Endometriosis: Pathogenesis and Treatment 2014 Ed.

4. Role of Stem Cells in the Pathogenesis of Endometriosis

Tetsuo Maruyama 

(1)

Department of Obstetrics and Gynecology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

Tetsuo Maruyama

Email: tetsuo@a5.keio.jp

Abstract

Endometriosis can be defined as a benign estrogen-dependent disorder in which endometrium-like tissues reside outside of the uterine cavity. Studies now indicate that multiple genetic and epigenetic changes (reminiscent of neoplastic processes) are involved in the pathophysiology of endometriosis. Given the molecular similarities between endometriosis and cancer, it is reasonable to apply the “cancer stem cell model” concept to the pathogenesis of endometriosis. In this article, I review and discuss “the stem cell model for endometriosis” in which endometriosis originates from endometrial stem/progenitor cells within eutopic and ectopic sites.

Keywords

CancerEndometriosisEndometriumEpithelial–mesenchymal transitionStem cells

4.1 Introduction

Endometriosis can be defined as the presence of endometrium-like tissues outside of the uterine cavity and is frequently associated with dysmenorrhea and dyspareunia [12]. Endometriosis is commonly found associated with the ovaries, pelvic peritoneum, uterine ligaments, and the rectovaginal septum. More rarely, endometriotic sites can include pelvic lymph nodes, the cervix, the intestine, the bladder, and the vagina, and fallopian tubes. More distant sites can include the lungs, skin, kidneys, brain, and spinal column [13]. Microscopically, glandular components surrounded by endometrium-like stroma are observed [4]. Smooth muscle cell components (perhaps via smooth muscle metaplasia) can be associated with endometriotic lesions, particularly deeply infiltrating endometriosis [5]. The lesions are often accompanied by angiogenesis and innervation [67]. A number of causes of endometriosis have been proposed. These include retrograde menstruation, iatrogenic direct implantation, coelomic metaplasia, lymphatic and vascular metastasis, embryonic rest, and mesenchymal cell differentiation (induction). Importantly, none of the theories can completely account for all types of endometriotic lesions. Thus, the pathophysiology might be complex, involving several mechanisms.

Current analyses of endometriosis indicate that multiple genetic, epigenetic, environmental, immunological, and/or endocrine processes are involved [8]. Thus far, research has failed to identify one or more specific susceptibility genes. Endometriosis is in fact a benign disorder. However, the underlying molecular mechanisms appear similar to those of cancer [8]. Indeed, evidence indicates that both endometriosis and tumors are monoclonal in origin [912]. Furthermore, both endometriotic cells and cancer cells are invasive [13]. To support this interpretation, we point out the enhanced susceptibility to ovarian clear-cell and endometrioid cancers in patients with endometriosis [8]. Given this background, it is reasonable to examine whether the pathophysiology of endometriosis can be explained, at least in part, by the cancer stem cell (CSC) hypothesis. CSCs have the abilities to self-renew and to give rise to differentiated tumor cells. They are also responsible for the overall organization of tumors [1415]. Here, I review and discuss an emerging concept and hypothesis, i.e., the “endometriosis stem cell theory” in which endometriosis arises from stem cell(s) originating from bone marrows or eutopic and/or ectopic endometrial stem/progenitor cells [1618].

4.2 Cancer Stem Cell Theory

Before discussing the stem cell theory for the pathogenesis of endometriosis, I will briefly introduce the current paradigm regarding tissue stem cells (adult stem cells), CSCs, and their roles in cancer formation and metastasis.

4.2.1 Tissue Stem Cells

Tissue-specific stem cells (also termed somatic stem cells or adult stem cells) are found in a quiescent, undifferentiated state throughout the body [19]. They self-renew through symmetric and/or asymmetric cell divisions. Growth is modulated by physiological signals originating from the microenvironment or “stem cell niche.” Asymmetric divisions generate lineage-committed cells that differentiate and thereby maintain the tissue of origin. The tissue-specific stem cells and the microenvironmental niche work together to keep a balance between the need for cell replacement and the necessity of retaining a pool of primitive cells. In this fashion, the structural and functional requirements of organs and tissues can be met [19]. The hierarchy of tissue stem cells is illustrated in Fig. 4.1.

