported either in preclinical studies or \nin clinical studies during the treatments of various dis -\neases with MenSCs over the past yeas [54–56] (Table  2). \nTable 2 Some of the disorders could be (or already are) treated by MenSCs\nMenSCs menstrual stem cells, IUA intrauterine adhesion, ARDS acute respiratory distress syndrome\nDisorder Subjects References\nIUA Human [57]\nRat model [151]\nEndometrial injury Mice model [152]\nPremature ovarian failure Rat model [58]\nMice model [59, 78]\nLiver failure Mice model [60–62]\nPig model [153]\nLiver fibrosis Mice model [154]\nExperimental stroke In vitro stroke model of oxygen glucose deprivation [63]\nPulmonary fibrosis Mice model [64, 65]\nARDS Patients with H7N9-induced ARDS [71]\nMyocardial infarction Rat model [46, 68]\nCardiac allograft Mice model [67, 90]\nAlzheimer’s disease Mice model [69]\nAcute lung injury Mice model [70]\nRenal ischemia reperfusion injury Mice model [72]\nType 1 diabetes Mice model [75]\nChronic nonhealing wounds Diabetic mice model [74]\nSciatic nerve injury Rat model [73]\n\nPage 7 of 16\nKong et al. Stem Cell Res Ther          (2021) 12:474 \n \nExisting studies have found that MenSCs therapy may be \nan attractive alternative approach for intrauterine adhe -\nsion (IUA) [57], premature ovarian failure (POF) [58, 59], \nliver failure [60–62], experimental stroke [63], pulmo -\nnary fibrosis [64, 65], cardiac diseases [66, 67], myocar-\ndial infarction [46, 68], Alzheimer’s disease [69], acute \nlung injury [70], acute respiratory distress syndrome \n[71], renal ischemia reperfusion injury [72], sciatic nerve \ninjury [73], chronic nonhealing wounds [74], and type 1 \ndiabetes [75] (Table 2).\nStudies reported that MenSCs may be used for patients \nwith severe IUA. MenSCs co-cultured with endome -\ntrial stromal cells (ESCs) promote the proliferation and \nwound repair of ESCs, down-regulate the expression of \nαSMA and collagen I in ESCs, and reverse  the fibrotic \ngene expression in ESCs induced by TGF-β through the \nHippo/TAZ signaling pathway [76]. Intrauterine trans -\nplantation of MenSCs in the IUA rat model  demonstrate  \nthat the endometrial pathology and uterine fertility of \nthe rat are significantly improved [77]. Human autolo -\ngous MenSCs transplantation may significantly promote \nthe endometrial morphology regeneration and functional \nrecovery in patients with severe IUA, which thereby helps \nsome patients achieve a positive pregnancy [57].\nMenSCs with  properties  of high  survival rate  in vivo \nand easy access make them very useful for stem cell trans-\nplantation in POF therapy. By two-dimensional culture \nand 3D scaffold culture system, MenSCs can differentiate \ninto germ-like cells in vitro [49, 50]. MenSCs transplan -\ntation increases the body weight of POF mice, improves \nthe estrus cycle, and restores the fertility of POF mice \n[78]. The transplanted MenSCs can be detected in the \novarian stroma and survive in the ovaries of POF mice \nfor at least 14 days [59,78], and can be differentiated into \ngranulosa cells and traced to two months in the ovaries of \nPOF rats [58]. The ovaries receiving MenSCs transplan -\ntation express the higher levels of ovarian reserve mark -\ners (AMH, inhibin α/β, and follicle-stimulating hormone \nreceptor) and increase the ovarian weight, the plasma E2 \nlevel, and the normal follicle counts [59].