{"paper_id":"4a6b9e10-504d-4cf5-9c1c-3ddb48607e52","body_text":"Unus pro omnibus, omnes pro uno: A novel, \nevidence-based, unifying theory for the pathogenesis\nof endometriosis\nThis is the Accepted version of the following publication\nLaganà, AS, Vitale, SG, Salmeri, FM, Triolo, O, Ban Frangež, H, Vrtačnik-\nBokal, E, Stojanovska, Lily, Apostolopoulos, Vasso, Granese, R and Sofo, V \n(2017) Unus pro omnibus, omnes pro uno: A novel, evidence-based, unifying \ntheory for the pathogenesis of endometriosis. Medical Hypotheses, 103. 10 - \n20. ISSN 0306-9877  \nThe publisher’s official version can be found at \nhttp://www.sciencedirect.com/science/article/pii/S0306987716305527?via=ihub#\nNote that access to this version may require subscription.\nDownloaded from VU Research Repository  https://vuir.vu.edu.au/33985/ \n\n\nPage 1 of 40 \n \nFormatted for: \nMedical Hypotheses \n \n \nUnus pro omnibus, omnes pro uno: a novel, evidence -based, unifying \ntheory for the pathogenesis of endometriosis. \n \nAntonio Simone Laganàa,*, Salvatore Giovanni Vitale a, Francesca Maria Salmeri b, Onofrio \nTrioloa, Helena Ban Frangežc, Lily Stojanovskad, Vasso Apostolopoulosd, Vincenza Sofob. \n \na Unit of Gynecology and Obstetrics, Department of Human Pathology in Adulthood and \nChildhood ‘‘G. Barresi’’, University of Messina, Messina, Italy. \nb Department of Biomedical Sciences, Dentistry and Morphological and Functional Imaging. \nUniversity of Messina, Via C. Valeria 1, 98125 - Messina, Italy. \nc Department of Reproduction. University Medical Center Ljubljana, -  Slajmerjeva 3, 1000 \nLjubljana. \nd Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, VIC \nAustralia \n \n* Corresponding author at: Unit of Gynecology and Obstetrics, Department of Human \nPathology in Adulthood and Childhood “G. Barresi”, University of Messina, Via C. Valeria 1, \n98125 - Messina, Italy. Email: antlagana@unime.it \n  \n\nPage 2 of 40 \n \nABSTRACT \nThe theory of retrograde menstruation as aetiopathogenesis  of endometriosis formulated by \nJohn A Sampson in 1927, shows clear shortcomings: this  does not explain why retrograde \nmenstruation is a physiological process that affects 90 % of women, while endometriosis \noccurs in only 10 % of cases; it also does not explain the endometriotic foci distant from the \npelvis, nor explains the cases of endometriosis in male patients. The immunological \nalterations of the peritoneal fluid explain s the effects of disease, such as the inhibition of the \nphysiological processes of cytolysis, but  does not explain the cause. There is evidence to \nsupport the hypothesis  that müllerian remnants of the endometrium, and endocervix \nendosalpinx, ectopic, are items from the genital ridge leaked during organogenesis . It  is \nknown that tissues derived from coelomatic epithelial and mesenchymal cells have the \npotential to metaplas tically differentiate into epithelium and stroma . In addition, the \nphenotype of the ectopic endometrial cells is significantl y different from those eutopics . \nThere is no scientific evidence that, during organogenesis, the genes of the H omeobox and \nWingless family play a fundamental role in the differentiation of the ducts of Muller and \ndevelopment of the anatomical structure of the urogenital tract. We present here a hypothesis \nthat deregulation of genes and the Wnt signaling pathway Wnt /β-catenin leads to aberrations \nand deregulation within the mesoderm, thus, may cause aberrant placement of stem cells . In \naddition, immune cells, adhesion molecules, extracellular matrix metalloptroeinases and pro -\ninflammatory cytokines  activate/alter cells, creating the conditions for differentiation, \nadhesion, proliferation and survival of ectopic endometrial cells.  \n \nKeywords: Endometriosis, Embryology, Body Patterning, Embryonic Stem Cells, Proteins \nhomeodomain, Wingless Type Proteins. \n \n\nPage 3 of 40 \n \nBackground \n \n Endometriosis is characterized by the presence, in the anomalous endometrial tissue, \nfunctionally active, with the presence of stroma and glands [1]. Numerous  theories have been \nproposed for the pathogenesis of endometriosis , such as, retrograde menstruation, coelomic \nmetaplasia and m üllerian remnants [2] , a hormonal disease, autoimmune  disease, genetic \ndisorder or due to an environmental stimuli [3]. Amongst the various hypotheses, the one that \nenjoys the greatest consensus is retrograde menstruation . Retrograde menstruation  is when \nendometrial cells and fragments desquamate during menstruation and are transported via the \nfallopian tubes into the peritoneal cavity , instead of flowing out the body , and implant and \nproliferate onto peritoneal surfaces or pelvic orga ns [1]. The prevalence of endometriosis is  \nestimated to be 10  % [4], with a further 11 % of women whose  disease is not clinically \ndiagnosed [5]. Endometriosis predominantly affects the ovaries (up to 88 %), the ligaments of \nthe uterus, fallopian tubes, th e cervical-vaginal area, urinary tract  and the rectum ; the \ninvolvement of the urinary tract is rare ( 1-2 % of all cases ) [6,7], of which 84 % are located \nwithin the bladder [8] ; other organs of involvement include, pancreas, spleen [9], liver, \nintestinal tract, gallbladder [10], wall of the abdom en and the umbilicus [11]; with brain \nendometriosis also being reported [12]. The foci of endometriosis distant from the pelvis can \nbe explained as being derived from buds of the embryonic genital ridge and originate within \nthe müllerian ducts which, during organogenesis, are located at the top. R etrograde \nmenstruation is a physiological phenomenon which occurs in 76- 90 % of women [13], whil st \ndisease occurs in 10 % of cases. The hypothesis of retrograde mens truation as the \npathogenesis of endometriosis does not explain the gap between physiological prevalence \n(76-90 %) and the pathological (10 %). Interestingly, a case of endometriosis in the cul-de-sac \nand uterosacral ligaments was histologically confirmed in a patient undergoing pre -menarche \n\nPage 4 of 40 \n \nat 9 years  of age  [14]. However, this  does not explain the cases of endometriosis in male \nindividuals with normal phenotype (46, XY) , such as: endometrioma in the abdominal wall \n[15]; endometriosis of the bladder [16]; a  case histologically indistinguishable from \nendometrial tissue [17]; cystic endometriosis of the epididymis [18]; paratesticular \nendometriosis [19]; a mass located lateral ly to the spermatic cord, removed surgically, whose \nhistology showed tissue similar to the endometrium, a proliferation of smooth muscle, \nendometrial glands and stroma [20]. Such cases of male patients can only be explained by the \nincomplete differentiation of the müllerian ducts. \n \nHypothesis \n \n The theory of \"retrograde menstruation\" , as a \"cause\" of endometriosis, does not \ncorrelate with the incidence among physiological event s, and prevalence of the disease does \nnot correlate with the endometriotic foci distant from the pelvis  in the reported cases in male \npatients. Since 1927, the year of Sampson's theory, many advances have been made in the \ndirection of  the effects but not the  causes. We hypothesize that, during organogenesis, a \nderegulation of genes and the Wnt signaling pathway Wnt/β -catenin would produce an \naberration and the axial extension of the identity of the anterior -posterior patterning, whilst a \nderegulation of Hox genes and cofactor Pbx1 produce s an aberration in the segmentation of \nthe mesoderm  (Fig. 1, Fig. 2) . T his may  cause aberrant placement of stem cells with \nendometrial phenotype, ectopic, and maintain them in quiscent  niche. In post -pubertal, the \nestrogenic activity activ ate peritoneal macrophages with consequent induction of pro-\ninflammatory cytokines TNF-α and IL-1β which, in turn, activate the binding to DNA through \nthe transcription factors of NFҡB; transcriptional activity, through the inflammatory cytokines \nIL-6 and IL -8, induces the expression of VEGF that activates the vascular endothelial cell , \n\nPage 5 of 40 \n \nwhile MIF induces cell endometrial, mitosis, and the survival is supported by the activation of \nanti-apoptotic gene Bcl-2, from the degradation of the extracel lular matrix by MMPs and the \nentry phone via ICAM and VCAM, creating the conditions for differentiation, adhesion, \nproliferation and survival of ectopic endometrial cells. U nderstanding of the biological \nmechanisms, genetic and epigenetic, which regulate t he differentiation and development of \nthe urogenital tract during the fetal stage, might be a priority for research ing the \naetiopathogenesis of endometriosis and understanding of our hypothesis. \n \nEvaluation of the hypothesis \n \nEmbryogenesis \n The primordial germ cells are derived from the primitive streak ( from epiblast to \ncaudal area); remain ing in the extra -embryonic mesenchyme to complete gastrulation and \nsubsequently migrate along the allantois  endoderm; maintain ing the feature of cell division \nthroughout the development of the embryo and preserving all the characteristics of stem cell s. \nFollowing gastrulation, the embryonic germ cells contribute to the formation of  the epithelial \nand mesenchymal tissues. The epithelial cell s population of the embryo have similar \nmorphological characteristics of differentiated epithelia, whil st mesenchymal cells contribute \nto the basal membrane, forming the lamina and smooth muscle of tubules and differentiation \ninto connective tissue. The space beneath the epithelium and between the mesenchymal cells \nis filled with extracellular matrix molecules and their receptors  [21-23]. During the early \nstages of organogenesis, the mesoderm arises  from the primitive streak and give s rise to the \nepithelial coelomatic. The mü llerian ducts born by invagination  of coelomatic epithelium, \nduring fetal development results in  the female reproductive tract,  which is further \ndifferentiated to form the uterus, oviduct and vaginal canal higher. Animal studies have \n\nPage 6 of 40 \n \ndemonstrated that the coelomic epithelium form s the müllerian ducts [21]. The coelom is \nderived from the same lateral plate mesoderm that, in turn, are derived from the primitive \nstreak [22]. The anatomy of the female urogenital tract arising from the mü llerian ducts is \ncompleted at the time of birth with the exception of the uterus; the histological architecture \nand the tissue specificity reach full development in the post- natal period w ith the full radial \npatterning of 3 basic histological structures: (i) endometrium, (ii) myometrium and (iii) \nperimetrium. This results in the structured development of endometrial glands luminal \nepithelium, the organization and stratification of the endometrial stroma , and, the  \ndifferentiation and growth of the myometrium [23-27]. \n \nHox - Homeobox genes \n In mammals, the H ox genes are well known for their crucial role during \nembryogenesis, and in particular the axial development of the skeleton, the hind brain, and, \nthe limbs. Their involvement in organogenesis has been shown, in particular, during \nurogenital differentiation [28]. The H ox genes control the fate of cell s and the segmental \nembryonic formatting. The  sequential arrangement of the Hox genes on its chromosome \nassociates with the spatial distribution  and protein expression along the antero- posterior axis \nof the embryo [29]. The biological specificity of Hox proteins derive s from cooperation with \nspecific cofactors that contribute to modulate the binding to DNA f or the control of the \nexpression of target genes [30]. The protein cofactors include , pre-B-cell leukemia homeobox \n(PBX) and m yeloid ecotropic viral integration site (MEIS) [31,32]. The sub- cellular \nlocalization of proteins PBX is highly regulated in diffe rent cellular contexts; it has been \nhypothesized that the binding of PBX with MEIS induces translocation to the nucleus where it \nassociates with H ox proteins which regulate target genes; Pbx is necessary to allow the \nformation of heterotrimeric complex DNA binding involving Meis proteins [33, 34]. Pbx has \n\nPage 7 of 40 \n \nbeen shown to act as a direct regulator of expression of the target gene, and this adjustment \ntakes place via interactions that require the cooperation of other members of the family \nhomeobox as Meis and Hox [35]. These have been shown to be involved in malformations of \nthe urogenital tract and its inactivation which leads to complete