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Fig. 4.1

Hierarchy of adult stem cell differentiation. Within its microenvironmental niche, adult stem cells generally remain quiescent. Under the proper conditions, the cells can be stimulated to undergo asymmetric divisions to renew themselves and produce daughter/progenitor cells. The latter cell further divides to produce transit-amplifying (TA) cells. The TA cells promptly proliferate and differentiate into a variety of mature, functional cells

4.2.2 CSCs and Primary Tumor Formation

The “classical” or stochastic model (clonal evolution model) posits that any normal (stem) cell, upon acquiring genetic and/or epigenetic modification(s) giving it selective growth advantage, gives rise to a neoplastic clone of homogenous neoplastic cells [1415]. Upon the acquisition of additional genetic and/or epigenetic change(s), it expands as a tumor. In this model, all cells within a tumor have equal tumorigenic potentials [1415].

More recently, a hierarchical or CSC model has been developed. This model is based upon the hypothesis that tumors consist of a heterogeneous population of cells, only a small proportion of which are CSCs, also termed tumor-initiating cells [141520]. As depicted in Fig. 4.2, a small, self-renewing population of CSCs is responsible for tumor initiation and growth maintenance. Thus, CSCs have been operationally defined by their ability to generate tumors, and tumor-initiating cells are thought to reflect the operational definition of CSCs [20]. The model states that CSCs could originate from tissue stem cells or even differentiated cells that acquired stem cell-like properties (including self-renewal) as a result of genetic and/or epigenetic modifications [1415]. In the CSC model, completely mature cells can fully dedifferentiate to become CSCs. In addition to genetic/epigenetic modifications, the tumor microenvironment (the CSC niche) is required for the maintenance of stem cell properties. It likely includes many components, such as stromal cells, blood vessels, extracellular matrix (ECM), growth factors, and cytokines in a hypoxic environment. Exposure of non-CSCs to niche factors might result in their acquisition of stem cell properties [1415].

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Fig. 4.2

Cancer stem cell (CSC) model for tumor formation and metastasis. Within tumors, a small population of self-renewing CSCs is responsible for initiating tumor growth and maintaining its presence. CSCs might be derived from tissue stem cells or more differentiated cells that gained stem cell properties (including self-renewal) upon genetic and/or epigenetic modifications. Even completely differentiated cells can develop into CSCs through dedifferentiation. The tumor microenvironment (niche) maintains stem cell properties. CSCs that migrate away from the primary site are capable of invasion, intravasation, systemic dissemination, and extravasation. This behavior might be due to the EMT. Upon reaching distant tissues, the cells can reverse the epithelial state by undergoing the MET. This promotes growth and the initiation of angiogenesis. Alternatively, EMT programs per se might lead to the generation of CSCs

4.2.3 Cell Metastasis and Tumor Formation

The metastatic cascade includes tumor cell migration away from the site of the primary tumor. It is now believed by many researchers that this process requires the epithelial–mesenchymal transition (EMT) [2021]. The EMT is a biological process in which epithelial cells lose their cell polarity and cell–cell adhesive properties. In exchange, the cells gain migratory and invasive properties and undergo multiple biochemical changes, thereby exhibiting a mesenchymal cell phenotype [22]. The EMT is observed in many processes, including mesoderm and neural tube formation as well as wound healing, tissue regeneration, and organ fibrosis [22]. Our own data indicated that endometrial epithelial cells undergo EMT during embryo implantation [23].

CSCs are likely involved in the formation of metastases [2021], as they exhibit invasion, intravasation, systemic dissemination, and extravasation. It is believed that such processes are enhanced by the EMT conversion [2021]. Subsequently, CSCs that metastasize to distant tissues show colonization and reversion to an epithelial state through reversal of the EMT, i.e., the mesenchymal–epithelial transition (MET), giving rise to metastatic lesions accompanied by angiogenesis [20]. Alternatively, the activation of EMT programs has been implicated in the generation of CSCs [2021]. Furthermore, in addition to CSCs, non-CSC progeny cancer cells might become CSCs through dedifferentiation at the metastatic sites and thereby generate metastatic cancer lesions [2021] (Fig. 4.3).