\nThe application of MenSCs in tissue engineering is \nalso promising. A wide variety of 3D scaffolds has been \napplied to induce differentiation and co-culture of Men -\nSCs. On the nanofiber scaffolds with the specific growth \nand differentiation factors, MenSCs may be differentiated \ninto chondrocytes to anchor firmly on the highly porous \nscaffold, and to penetrate and spread on the scaffold. The \nscaffold contains an extensive cartilage-like extracellular \nmatrix whose glycosaminoglycan content is about 50% \nhigher than that of the 2D culture system through which \nMenSCs  differentiated [79]. On the 3D wet-electrospun \npoly (lactic acid)/multi-wall carbon nanotube scaffold, \nMenSCs can  be differentiated into germ-like cells [50]. \nBased on the bilayer amniotic membrane/nano-fibrous \nfibroin scaffold, MenSCs can be  differentiated into \nkeratinocyte like cells in the presence of keratinocytes \nderived from human foreskin [80]. In the 3D co-culture \nsystem of mouse preantral follicles and human MenSCs, \nthe  follicular growth indices are significantly increased, \nincluding survival rate, diameter and antrum formation \nas well as the rate of in vitro maturation rate [81].\nInteraction of MenSCs with immune cells\nMenSCs interact with a variety of immune cells and \nparticipate in the regulation of cellular immunity and \nhumoral immunity (Fig.  3B). Menstrual blood can be \nused not only as a source of MenSCs, but also as a source \nof DCs. Monocytes in menstrual blood can be induced \ninto DCs by a two-step protocol [82]. DCs, the profes -\nsional antigen-presenting cells, may form an indispen -\nsable interface between the innate sensing of pathogens \nand the activation of adaptive immunity, which  thereby \nenables DCs to be used as a novel and promising immu -\nnetherapeutic approach for cancer, persistent infection \nand autoimmune diseases treatment [83–85]. Similar to \n SUSD2+ eMSCs, MenSCs inhibit the optimal phenotypic \ndifferentiation of human peripheral blood monocytes \n(PBMCs) into immature and mature DCs, in which IL-6 \nand IL-10 may play an important role [86]. Moreover, \nMenSCs may also affect the proliferation of monocytes \nin a dose-dependent manner [87]. The immunosuppres -\nsive effects of MenSCs on PBMCs,  CD4+IFN-γ+, and \n CD8+IFN-γ+ cells are weaker than those of BMDSCs, but \nMenSCs appear with a higher capacity to migrate into \nthe intestine and liver [88].\nIn vivo studies showed that MenSCs may protect mice \nliver from acute injury through the  anti-inflammatory \nand immunomodulatory effects. In the mice model with \nacute injury  liver, the proportion of  CD4+ and  CD8+ T \ncells in spleen was significantly down-regulated after \nintravenous injection of MenSCs, while the percentage \nof  CD4+CD25+Foxp3+Tregs in spleen was significantly \nup-regulated. Additionally, the  splenic DCs in MenSCs-\ntreated mice displayed a significant decrease of the MHC-\nII expression. The serum and liver levels of IL-1β, IL-6, \nand TNF-α in mice receiving MenSCs transplantation \nare lower, but the expression level of IL-10 is higher \n[60]. In the colitis mice model, the treatment with Men -\nSCs mainly regulated the response of B-lymphocytes, \nwhereas the intravenous injection of MenSCs decreased \nthe percentage of immature plasma cells in spleen and \nIgG deposition in colon but increased the secretion of \nIL-10 and the production of Bregs  (CD19+IL-10+) [89]. \nOn wound-healing process, MenSCs-derived exosomes \ncan attenuate inflammation through the induction of the \nM1-M2 macrophage polarization [74].\n\nPage 8 of 16Kong et al. Stem Cell Res Ther          (2021) 12:474 \nThe therapeutic function of MenSCs used to alleviate \nthe antibody-mediated allograft rejection can be partly \nattributed to the cellular immunity regulation [67] and \nthe  humoral immunity suppression [90]. The  MenSC-\nmediated therapy can prolong the survival of the  mice \nreceiving cardiac allotransplantation due to the decrease \nof IgM and IgG deposition and the circulation of the anti-\ndonor antibodies secreted by  CD19+ B cells. In addition, \nby ex vivo stimulation, because the proliferation of B cells \nfrom the MenSC-treated heart transplant recipients is \nimpaired, and the production of IgM and IgG antibod -\nies is reduced [90]. Stromal-cell-derived