absence of mü llerian \nstructures [36,37]. This plays a critical role as a regulator of the development and the absence \nof which leads to embryonic lethality and multiple system abnormalities of tissues and organs. \nPbx1 is extensively  expressed in the mesenchymal tissues during differentiation of the \nurogenital organs , and inadequate cell proliferation leads to total absence of the adrenal \nglands, whilst the formation of the gonads shows a rudimentary sexual differentiation. T he \nlack of expression of P bx1 greatly reduces the evolution of the urogenital ridge w hich \ntranslates into reduced differentiation of the mesonephros and kidneys and in the absence of \nthe müllerian ducts [38- 40]. Pbx1 has been proven to be expressed in the ductus Müller but \nabsent in the Wolff ductus during the differentiation of both sexes  [40]. The clusters of Hox \ngenes during development, are subject to transcriptional control by cofactors such as RA \n(Retinoic Acid) [40], FGF (Fibroblast Growth Factor) [41,42] and the genes of the Wnt \nsignaling [43]; this loop of self -induction and/or repression of H ox genes occurs within the \nsame cluster [44 -46], as well as the post -transcriptional regulation [47,48]. During \norganogenesis patterning of female genital tract is regulated by homeobox transcription \nfactors [49]: H oxA9 is expressed in the oviduct, HoxA10 (via BMP -4 Bone Morphogenetic \nProtein, Wnt7a and β3-integrin) and Hoxa-11 (by Emx-2 Empty spiracles homeobox gene and \nIGFB1 Insulin-like Growth Factor Binding protein) are expressed in the uterus [50]. HoxA11 \nand 13 in the cervix and vagina [51] . HoxA genes play a role in regulating temporal and \nspatial expression in the formation and differentiation of the müllerian ducts [52]. \n \nWnt - Wingless genes \n\nPage 8 of 40 \n \n Wnt4 is essential for the formation of the m üllerian ducts. [53] In fact it is  involved in \nnumerous anomalies and female genital morphology in endometrial glandular and stromal \nbreakdown. Wnt7 is involved in the maintenance of HoxA10 and HoxA11 genes whilst Wnt5 \nin the  development of the genital anterior -posterior axis [54,55]. Wnt5a and Wnt7a are \nnecessary for proper glandular genesis and are expressed, respectively, in the stroma of the \nuterine and uterine epithelium [56]. Downstream of Wnt genes, β -catenin [57] is associated \nwith the Foxa2 forkhead family [58]. There are 3 types of signaling pathways: Wnt/β-catenin, \nWnt/JNK (c-Jun N-terminal kinases) and Wnt/Ca2 +. Wnt binds via cell surface receptors, to \ndisable the Axin complex , consequently inhibiting the phosphorylation of β -catenin from the \ncomplex by Axin [59] . β-catenin enters the nucleus in cooperation with factors Lymphoid \nEnhancer Factor / Transcription Factor (LEF / TCP), which by binding to DNA activates gene \ntranscription [60]; the absence of stimulation by Wnt causes the phosphorylation of β -catenin \nfrom t he Axin complex, which is phosphorylated and then targeted for ubiquitination and \ndegradation in the proteasome [61]. It w as shown that an estrogenic compound may  interfere \nwith Wnt expression and/ or β-catenin target genes with a consequent alteration of t he \ndevelopment of the female reproductive tract [62, 63]. The signaling pat hway of canonical \nWnt genes and Wnt/β-catenin, are associated in the control of different types of stem cells and \ncan act as a factor niche to keep the embryonic stem cells ( EmSC) in a state of self -renewal \n[64-66]. \n \nMüllerian derivatives and remains \n \nCongenital anomalies of the urogenital tract : During organogenesis differentiation between \nmale and female urogenital system s takes place. B etween the eighth week and the fourth \nmonth the male urogenital tract initially develops from embryological structures which are \n\nPage 9 of 40 \n \nresolved with female -specific activation of the male genome. A  missing or incomplete \ndifferentiation results in disorders of se x development, chromosonic abnormalities (such as, \nTurner syndrome and Klinefelter's syndrome ), M üllerian agenesis , Rokitansky syndrome, \ndevelopmental disorders or testicular androgen insensitivity syndrome (or Morris syndrome). \n \nRemains and Müllerian deri vatives: Sexual differentiation is, in some congenital diseases, \nabsent or incomplete, thus, it is plausible to assume that they can co -exist in the development \nof müllerian remnants in asymptomatic individuals. Many mü llerian events suggest that \ntissues derived from the epithelium and mesenchymal cells coelomate (Secondary Müllerian \nSystem) and have the potential to differentiate directly into epithelial cells  and stromal cell; \npossibly a metaplastic hypothesis for the pathogenesis o f endometriosis [67]. The peritone al \ncavity is a matrix for the benign and malignant proliferation  of the  secondary müllerian \nsystem where it can develop endometriosis, endosalpingiosis and endocervicosis [68]. Under \nimmunologically  “normal” conditions, the peritoneal cavity has the ability to prevent the \nevolution towards endometriosis, however, failure to remove fragments of endometrial tissue  \nfrom the peritoneal cavity induces local inflammation, activation of  macrophages which \nsecrete cytokines and che mokines some of which c an cause metaplasia of the peritoneum or \nthe development of m üllerian residues [69]. P elvic masses  and congenital malformations \nassociated with mü llerian have been reported at the time of diagnos is of endometriosis, \ncomprising of smooth muscle tissue within the uterine cavity, but , pose diagnostic uncertainty \nbetween smooth muscle metaplasia or m üllerian remnant of the system [70,71]. It is \nspeculated that in males  with normal male phenotype who develop endometriosi s, have \nprostatic utricle as a remnant of the uterus embryo [15]. \n \n\nPage 10 of 40 \n \nMüllerianosis: There are considerable difficulties in the differential diagnosis between \nendometriosis and müllerianosi s. The main difference is that , in endometriosis , ectopic \nendometrial tissue cyclically executes outside of the uterine cavity invading  the outer surface \nof other organs,  whilst, in müllerianosis , there is tissue present in the endosalpinx, \nendometrium and endocervix, whose most common form is