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Fig. 4.3

Three proposed stem cell models for the pathogenesis of endometriosis extrapolated from the CSC model. Model I. Endometrial stem cells (EmSCs) are released from eutopic endometrium most likely upon menstruation. EmSCs are transported to ectopic sites via retrograde menstruation, lymphatic and vascular dissemination, direct migration, and invasion or some combination. The EmSCs remain at the ectopic site through attachment, implantation, and/or extravasation followed by invasion. EmSCs initiate self-renewal and/or asymmetric division to generate progenitor cells, transit-amplifying cells, and more differentiated endometrial cells. Because EmSCs and their progeny require a blood supply, angiogenesis is initiated, supporting the expanding colony/endometriotic lesions. Model II. EmSCs undergo genetic and/or epigenetic modifications at the eutopic or ectopic sites and thereafter behave as endometriosis-initiating cells (EmoICs), giving rise to endometriotic lesions as shown in model I. Model III. EmSCs undergo more extensive genetic and/or epigenetic modifications than in model II. Alternatively, terminally differentiated endometrial cells undergo multiple and profound genetic and epigenetic changes and thereby dedifferentiate into EmSC-like cells (not depicted in the schema). In either case, the EmoICs are capable of generating a variety of endometrial cell components in a fashion similar to model I

For reference, Fig. 4.2 provides a representative CSC model. However, recent studies have revealed complexities, such as plasticity of stem cell properties and clonal diversity of CSCs in certain tumor types requiring revision of the original CSC model. As a result, more complex models such as the dynamic stemness model and the combinatory CSC and stochastic models have recently emerged [15].

4.3 Endometriosis Stem Cell Theory

Based on the principles of the cancer stem cell model illustrated in Fig. 4.2, I here propose a stem cell model for the pathogenesis of endometriosis as depicted in Fig. 4.3. This model incorporates the implantation theory, which is the most widely accepted version among the many theories in this field. Note, however, that the coelomic metaplasia theory and embryonic rest theory are also compatible with the second part of this model in which some types of mesothelial cells and/or embryonic cell rests of müllerian origin behave as endometriosis-initiating cells (endometriotic stem cells) and thereby give rise to endometriotic lesions at ectopic site(s) [18].

4.3.1 A Stem Cell Model for the Development of Endometriosis

A stem cell model for endometriosis development is presented below in three variations, i.e., models I, II, and III (Fig. 4.3). In model I, endometrial stem cells are released from eutopic endometrium upon menstruation. The cells could move to ectopic sites via many routes, including lymphatic and vascular dissemination, direct migration and invasion, retrograde menstruation, or some combination thereof. The endometrial stem cells settle ectopically in new sites by attachment, implantation, extravasation, and, finally, invasion. Upon reaching the ectopic site, the endometrial stem cells might undergo self-renewal or divide asymmetrically. In this way, they can self-renew as well as produce progenitor cells, transit-amplifying cells, and more differentiated endometrial cells (Fig. 4.3, model I). This process is based on the behavior of general tissue stem cells (Fig. 4.1). Endometrial stem cells and their proliferating daughter cells require a blood supply to flourish. Therefore, they induce angiogenesis, permitting them to undergo clonal growth. In this fashion, endometriotic lesions are formed.

In model II, endometrial stem cells are subject to genetic (or epigenetic) modifications within the eutopic or ectopic sites. The modifications permit them to act as “endometriosis stem cells,” also termed “endometriosis-initiating cells,” producing endometriotic lesions. Notably, in this model, they retain the proliferative and differentiative potential of endometrial stem cell-like cells, allowing them to generate components of the endometrium, including glandular, stromal, endothelial, and smooth muscle cells. Like CSCs and tumor-initiating cells as mentioned previously [20], I here operationally define “endometriosis stem cells” by their stem cell-like properties and ability to generate endometriosis with high efficiency, and “endometriosis-initiating cells,” therefore, reflect the operational definition of “endometriosis stem cells.” Thus, “endometriosis-initiating cells” is used herein as a synonym of “endometriosis stem cells.”