factor‐1 (SDF‐1), \nalso known as CXCL12, can be secreted in a substantial \namount by MenSCs. The  MenSC-mediated therapy can \ninduce immunosuppression and donor-specific allograft \ntolerance in which the SDF-1 secreted by MenSCs plays \nimportant roles. Based on MenSCs therapy, SDF-1 can \nreduce the  antibody-mediated rejection and acute cel -\nlular rejection  to increase the percentages of Tol-DC \n (CD11c+MHC class  II+), Treg  (CD4+CD25+Foxp3+), \nBreg  (CD19+IL‐10+), and M2  (CD68+CD206+) cells, and \nto  reduce the percentage of total macrophages [67]. As \neasily accessible and expandable stem cells, MenSCs are \nworthy of the  researchers’ attention for their functions \nin the regulation of the immune system-related cells and \nhumoral immunity.\nSide population cells\nSide population cells (SPs) are considered a universal \nmarker for adult stem cells in mammalian species. This \nphenotype results from the high expression of plasma \nmembrane transporters (such as ABCG2), which trans -\nports the DNA-binding dye Hoechst 33,342 out of the cell \n[91]. SPs were first isolated from normal human endome-\ntrial cells by Kato et al. in 2007 and can be differentiated \ninto gland- and stromal-like cells [92]. Human endome -\ntrium contains approximately 1–7% SPs in freshly iso -\nlated human endometrial at various stages, including \nproliferative phase [93], secretory phase and decidual of \nearly pregnancy [94, 95]. Most SPs in the endometrium \nare resting cells in  vivo, but during the proliferative \nphase, a small number of SPs become active to be differ -\nentiated into endometrial cells [93, 94]. SPs are located \nat the vascular endothelium cells lining blood vessels in \nboth the functionalis and the basalis of the endometrium \n[94] (Fig. 1).\nSpecific markers have been identified for SPs (Table  1). \nEndometrial SPs are composed of heterogeneous popu -\nlations, with endothelial cell markers (CD31), hemat -\nopoietic cell markers (CD34 and CD45), the epithelial \ncell marker EMA and mesenchymal stem cell markers \n(CD90, CD105, and CD146) [94, 96, 97]. The enrichment \nof endothelial and  CD146+CD140b+ eMSCs suggests \nthat the endometrial SPs play a role in angiogenesis dur -\ning  the endometrial regeneration [98]. However, SPs in \nhuman decidua of early pregnancy are negative for CD13, \nCD34, and CD45, but about 95% of SP cells in human \ndecidua are  CD31−CD146− [99] (Table  1). No differ -\nence in the percentage of  SUSD2+ cells exist between the \nendometrial SP and non-SP components,  but  CD140b+ \n CD146+ cells are much more abundant in endometrial \nSPs than in non-SP components [100]. With the greater \ncolony-forming efficiency than non-side population cells \n[94], SPs can be differentiated into various types of endo -\nmetrial cells, such as stroma, glandular epithelium, and \nendothelium cells [93], adipocytes and osteoblasts [96, \n101]. SPs also rebuild the  well-organized endometrial \ntissues and glandular structures in vivo [93, 96, 97, 100, \n102].\nAlthough the endometrial SPs are featured with the \nexcellent self-renewal and differentiation abilities, the \ndynamic labeling is technically difficult to be performed, \nthe co-labeling with other markers is unreliable, the \nHoechst dye is toxic to cells, and flow cytometry sorting \ndamages cells [14, 103]. Therefore, the heterogeneity of \nthe SPs and their isolation method hinder their clinical \napplications.