found in peritoneal pockets. Batt \nRE et al . have laid down 3 conditions for the diagnosis of müllerianosi s: 1) no e vidence of \npelvic endometriosis , 2) no direct communication with endocer vix, endometrium or \nendosalpinx, and, 3) n o surgery to the reproductive organs. G iven the presence of the 3 \ncomponents, endometrium, endocervix  and endosalpinx, support s the hypothesis that  \nmüllerian remnants generated from the genital ridge leaked during organogenesis [72]. In the \npresence of defects in the genesis of the genital tract , differentiation and cell migration can be \nincomplete or aberrant. Any cells with aberrant gene expression in the migratory path through \nthe rear pelvic floor can be implanted abnormally. Pluripotent cells can cause endometrial \nmetaplasia or endometriosis in post pubert y. Studies on the coelomic cavity and m üllerian \nduct, both in the fetal period and in adulthood, suggest s that the epithelium coelomatic , \nfabrics and related adult epithelia m üllerian derivatives, have  common embryological origin \n[73]. In fact, in peritoneal biopsies of the cul -de-sac in female infants who had died from \nsudden infant death syndrome (SIDS), had a small whitish plaque, (~ 200μm in diameter ), \nwhich showed glandular epithelium with well -defined structures surrounding the stroma [74]. \nIn addition, in fetal autopsies, the incidence of ectopic endometrium in 5  different locations \nidentified in the recto -vaginal septum close to the cable Douglas near the mesenchymal \ntissues of the wall r ear of the uterus in the cannula at the level of the muscular wall of the \nuterus. Thus, one  possible reason of endometriosis , is th e dislodgement of primitive \nendometrial tissue outside the uterine cavity during organogenesis [75,76]. \n \n\nPage 11 of 40 \n \nMüllerian cyst remai ns in cavitated:  Accessory and Cavitated Uterine Masses  (ACUM) is a \nsporadic condition seen in young females, which has significant clinical manifestations , in \nparticular severe dysmenorrhea and recurring pelvic pain. The diagnosis presents considerable \ndifficulties, so as to be placed in the differential with uterine malformations such as \nbicornuate uterus and segmental atresia, cystic areas or degenerate with adenomyosis, \nleiomyomas and degenerated primary dysmenorrhea essential [77]. ACUM is diagnosed more \nfrequently in women aged less than 30 years and in nulliparous women (although sporadic \ncases are reported of women over the age of 30 years and multiparous) [78]. T he term Asian \njuvenile cystic adenomyoma was used for the diagnosis of cases with clinical and \nhistopathological features similar to ACUM [77,78]. The ACUM are generally located at the \nlevel of insertion of the round ligament and is likely associated  to a dysfunction of the female \ngubernaculum. The aetiopatogenic hypothesis classifies t his as a new variety of M üllerian \nanomalies [79] which may  be caused by duplication or from ectopia and the persistence of \nmüllerian duct, whose fabric is to be placed in an ectopic position at the level of the attack of \nthe round ligament and could be related to a dysfunction of the gubernaculum [79,80]. \n \nStems cells \n \nHuman embryonic stem cells (hEmSC): hEmSC are pluripotent cells derived from various \nstages of embryonic development and represent the only form of stem cells able to proliferate \nindefinitely and to differentiate into all types of tissue -specific cells. The hEmSC are \ngenerally derived from the in ner cell mass of the blastocyst to the stage of pre -implantation \nembryo. hEmSC cell lines are well characterised in regards to genomic integrity and \npluripotency and express high levels of telomerase activity. Telomerase (or terminal \ntransferase) is a ribo nucleoprotein that adds telomere repeats to the chromosom al ends and \n\nPage 12 of 40 \n \nthus, maintains telomere length, and is crucial in the replication life span [81]. The expression \nof telomerase correlates  with immortality of cell lines, and , the reintroduction of telom erase \nactivity in some cell lines extends the ir replication activity  [82]. The hEmSC, being \npluripotent possess the characteristics to differentiate into the 3 germ layers which  form all \ntissues of the embry o - (i) ectoderm, (ii) mesoderm, and, (iii) endoderm. They have specific \nmorphological and molecular  properties, they  possess specific properties that epigenetic \nchromatin structure is open- ended to allow the entry of transcription factors , and, regulates \ngene expression [83] . In the promoter regions of pluripotency genes OCT4 ( octamer-binding \ntranscription factor 4) and Nanog (homeobox transcription factor - regulator involved-in inner \ncell mass and embryonic stem) it denotes a marked reductio n in methylation of CpG \nnucleoids (cytosine-phosphate-guanine nucleotide) [84]. These properties are necessary to \ncharacterize the epigenetic hEmSC in a pluripotent state and distinctive , undifferentiated stem \ncell hEmSCs derived from cell lines that form both the endoderm and mesoderm. For \nendoderm differentiation Activin-A ligand activates transforming growth factor beta (TGF-β) \n[85], bone morphogenetic protein (BMP),, fibroblast growth factor (FGF) and the Wnt family \nof genes, which are typical modulators of the mesoderm [86]. \n \nEndometrial stem progenitor cells (hESP): Adult stem cells are found in an undifferentiated \nform and have the characteristics  of self -renewal through cell division dependent \nmicroenvironment or niche. They are important for the regeneration and recovery of organs \nand tissues by ensuri ng regular  functional maintenance. The human endometrium is \ncomposed of epithelium, glands and stroma , which during the menstrual cycle are subject to \nprofound changes in tissue structure and function ; the recovery is ensured by the presence of \nthe endometrial progenitor stem cells that are assumed to reside with in the basal layer [87]. \nSeveral lines of endometrial stem cells and progenitor cells have been characterized that show \n\nPage 13 of 40 \n \nlarge plastic capacity with high availability differentiation [23 ,88-90]. Endometrial stem \nprogenitor cells ( hESP), differ for patterns of expression of cell surface markers for clonal \nefficiency, to the microenvironment of the niche, and endometrial localization [91,92]. In fact, \nin a study of clonal analysis of endometrial epithel ial cells and stromal cells derived \ntemporally on the phases of the cycle, non- clonogenicity ranged from proliferative to \nsecretory phase endometrium and between cycling and inactive, for both epithelial stromal \ncells, showing that the inactive endometrium  contains clonogenic epithelial  cells and stromal \ncells [93]. Some studies have suggested the origin of hESP  from bone marrow as a source of \nexogenous [94,95]. Endometriotic lesions are detectable  in a functionally pathological stage , \nand it is extremely rare to detect microscopically the phases of attachment and proliferation of \nendometrial tissue in the peritoneum, which is an area with  high incidence of injury [96]. The \norigin of the cells within ovarian endometriomas are monoclonal, whilst peritoneal lesions are \npolyclonal [97- 99]. The cells that give rise to ectopic endometrial implantation must \nnecessarily possess the ability to migrate, the angiogenic potential for proliferation and \npluripotency to form  glandular tissue and the hESP cells demonstrate all the requirements \n[87]. Inded a hypothesis was formulated in that repeated physical and biochemical injuries \ncaused by inflammatory cytokines and reactive oxygen species are able to  trigger the cell \ncycle of quiescent stem cells that may be involved in  the development of benign and \nmalignant endometrial aberrations as endometrial hyperplasia, endometriosis and endometrial \ncancer [100]. \n \nStem/progenitor cells residing in adult uterus (SP) : The mucosal lining of the uterus \nremarkably regenerates during the reproductive years of a woman and this plasticity of the \nendometrium has been attributed to a small population of stem/progenitor cells, known as side \npopulation (SP). In fact, SP cells reside in the adult basal endometrium and is assumed to be \n\nPage 14 of 40 \n \nthe remains of the original epithelial cells , the Müller Duct (MD) [101]. The SP ha s all the \nfeatures that define poorly differentiated stem cells that are able to divide asymmetrically and \nquiescently [102]. The stem  cells, to maintain the pool of progenitors from which arise the \ndifferentiated cells , are programmed to have a long lifespan; in order to activate the \nmechanisms of protection from senescence and stress of DNA, including  the activation of \nseveral signalin g pathways such  as Shh (Sonic hedgehog), Wnt/ β-catenin, Bmi -1 (B \nlymphoma Mo-MLV insertion region 1 homolog)  the expression of Bcl -2 anti-apoptotic and \nthe increased capacity of the repair of DNA damage [103 -108]. The SP are characterized by \nhigh expressi on of stem cell markers and low levels of differentiation markers, high \nexpression of genes that are part of some of the signal transduc tion pathways such as the \nWnt/β-catenin [109] and of genes involved in regulation of cell cycle [110]. Compared with \nother stem cells, the SP are small, even smaller than those fr om non SP [111,112] and ha ve \nendoplasmic reticulum s with ribosomes which  indicates a lack of metabolic activity [113]. \nThe SP are generated in the embryo, and , persist in specific niches, where the y can remain \nmitotically quiescent for long periods of time maintaining the capacity for self -\nrenewal,symmetric division and the ability to rapidly produce progenitors for asymmetric \ndivision [114]. The  microenvironment surrounding stem cells  contribute to a number of \nfunctions, such as, physical  anchorage for stem cells as well as  cell-cell communiation  \nmediated by direct contact and/or indirect extracellular factors . In as such, Wnt ligands are \nsecreted by both stem cells and niche cells, BMPs are released from the cells and niche Shh \nepithelial cells, which interact between neighboring cells through the Notch signal \ntransmembrane. This microenvironment also provides signaling through the cellular recepto r \nintegrin [115] and its co- expression with CD133 (prominin-1) in basal cell lysophospholipids \n[116] as well as through signaling m ediated by metalloproteinases [ 117]. The identification \nand characterization of SP cells will further aid in our  understanding of normal human \n\nPage 15 of 40 \n \nendometrial regenerative cyclic processes and the pathophysiology of human endometrial \nproliferative diseases, including endometriosis, endometrial hyperplasia and cancer [118,119]. \n \nMesenchymal stem cells from bone marrow :  Mesenchymal stem cells (MSC) are multipotent \nstromal cells  which have the ability to differentiate into a variety of  specialized cell  types. \nCells derived from bone marrow, known as bone marrow stromal cells ( BMSC) have been \nused in a number of  studies. It  has been hypothesized that endometrial stem cells may \noriginate from mesenchymal stem cells of the bone marrow. Stem cells derived from bone \nmarrow are able to differentiate into hematopoietic cells and contribute to the maintenance of \ndifferent tissues; cells  of the bone marrow donor -derived have been identified in the uterine \nhuman endometrium [120]. In fact,  CD45\n+ hematopoietic progenitor cells colonize within the \nepithelial layer of the uterus , and. during pregnancy over 80 % of epithelial cells are derived \nfrom these cells [121]. In addition, in intravenous transplantation of bone marrow stem cells , \nthe epithelial (0.02÷48 %) and stromal (0.03÷ 52 %) compartments arose from the donor \n[122]. Furthermore, endometrial regenerative cells ( ERC) compared to  BMSC cells are \nsimilar but not identical in regards to , their morphology, the production of cytokines, the \ninhibition of mixed leukocyte reactions, the expression micro RNA (miRNA) and global gene \nexpression. However, ERC  are affected by over -expression of gene immune path, whil st \nBMSC are affected by over -expression of gene path stem/ tumor; ERC also  show greater \ninhibition of proliferation [123]. In other studies , ERC have been isolated from menstrual \nblood, which are distinct  from the MSC as they do not express the BMSC marker STRO -1 \n(cell surface protein expressed by bone marrow stromal cells and erythroid precursors) \n[124,125]. It is not known whether