In model III, endometrial stem cells undergo additional genetic and/or epigenetic modifications and thereafter behave as “endometriosis-initiating cells,” producing endometriotic lesions. Alternatively, terminally differentiated endometrial cells could undergo multiple profound genetic and epigenetic modifications resulting in dedifferentiation into endometrial stem cell-like cells capable of generating a variety of endometrial cell populations, including glandular, stromal, endothelial, and smooth muscle cells. However, it seems likely that such profound modifications would destroy the cells’ capability for multipotential differentiation. Hence, this pathway might result in carcinogenesis. Thus, model III might explain endometriosis-originated cancers such as clear-cell carcinoma and endometrioid cancer. In fact, Pten and K-ras double mutations in the mouse give rise to endometrioid adenocarcinoma of the ovary, whereas single mutation of K-ras results in pelvic endometriosis [24].

It is important to note that the processes displayed in models I–III are likely modulated by the microenvironments in which the cells associate themselves. Microenvironmental influences could include menstrual efflux, peritoneal fluids, inflammation, and the ECM of the peritoneum, all of which might regulate molecular/cellular events. Thus, invasion, intravasation, extravasation, colonization, angiogenesis, EMT, and MET could all be affected by the microenvironment. It should be emphasized that EMT and MET could play critical roles in the passage of endometrial stem cells from eutopic sites to ectopic sites and the resultant generation of endometriotic lesions.

4.3.2 Evidence Supporting the Endometriosis Stem Cell Model

The stem cell theory for the pathogenesis of endometriosis is not merely a hypothesis. Rather, a number of studies have emerged that support this model [1816]. The supportive evidence is summarized below.

4.3.2.1 EMT and MET Appear to Be Involved in the Pathogenesis of Endometriosis

The metastatic cascades initiated by CSCs and non-CSC cancer cells likely involve the EMT and the MET [2021]. In fact, generation of CSCs probably involves the activation of EMT programs [2021]. Thus, it is intriguing that EMT- and MET-like processes are also involved in the pathogenesis of endometriosis [25]. For example, menstrual effluent can induce the EMT in mesothelial cells [26]. Consider also “side population” (SP) cells, a population with a high efflux ability of Hoechst 33342 dye defined by flow cytometric techniques [27]. SP cells constitute an undifferentiated population that resides in a number of tissues [28]. SP cells have been isolated from an endometrial cancer cell line, and they represent likely candidates for endometrial CSCs. These cells possess a high capacity to develop into mesenchymal cell lineages, a reflection of EMT activity [29]. These data are consistent with the endometriosis stem cell model. In other words, menstruation might induce EMT pathways in endometrial stem cells and their progeny. In turn, this might induce the cells to migrate away from the eutopic endometrium. Once implanted in an ectopic microenvironment, invasion and establishment of endometriotic lesions could occur through MET at the ectopic site.

4.3.2.2 Expression of Stem Cell Markers in Endometriotic Lesions

In models II and III, Fig. 4.3, primitive endometriosis-initiating cells are thought to express several stem cell markers. Thus, clonal expansion generates endometriotic lesions and the endometriosis-initiating cells retain their original stem cell markers. Experiments have shown that cells present in or adjacent to endometriotic lesions express several stem cell markers including OCT4/POU5F1 and ABCG2 [3033]. OCT4/POU5F1 is expressed by embryonic stem cells, germ cells, and some types of adult stem cells. This protein plays a crucial role in maintaining stem cell pluripotency [34]. Another stem cell marker is adenosine triphosphate-binding cassette transporter G2 (ABCG2). ABCG2 is highly expressed in a variety of stem cells. It is responsible for removing exogenously added fluorescent dye, Hoechst 33342, and produces the SP phenotype characteristic of stem cells [35]. Thus, the expression of these stem cell markers in endometriotic lesions supports the presence of stem cells and provides indirect evidence for the stem cell model.

4.3.2.3 Tumor Clonality

Most neoplasms are monoclonal in origin. Thus, it is particularly intriguing that endometriotic lesions can also be clonal in nature. The clonality of an endometriotic lesion provides clues to its developmental history. For example, several studies have demonstrated that ovarian endometriomas are in fact monoclonal in origin [911]. These molecular findings support the single-cell derivation of endometriomas. However, the developmental history of endometriotic lesions can be more complex. For example, whereas peritoneal endometriotic lesions are polyclonal [1236], individual glands of endometriotic lesions are monoclonal [12]. Thus, either single or multiple precursors might give rise to a single peritoneal endometriotic lesion, while the glands arise individually from single stem/progenitor cells [12].