\nEndometrial epithelial stem/progenitor cells\nEndometrial epithelial progenitor cells were first isolated \nby Gargett et  al. [15]. Individual colonies in  the differ -\nentiation induction medium are  characterized as adult \nstem cells by analysis of the  self-renewal, differentia -\ntion, and high proliferative potential of single epithelial. \nThe  stage-specific embryonic antigen-1 (SSEA-1), as a \nmarker of human endometrial basal glandular epithe -\nlial cells, is used to distinguish the epithelium of basalis \nfrom functionalis [104, 105] (Fig.  1). SSEA-1+ endome -\ntrial epithelial cells displaying some characteristics of the \nbasalis epithelium and the higher telomerase activity may \nproduce a higher number of endometrial gland-like sphe-\nroids than SSEA-1 − endometrial epithelial cells in 3D \nculture system.\nRecently, through in  vivo lineage tracking, research -\ners found that  the endometrial epithelium maintains \nthe  continuous self-renew during the  development, \nnormal growth, and regeneration of the whole life, and \ndemonstrated that a multipotent endometrial epithe -\nlial stem cells with naturally occurring somatic mito -\nchondrial DNA mutations (CCO gene) can regenerate \nthe entire complement of glandular lineages [106, 107]. \nAxin2, a key negative regulator of the  Wnt signaling \npathway is expressed in the stem cells of various organs \n[108], and is also identified as a marker of long-lived \nbipotent epithelial progenitors that reside in endome -\ntrial glands [107]. Cytoplasmic Axin2 is also  expressed \n\nPage 9 of 16\nKong et al. Stem Cell Res Ther          (2021) 12:474 \n \nin the functionalis of proliferative and secretory endo -\nmetrial glandular epithelia from premenopausal women. \nIn contrast, the nuclear Axin2 expression is observed in \nthe proliferative and secretory basalis of premenopausal \nand postmenopausal endometrial epithelia [105]. Axin2-\nexpressing glandular cells express  the known stem cell \nmarkers, such as Lgr5, Trop2 and Sox9 to fuel endome -\ntrial epithelial growth and regeneration in vivo. In addi -\ntion,  Axin2+ cells can form fully functional endometrial \norganoids in vitro [107]. The above findings seem to pro -\nvide evidence for the involvement of the  mesenchymal-\nto-epithelial transition (MET) in the maintenance and \nregeneration of the uterine epithelium [109]. However, \na recent cell fate tracing study found that the  conclu -\nsive evidence for the conversion of mesenchymal cells \nto epithelial cells in adult uterine is lacking. The study of \nthe embryonal cell lineage tracing with reporters driven \nby mesenchymal cell marker genes of the female repro -\nductive tract (AMHR2, CSPG4, and PDGFRβ) showed \nthat these reporters are also expressed in some oviductal \nand uterine epithelial cells at birth [110].\nThe endometrial epithelial stem cell population of \nmouse residing in the intersection zone between luminal \nand glandular epithelial compartments is also identified \nby in  vivo lineage tracking  in which the tissue distribu -\ntion allow the bipotent endometrial epithelial stem cells \nto  be differentiated bidirectionally into luminal epithe -\nlial cells and glandular epithelial cells and  to maintain \nthe  homeostasis and regeneration of the  mouse endo -\nmetrial epithelium under physiological conditions [111]. \nHowever, no labeled epithelial cells were found in any \nfallopian tubes or uterine epithelium after the mesenchy -\nmal cell labeling is induced in adult mice, indicating that \nno definitive evidence of MET  happens in the fallopian \ntubes and uterine epithelium in murine [110]. Very small \nembryonic-like stem cells (VSELs) are recently identified \nin mouse uterine [112], but they  are still controversial \n[113] because without the sufficient functional analysis to \nprove their pluripotency until now [4].