the transplanted cells retain all the characteristics of stem \ncells, and whether they behave like those for the physiological endometrial cyclicity ; the \n\nPage 16 of 40 \n \nmechanism of physiological recruitment of stem cells from the bone marrow into the uterus  is \nnot clear. \n \nStem cell niche: In adults, stem cells reside in a  physiologically limit ed and specialized  \nmicroenvironment, called a niche, which supports stem cells but changes  in nature and \nposition according to the type of fabric [126,127]. The niche is a collection  of cells in a \nspecific anatomic location which together aid in the  maintainance (number, proliferation and \nfate) of stem cells  via secretion of  extrinsic factors [128- 130]. The morphological \nconfiguration of the dimensional niche can define the number of stem cells within a tissue. \nThe asymmetric cell division of stem ce lls allows the self-renewal and differentiation of the \ncell produced by providing a simple method for tissue homeostasis; divisions are dependent \non cell polarity within the cell and are influenced by cell niche. Most of the  asymmetric \ndivisions determine a stem cell, and a cell differentiation in  which the daughter cell is placed \noutside of the niche. The self-preservation given to the daughter cell allows it to keep features \nsuch as stem cell proliferation and maintenance of undifferentiated state [131]. The ability of \ncells to divide asymmetrically to produce 2 different cell types provides the cellular diversity \nproper to each multicellular organism . T he asymmetric localization of cell- cell junctions \nand/or the intrinsic cells is  crucial to the fate and position within the niche and is  used to \nspecify cell polarity and asymmetric divisions that determine the polarity of the cell fate; the \nasymmetric divisions are directly regulated by genes that control the process of division and \ndetermine different fates for the two daughter cells [132]. The molecular signaling Shh, BMP, \nFGF and Notch are implicated in the control of stem -cell self-renewal and regulation of the \nfate of the lineage in different systems [128 -130]. Reactive oxygen species (ROS), a natural \nbyproduct of metabolism of oxygen plays an important role homeostastis. However, during \nstress, the levels of ROS increases  as well as the number of free radicals , such as, superoxide \n\nPage 17 of 40 \n \nradical anion, hydrogen peroxide and hydroxyl radical, which cause DNA damage. The levels \nof intracellular ROS plays a crucial role in the control of self-renewal capacity of stem cells in \nthe long term as they may involve signaling of JNK (c -Jun N -terminal kinases) and FoxO \n(trigger for apoptosis through up -regulation of gene s) and sub -regulation of Polycomb \n(protein Able to remodel chromatin and Hox gene silencing) [133]. \n \nMarking of endometrial cells \n \n The phenotype of SP cells is similar to that of adult stem cells  and is detected with \nfluoro-cytometric analysis using Hoech st 33342 dye (H33342 Bisbenzimide \ntrihydrochloride), through the expression of ABC transporters, Brand gene expression Bcrp1 \n(ABCG2) that characterizes the phenotype of SP [134]. It was shown that the upper fraction is \ncomposed mainly of epithelial cells w hile the lower  fraction contains both the epithelial and \nstromal cells; popula tions expressing epithelial CD9 + and E -cadherin while t he portion \nstromal express CD13+ demonstrated the presence of endometrial progenitor s tem cells [135]. \nCunha GR et al . obtained the differentiation of hEmSC into  mesodermal cells; the line of \nhESCs with genetic characterization of  Forkhead protein-  green fluorescent protein that \nregulates cell regionalization, placed under the control of MIXL1 (Mix paired- like), \nhomeobox protein that acts as a transcription factor for the regulation of cell fate, \ndemonstrating that FRT ( female reproductive tract) arises from embryon ic bodies \ncharacterized by MIXL + ; have also observed the expression of Hoxa -10 and Pax2 during \ndevelopment of hESCs epithelial FRT [136]. The use of cell surface markers was used for the \nisolation of endodermal progeny of hESCs. SOX17, FOXA1, FOXA2, HNF1β , HNF4 α, \nKITL, SHH and HB9 were used as markers expressed  in cells CD49e\n+ CD141+ CD238+ ; \n\nPage 18 of 40 \n \nOCT4, NANOG, and ME OX1 SOX7 were used to mark the pluripotency expressed in cells \nCD49e-/low CD141-CD238 [137]. \n \nConsequences and discussion \n \n John A Sampson, publi cation in 1921, reported observations i n 14 patients with cysts  \nin that the co ating was similar to that  in hematomas in the uterine lining with both having \ncontent similar to the phase of the menstrual cycle [138]; whilst  the study of 1927, of 293 \ncases in a period of 5 years, presented at the \"American Gynecological Society\", adopted the \ntheory of retrograde menstruation as the aetiopathology of endometriosis [139]. The problem-\nrelated histogenesis of endometriosis does not accept or reject the theory of Sampson JA, but \nprovided a direction for research . The basic question is why retrograde menstruation is a \nphysiological process that affects 90  % of women and endometriosis occurs only in 10 % of \ncases? How  do we   explain the endometriotic foci away from the pelvi s? How are we to \nexplain the cases of endometriosis in male patients? The theory of endometriosis, s uch as \nendometrial cells from functional retrograde menstruation, since its formulation,  has shown \ngaps. Endometriotic lesions are detectable  at a pathological stage, and it is extremely rare to \nbe able to detect  microscopically the phases of attachment an d proliferation of endometrial  \ntissue in the peritoneum [96]. Numerous studies  have attempted with rigorous methods, to \ngive answers as to why the eutopic plant develops resistance to the elimination by the immune \nsystem, demonstrating the altered function  of macrophages and natural killer cells: that in the \nearly stages of the disease there is a prevalence of pro -inflammatory cytokines (Th1 profile), \nwhilst in late stages this changes to a Th2 profile [140]; that alterations of immune peritoneal \nexert an i mmunosuppressive effect on the activity of phagocytic and cytotoxic immune cells \ninfiltrating