\nParticipation of endometrial stem/progenitor cells \nin the origin and development of endometriosis\nEndometriosis is characterized by the development of \nendometrial tissues outside the uterus to cause pain and \ninfertility. Due to the lack of effective biomarkers, endo -\nmetriosis is usually not diagnosed until the first onset of \nthe disease a few years later. So far, most of the existing \ntreatments are non-therapeutic [8]. Until the beginning \nof the twenty-first century, some scholars suspected that \nendometriosis may be a stem cell-related disease, because \nless differentiated endometrial cells in RM may be the \ncellular source of primary endometriotic lesions [8, 114, \n115]. Endometrial stem/progenitor cells with the altered \nmolecular properties reflux into the pelvic cavity via \nRM, where they adhere and form ectopic lesions. The \nprevalence of shed basalis fragments in the  menstrual \nblood of women with endometriosis is significantly \nhigher than that in the  healthy control menstrual blood \n[8]. The endometrium of endometriotic lesions displays \na cyclical pattern similar to the basalis and presents the \nsame cyclical pattern of ER and PR expression as the \ndeep basalis. The expression of adult stem cell markers \nMusashi-1 [116], OCT4, SOX15, SOX2 [117, 118], C-kit \n[119], Notch and Numb [120], and the corneal epithelial \nprogenitor cell marker importin13 [121] is significantly \nhigher in endometriotic lesions than in normal endome -\ntrium. The  peripheral lymphocytes from endometriosis \npatients are detected with longer telomeres than those \nfrom healthy controls [122]. Moreover, the expression \nof SSEA-1 in ectopic epithelial cells is similar to that in \neutopic basalis epithelium [104, 123]. These data support \nthe concept of a stem cell origin of endometriosis that \nthe presence of the  abnormally detached basalis endo -\nmetrium fragments in the RM is considered as the main \ncause of endometriosis (Fig. 1).\nPeritoneal microenvironment interacts \nwith ectopic cells in patients with endometriosis\nEndometriosis alters the peritoneal microenvironment of \nwomen, in which the immune response, angiogenesis, cell \nproliferation, cell adhesion, and apoptosis are uniquely reg-\nulated in peritoneal fluid (PF). A specific protein expression \npattern is present in PF with deep infiltrating endometriosis \n(DIE) compared in PF with non-DIE [124]. The detached \nendometrial fragments flow into the pelvic cavity, where \nthey directly interact with cytokines in PF [125] to secrete \nchemokines [126] and  to form a feedforward loop [127], \nwhich eventually induces the infiltration of immune cells \nand BMDSCs [128]. Seventy-four cytokines are increased \nand 4 cytokines are decreased in PF from endometriosis \npatients compared with those in  healthy control group \n[125]. Among these cytokines, activin A is significantly \nincreased in PF from endometriosis group, whereas ALK4 \n(activin A-specific receptor) is increased in ectopic endo -\nmetrial-derived  SUSD2+ eMSCs [129]. In addition, the \nlevels of Activin A secreted by glandular cells and stromal \ncells are significantly higher in the eutopic endometrium of \nendometriosis patients than in the eutopic endometrium \nof healthy controls [130]. The expression of the  connec -\ntive tissue growth factor (CTGF) in  SUSD2+ eMSCs may \nbe promoted by Activin A through the binding of Smad2/3 \nto the CTGF promoter to induce the myofibroblast differ-\nentiation of  SUSD2+ eMSCs. Endometriotic lesions may \nbe enhanced by Activin A through the increased IL-6, IL-8, \nand TNF-α in the ascites of endometriosis mice models \n[131, 132]. Inhibition of the activin A pathway prevents \n\nPage 10 of 16Kong et al. Stem Cell Res Ther          (2021) 12:474 \nthe myofibroblast differentiation of  SUSD2+ eMSCs and \nimproves fibrosis in endometriosis mice [129]. Endometri-\notic cells interact with the abnormal peritoneal microenvi-\nronment of patients with endometriosis. The ectopic cells \nsecrete inflammatory factors that may remodel the perito-\nneal microenvironment, and in turn, various cytokines in \nPF exert their function on the endometriotic cells.\nAbnormal expression profiles of endometrial stem \ncells from endometriosis patients\nEctopic eMSCs from endometriosis patients display \nstronger abilities of proliferation, migration, and angiogen-\nesis than eutopic eMSCs from the same individual or from \nhealthy controls [133]. The expression profiles of adeno -\nmyosis-derived mesenchymal stem cells (AMSCs) are dif-\nferent from those of eMSCs and BMSCs. Compared with \neMSCs, the expression of cyclooxygenase-2 (COX-2) in \nAMSCs is significantly increased, and inhibition of COX-2 \nblocks the migration and invasion of AMSCs and induces \ntheir apoptosis [134].\nCD73+CD90+CD105+ endometrial stem cells  (SCs+) \nfrom normal, ectopic and eutopic endometrium display a \nsignificantly higher level of  SUSD2+ with cloning efficiency \nand sphere formation capacity than  SCs−. Compared with \nin eutopic endometrium  SC+ samples, the expression of \nPTEN, ARID1A, and TNFα from paired-ectopic samples \nis significantly down-regulated. Analysis of the  hierarchi-\ncal and multivariate clustering from both  SC+ and tissue \ncohorts revealed the abnormal expression of stemness-\nrelated and cancer-related genes such as KIT, HIF2α, and \nE-Cadherin in 4 of 30 ectopic samples. C-kit is expressed \nhigher in the endometrial glandular cells of  the women \nwith endometriosis than in the endometrial glandular cells \nof the women without endometriosis [119]. Therefore, it is \nspeculated that the changes in stemness-associated genes \nmay be linked to the development of endometriosis [135].\nMenSCs from women with and without endometriosis \ndisplay different phenotypic and functional characteris -\ntics [136]. MenSCs from  the endometriosis (E-MenSCs) \nwomen appear with the higher expression of CD9, CD10, \nand CD29 and the  higher proliferation and invasion \npotentials than MenSCs from  the non-endometriosis \n(NE-MenSCs) women. The expression of the  indoleam -\nine 2,3-dioxygenase-1 (IDO1) and COX-2 in E-MenSCs is \nhigher than in NE-MenSCs. In addition, the supernatants \nof E-MenSCs contain the higher levels of IFN-γ, IL-10, and \nthe monocyte chemoattractant protein 1 than those of NE-\nMenSCs. These findings indicate that MenSCs may play \nan alternative role in the pathogenesis of endometriosis, \nwhich further supports the stem cell theory of endometrio-\nsis with RM.\nStem/progenitor cells or stem‑like cells \nof extrauterine origin promote endometriosis\nA study reported that a few of stromal cells and epithelial \ncells from doner mouse endometrial tissues were traced \nin the ectopic implant lesions of the recipient mice after \n10 weeks of transplantation, indicating that the cells from \nthe extrauterine origin may also promote  the develop -\nment of ectopic endometrium [137].\nBMDSCs participate in the pathogenesis of endome -\ntriosis to promote the development of the disease [138] \n(Fig.  1). BMDSCs implanted into ectopic endometrial \nand endometriotic lesions display the properties of stro -\nmal and epithelial cells [137, 139], while the cytokines \nsecreted by the implanted BMDSCs promote the pro -\nliferation of ectopic endometrial cells [138]. In turn, \nthe  endometriotic cells also stimulate the  BMDSCs dif -\nferentiation and increase the expression of PD-1 in T \ncells possibly through the paracrine signaling [140]. The \nectopic endometrium competes with the eutopic endo -\nmetrium for the limited supply of BMDSCs in blood cir -\nculation and the depletion of normal BMDSCs flux to the \nuterus. In addition, stem cells migrate from the endome -\ntriotic lesions to the uterus, to induce the dysfunction of \nthe  eutopic endometrium [141]. 17β-Estradiol can pro -\nmote the chemotaxis and migration of BMDSCs by up-\nregulating the secretion of chemokine SDF-1α [142]. In \na mouse endometriosis model, bazedoxifene [139], an \nestrogen receptor modulator, administered with the con -\njugated estrogens and letrozole [143] (aromatase inhibi -\ntor) not only alleviated the lesions of endometriosis, but \nalso dramatically reduced the recruitment of BMDSCs to \nthe lesions and restore the stem cell engraftment of the \nuterine endometrium.