the endometrial tissue, promoting immunoescaping, survival and growth of \n\nPage 19 of 40 \n \nendometrial cells [141 -144]. Therapeutic strategies can be improved through the use of non -\nsteroidal anti-inflammatory drugs [145], combination oral contraceptives [146,147], progestin \n[148], selective progesterone receptor modulators [149], GnRH agonists [150],  and, \naromatase inhibitors [151,152]. Ultimately we are able to demonstrate the pa thophysiological \nmechanisms that allow grafting of endometriotic cells and the inhibition of the physiological \nprocesses of cytolysis, but the origin of these cells  remains unknown. In 1987, Redwine and \ncolleagues examined peritoneal biopsies of the cul -de-sac of female infants who died from \nSIDS, reported a case with well -defined structure glandular epithelium surrounded by stroma \n[74]. Fujii S in 1991, suggested that the tissues derived from epithelial and mesenchymal cells \ncoelomatic accompaniment, called \" Secondary M üllerian S ystem\" have the potential to \ndifferentiate into epithelium and stroma, metaplastic, and that this potential is a basic concept \nin the pathogenesis endometriosis [153]. Batt RE et al. in 2007, concluded that the presence of \nendometrium and endocervix endosalpinx, which supports the hypothesis of m üllerian \nremnants generated from the genital ridge leaked during organogenesis [72]. Master PG et al . \nin 2012, investigat ed fetal autops ies and noted the presence of ectopic endometrium, \nassuming that one possible cause of endometriosis was  the dislocation of primitive \nendometrial tissue outside the uterin e cavity during organogenesis [76] . Bouquet de Jolinière \nJ et al . in 2012, demonstrated that  reproductive organs derived from autopsies of female \nfetuses (via immunohistochemical analysis) were identified ectopic, and, concluded that \nendometriosis may develop from misplaced endometrial glands and/ or residues of embryonic \ncells [154] . hESCs, ident ified in the basal layer of the endometrium, appear to possess the \nphenotype that contains all the characteristics of self-renewal and differentiation that occurs in \nthe context of the niche in which they exist, or in those in which they migrate. hESCs pos sess \na potential immunomodulatory triggered by hypoxic stimuli, proteolytic, inflammatory, in \norder to induce angiogenesis, intercellular communication, migration, and capacity to \n\nPage 20 of 40 \n \ndifferentiate into cells of the same lineage (Fig. 1, Fig. 2) [155]. It was also hypothesized that \nthe hESCs may have originated from mesenchymal stem cells of the bone marrow; studies on \nthe expression of miRNA and global gene expression, showed that they could be considered \nsimilar but not identical, and that the endometrial reg enerative cells were affected by over -\nexpression of gene immune path, whil st bone marrow stromal were characterized by over -\nexpression of gene path stem/tumor . I n addition, the regenerative cells showed a greater \ninhibition of endometrial proliferation (Fi g. 1, Fig. 2)  [123]. It ha s not been demonstrated \nwhether the transplanted cells retain the characteristics of stem cell, if they behave as \nphysiological ones for endometrial cyclicity, but, above all, mechanism of physiolog ical \nrecruitment in the uterus  has not been shown. Moreover, Delbandi and colleagues evaluated \ncharacteristics of the cells and ectopic endometrial stromal eutopics in women with respect to \ncontrols eutopics of healthy women and noted that ectopic endometrial stem c ells differ from \neutopics, with a greater capacity for proliferation, greater adhesion to the extracellular matrix, \nincreased invasiveness and higher levels of pro-inflammatory cytokines, IL-6 and IL-8 [156]. \nThe H ox genes control cell fate and segmental embryonic patterning along the antero -\nposterior axis of the embryo [29] in cooperation with specific cofactors and in particular, \nthrough the Notch signaling pathway, determini ng positional identity and the  activities of the \ngenetic cascade of somitogenesis [157]. The morphogenetic processes axial extension, the \nsegmentation of the mesoderm and anterior -posterior patterning are regulated by the \ninteraction between Hox genes and Wnt: while Wnt, RA and FGF regulate the a xial extension \nand the identity of the anterior-posterior patterning, Hox, Cdx (paraHox genes) and Notch are \ninvolved in the segmentation of the mesoderm [158]. PBX and MEIS contribute to modulate \nthe binding to DNA for the control of the expression of target genes and Pbx1, in particular, is \nwidely expressed in mesenchymal tissues during the differentiation of the urogenital organs \n[38-40]. Wnt7 has been shown to be involved in the maintenance of the genes HoxA10 and \n\nPage 21 of 40 \n \n11, and Wnt5 in the development of the genital anter ior-posterior axis [54,55]. Three \nmembers of the family Wnt (Wnt4, Wnt5a and Wnt7a) have proved to be fundamental for \nuterine development: inactivation of Wnt4 causes sex reversal; Wnt7 causes inactivation of \nstratified epithelium, stroma and the absence of thin gland; inactivation of Wnt5 inhibits the \ndevelopment of the corr ect anatomy of the uterus [119] . In the presence of defects of \nadjustment, on the part of the genes responsible, during organogenesis differentiation of the \nurogenital tract and/or the migration of the cells may be aberrant or incomplete , and any cells \nwith aberrant gene expression during the migratory path may implant themselves  in the \nanomalous [73]. Tissues derived from the epithelium and mesenchymal cells accompanying \ncoelomatic have the potential to differentiate directly into e pithelium and stroma and [67] . \nHoang Ngo c and colleagues  studied embryonic finds, and came to the conclusion that the \nmyometrium is derived from the primitive mesenchyme, and the endometrium is derived from \nmesoltelio coelomatic [159]. The signaling pathwa y of canonical Wnt, the Wnt/ β-catenin, is \nimplicated in the control of various types of stem cells and can act as a factor to maintain the \nniche hESP in a state of self -renewal [64-67]. Targeted r esearch on the coelomic cavity and \nthe müllerian duct epithelium suggest that coelomatic and associated tissues, epithelia adults \nand