\nEndometrial stromal cells express the  chemokine \nCXCL12, while BMDSCs express CXCR4, the receptor of \nCXCL12 [144]. In human and mice models of endometri-\nosis, higher levels of CXCL12 and CXCR4 were detected \nin ectopic lesions and serum than those in healthy con -\ntrols [145]. The fluctuation of CXCL12 concentration \nproduces a chemical gradient that guides the migration of \nstem cells [146]. The chemoattraction of mouse BMDSCs \nto CXCL12 in the conditioned medium (CM) of endo -\nmetriotic  cells is higher than that  in the CM of eutopic \nendometrium [145]. Activation of the CXCL12/CXCR4 \nsignaling axis promotes  the ectopic lesions to outcom -\npete eutopic endometrium to recruit the limited supply \nof circulating BMDSCs. Targeting CXCR4 by using the \nsmall molecule receptor antagonist AMD3100 reduces \nthe recruitment of BMDSCs into the endometriosis and \nthe size of the  endometriosis lesions [147]. Antagonist \ntreatment also reduces the production of pro-inflamma -\ntory cytokines and angiogenesis in the lesions of endo -\nmetriosis [147].\n\nPage 11 of 16\nKong et al. Stem Cell Res Ther          (2021) 12:474 \n \nCirculating endometrial cells (CECs) were identified \nin the peripheral blood of all the acknowledged endo -\nmetriosis stages: minimal, mild, moderate, and severe \n(Fig.  1). The CECs captured during the menstrual cycle \nphases display stem cell-like characteristics [148]. \nCECs are also found in the  patients with pelvic endo -\nmetriosis and spontaneous pneumothorax, with the \nproperties of epithelial, stroma-like, glandular [149], \nor stem cell-like  cells. A reporter found that   DsRed+ \ncells can be found in blood of  DsRed−  mice with endo -\nmetriosis receiving the peritoneal cavity transplanta -\ntion of DsRed+  mice endometrial tissues. Almost all \nof CECs originated from endometriosis rather than \nuterus express CXCR4 and MSCs biomarkers, but not \nhematopoietic stem cell markers, and contribute to \nboth endometriosis and angiogenesis. Cells originated \nfrom endometriosis lesions may migrate and implant in \nlung tissues and display the  abilities of differentiation \ninto adipogenic, osteogenic, and chondrogenic lineages \nin vitro, indicating a retained multipotency.\nOverall, endometrial stem/progenitor cells in men -\nstruation blood (MenSCs) are the most clinically acces -\nsible sources of stem cells with a great potential in  the \nregenerative medicine and tissue engineering. The \nadvantages of MenSCs are that they can be collected \nregularly and noninvasively. MenSCs are also promising \ncandidates in the stem cell therapy for inflammation and \nimmune-related diseases, and may play an immunosup -\npressive role in the regulation of the cell-mediated immu-\nnity and humoral immunity. The  bone marrow-derived \nand endogenous stem/progenitor cells participate in \nthe origin and development of endometriosis. Endog -\nenous stem/progenitor cells with  the altered molecular \nproperties from the shedding endometrium fragments \nmay  reflux into the pelvic cavity via RM, which may be \nconsidered as the main inducer of endometriosis. The \nectopic lesions compete with  the eutopic endometrium \nfor the limited BMDSCs in blood  circulation to induce \nthe establishment of the deep invasive endometriosis. In \naddition, stem-like cells in ectopic lesions may also enter \nthe peripheral blood circulation and cause distant inva -\nsion. The study of the molecular mechanisms of stem/\nprogenitor cells or stem-like cells in endometriosis may \nprovide some promising targets for molecular therapy of \nthe associated reproductive and cancerous diseases.