müllerian derivatives have a common embryological origin, and that pluripotent cells can \ncause endometrial metaplasia or endometriosis in post pubertal stage [73]. The estrogenic \nactivity active peritoneal macrophages with consequent induction of pro- inflammatory \ncytokines TNF -α and IL -1β which, in their turn, activate the binding to DNA through the \ntranscription factors of N FҡB; through inflammatory cytokines IL -6 and IL -8, induces the \nexpression of VEGF that activates the vasculature endothelial cell, while MIF induces cell \nmitosis endometrial, and survival is supported by the activation of anti -apoptotic gene Bcl-2, \nfrom the degradation of the extracellular matrix by MMPs and the entry phone via ICAM and \nVCAM (Fig. 1, Fig. 2) [160]. \n\nPage 22 of 40 \n \n \nConclusion \n \n It is n cessary to understand the biological and genetic mechanisms that regulate the \ndifferentiation of the urogenital tract during the phase of embryonic organogenesis, in the \nperiod of completion of development of the urogenital tract, and in post -puberty. It is \nimportant to study the signaling pathways of Hox genes and cofactors Pbx and Meis genes \nand Wnt signaling pathway Wnt/ β-catenin. It is necessary to deepen the knowledge on \nembryonic stem cells, niches and the functioning of the regulatory mecha nisms of the state s \nof quiscenze , self -renewal, proliferation and functional specialization. T he research on \nimmuno-phenotype, proliferation capacity, invasiveness and adhesion to the extracellular \nmatrix of the endometrial stem cells (hESCs) eutopic and ectopic should be implemented. The \nstudy of the causal mechanisms of endometriosis involves in- depth knowledge of \nembryology, genetics, biology, histology, immunology and specific expertise in medical \nresearch with multidisciplinary team s which together, will lead to underst anding our \nhypothesis and etiology of endometriosis.. \n \n  \n\nPage 23 of 40 \n \nReferences \n [1]  Vinatier D, Dufour P , Leroy JL . The mechanisms of endometriosis. 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Fertil Steril. 2012; 98(3):529-55. \n  \n\nPage 38 of 40 \n \n \nFigure legends \n \nFig. 1.  \nThe epithelial cell populations of the embryo have similar morphological characteristics of \ndifferentiated epithelia, whilst  mesenchymal cells contribute to the basal membrane, forming \nthe lamina and smooth muscle of tubules and differentiation into connective tissue. During the \nearly stages of organogenesis, the mesoderm emerges from the primitive streak and give s rise \nto coelomic epithelium. The müllerian ducts (Wnt4 is essential) arise from invagination of the \ncoelomic epithelium during fetal development resulting in  the female reproductive tract , \nwhich further differentiates to form the oviduct, uterus and vaginal canal higher. The clusters \nof Hox genes during development, undergo the transcriptional control by cofactors such as \nretinoic acid RA [40], FGF and Wnt signaling; during organogenesis patterning of the female \ngenital tract is regulated by homeobox transcription fact ors: HOXA9 is expressed in the \noviduct , Hoxa-10 (by BMP-4, Wnt7a and β3-integrin) and Hoxa-11 (via Emx-2 and IGFB1 ) \nare expressed in the uterus, Hoxa -11 and 13 cervix and vagina. The Wingless genes are \nimplicated in endometrial glandular and stromal morp hology: Wnt7 has been shown to be  \ninvolved in the maintenance of the genes HoxA10 and HoxA11, while in the development \nWnt5 genital anteroposterior axis: Wnt5a and Wnt7a are  both necessary for proper glandular \ngenesis , and Wnt5a, in particular, is a critical element in the endometrial glandular formation \nwhich entails the role of epithelial-mesenchymal interaction required for uterine development. \nAs a downstream effector of the Wnt genes , it has been demonstrated that the involvement of \nβ -catenin and FoxA2, in the absence of stimulation by Wnt, causes the phosphorylation of β -\ncatenin which is phosphorylated and then targeted for ubiquitination and degradation in the \nproteasome. In t he signaling pathway of the canonical Wnt genes, Wnt/β -catenin, is \n\nPage 39 of 40 \n \nimplicated in the control of various types of stem cells and can act as a niche factor to keep \nthe EmSC (Embryonic Stem Cell) in a state of self-renewal. \n \nFig. 2.  \nFetal development: the morphogenetic processes of the axial extension, of the segmentation \nof mesoderm and anterior -posterior patterning are regulated by the interaction between Hox \ngenes and Wnt signaling network in a gene that involves Wnt/β -catenin, in the extension and \naxial the identity of the anterior -posterior patterning, while the cofactors of H ox gene, Pbx1 \nand Meis1 are involved in the segmentation of the mesoderm; Wnt7 has been shown to be \ninvolved in the maintenance of the genes HoxA10 and HoxA11, while in the development \nWnt5 genital anterior -posterior axis; Wnt4 is involved in the sexual wa y, Wnt7 in the \nepithelium, stroma and glands, Wnt5 in the anatomy of the uterus. Postnatal development: \nmolecular signaling of Shh, BMP, FGF and Notch are implicated in the control of stem cell \nself-renewal and in regulating the fate of the lineage; the es trogenic activity active peritoneal \nmacrophages with consequent induction of pro- inflammatory cytokines TNF -α and IL -1β \nwhich, in turn, activate the binding to the DNA through the transcription factors of NFҡB; the \ntranscriptional activity through inflammatory cytokines IL-6 and IL-8, induces the expression \nof VEGF that activates the vasculature endothelial cell, while MIF induces cell mitosis \nendometrial and survival is supported by the activation of the anti-apoptotic gene Bcl-2 , from \nthe degradation of the extracellular matrix by MMPs and the entry phone via ICAM and \nVCAM. Post -pubertal development: the eutopic plant develops resistance to elimination by \nthe immune system, demonstrating altered function of macrophages and natural killer \nperitoneal cells; in the early stages of the disease there is a prevalence of proinflammatory \ncytokines (Th1 profile), while in the late stages cytokines predominantly fibrogenic and \nangiogenic action (Th2 profile) prevails. \n  \n\nPage 40 of 40","source_license":"CC0","license_restricted":false}