\nAbbreviations\neMSCs: endometrial mesenchymal stem cells; SPs: side population cells; \nMenSCs: menstrual stem cells; BMDSCs: bone marrow mesenchymal stem \ncells; RM: retrograde menstruation; CFUs: colony-forming units; LRCs: label-\nretaining cells; ABCG2: ATP-binding cassette transporter G2; Erα: estrogen \nreceptor alpha; PR: progesterone receptor; SSEA-1: stage-specific embryonic \nantigen-1; MSC: mesenchymal stem cell; CXCL1: C-X-C motif ligand 1; CYR61: \ncysteine-rich angiogenesis inducer 61; NTPDase2: nucleoside triphosphate \ndiphosphohydrolase 2; BMI: body mass index; IVF: in vitro fertilization; SHH: \nSonic hedgehog; POP: pelvic organ prolapse; PCL: poly ε-caprolactone; IUA: \nintrauterine adhesion; ESCs: endometrial stromal cells; POF: premature ovar-\nian failure; DCs: dendritic cells; PBMCs: peripheral blood mononuclear cells; \nSDF‐1: stromal cell‐derived factor‐1; DIE: deep infiltrating endometriosis; \nPF: peritoneal fluid; CTGF: connective tissue growth factor; AMSCs: aden-\nomyosis-derived mesenchymal stem cells; COX-2: Cyclooxygenase-2; SC+: \nCD73+CD90+CD105+ multipotent stem cell; IDO1: indoleamine 2,3-dioxyge-\nnase-1; CECs: Circulating endometrial cells; MET: mesenchymal-to-epithelial \ntransition.\nAcknowledgements\nWe are grateful to the National Natural Science Foundation of China \n(81402153 for CR, and 81572553, 81772789 for GY).\nAuthors’ contributions\nYK performed literature search and wrote the first draft of the manuscripts. SY \nwas involved in the revision of the manuscripts. CR and GY were responsible \nfor discussing and revising the content. All authors read and approved the \nfinal manuscript.\nFunding\nThis study was supported by grants from the National Natural Science Foun-\ndation of China (81402153 for CR, and 81572553, 81772789 for GY).\nAvailability of data and materials\nNot applicable.\nDeclarations\nEthics approval and consent to participate\nNot applicable.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare that this article has no conflict of interest.\nAuthor details\n1 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, \nChina. 2 Department of Oncology, Shanghai Medical College, Fudan University, \nShanghai 200032, China. 3 Center for Reproductive Medicine, Shuguang Hos-\npital Affiliated to Shanghai University of Traditional Chinese Medicine, Shang-\nhai 200120, China. 4 Central Laboratory, The Fifth People’s Hospital of Shanghai \nFudan University, Shanghai 200240, China. \nReceived: 16 May 2021   Accepted: 19 July 2021\nReferences\n 1. 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Stem Cell Res Ther          (2021) 12:474 \n•\n \nfast, convenient online submission\n •\n  \nthorough peer review by experienced researchers in your field\n• \n \nrapid publication on acceptance\n• \n \nsupport for research data, including large and complex data types\n•\n  \ngold Open Access which fosters wider collaboration and increased citations \n \nmaximum visibility for your research: over 100M website views per year •\n  At BMC, research is always in progress.\nLearn more biomedcentral.com/submissions\nReady to submit y our researc hReady to submit y our researc h  ?  Choose BMC and benefit fr om: ?  Choose BMC and benefit fr om: \n 153. Cen PP , Fan LX, Wang J, Chen JJ, Li LJ. Therapeutic potential of men-\nstrual blood stem cells in treating acute liver failure. World J Gastroen-\nterol. 2019. https:// doi. org/ 10. 3748/ wjg. v25. i41. 6190.\n 154. Chen L, Zhang C, Chen L, Wang X, Xiang B, Wu X, et al. Human \nmenstrual blood-derived stem cells ameliorate liver fibrosis in mice by \ntargeting hepatic stellate cells via paracrine mediators. Stem Cells Transl \nMed. 2017. https:// doi. org/ 10. 5966/ sctm. 2015- 0265.\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub-\nlished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}