4.3.2.4 Endometriotic Lesions Contain Self-Renewing Mesenchymal Stem Cells

The endometriosis stem cell model predicts that endometriotic lesions should contain a stem cell-like cell population. Chan et al. reported that ovarian endometriomas contain a subset of cells displaying a number of somatic stem cell properties. They include colony-forming activity, self-renewal capacity, and multipotency [37].

4.3.3 The Origin of Stem Cells

Several theories have been proposed to explain both the origin and pathogenesis of endometriosis. These hypotheses include retrograde menstruation (implantation), coelomic metaplasia, and the embryo rest theories [218163840]. Retrograde menstruation (implantation) is the most widely accepted because it is a reasonable explanation for various types of endometriosis, including peritoneal endometriosis [3840] and even prepubertal endometriosis when neonatal bleeding is taken into account as a possible cause [4142]. In the implantation theory, endometriosis stem cells originate from stem cells that are present in eutopic endometrium and reach ectopic sites via many possible routes as discussed above.

Sasson and Taylor [16] and others proposed that the pathogenesis of endometriosis could be due to endometriosis stem cells that originate from the bone marrow of humans [4344], data supported by work in mice [4546]. These theories are plausible because a variety of stem/progenitor cells reside in the bone marrow. In this regard, the presence of mesenchymal stem cells is of particular interest. In support of this theory, a murine model of endometriosis was used to demonstrate that bone marrow-derived cells participate in the genesis of epithelial and stromal cells when endometrium was ectopically transplanted into the peritoneum [45].

Theories that propose different stem cell origins do not necessarily contradict one another. It is quite likely that endometrial SP cells include endometrial stem cells [4751]. Our laboratory showed that endometrial SP cells possess phenotypic properties that are similar to endothelial progenitor cell (EPC)-like cells [49]. Given that EPCs originate from bone marrow [5253], it is entirely possible that endometrial SP cells have a similar origin. The fact that bone marrow-derived cells are incorporated into human endometrium at a low level [4344] suggests that resident endometrial stem/progenitor cells such as endometrial SP cells are more likely responsible for the cyclic renewal and regeneration of endometrium and also possibly for the establishment of endometriosis than circulating bone marrow-derived cells [54].

4.3.4 Endometrial Stem Cells and Their Relevance to the Pathogenesis of Endometriosis

The best current theory for the pathogenesis of endometriosis posits that stem/progenitor cells in the eutopic endometrium reach ectopic sites through retrograde menstruation or systemic dissemination. At that point, they give rise to endometriotic lesions. Integral to this theory is the presence of EmSCs. Below, the identity and function of EmSCs are discussed.

4.3.4.1 Endometrial Stem Cells

Endometrial stem/progenitor cells and related cells have been isolated and characterized by a number of laboratories [181755]. Some of the precursors show “plasticity,” i.e., the capacity to differentiate into a variety of endometrial tissue types. For example, endometrial SP cells can differentiate into endothelial, glandular, smooth muscle, and stromal cells, both in vitro and in vivo [4751]. Endometrial SP cells have been observed in the functional layer of the human endometrium [49]. Hence, they might contribute to renewal of the endometrium [19]. Intriguingly, when endometrial SP cells are transplanted under the mouse kidney capsule, they migrate into the kidney parenchyma and initiate the formation of blood vessels [49]. Endometrial SP cells can be found in the vascular walls of endometrial small vessels in functional and basal layers, and they have functional properties like EPCs [49]. Endometrial SP cells might initially trigger neovascularization followed by propagation and differentiation into various cellular components of the human endometrium [49].

In addition to endometrial SP cells, endometrial mesenchymal stem cells and endometrial epithelial progenitor cells have been identified and isolated. This was achieved through the use of cell surface markers such as CD146, CD140b/PDGFR-b, EPCAM, and W5C5 [5659]. These cell populations are capable of self-renewal and multilineage differentiation, at least in in vitro experiments, except for W5C5-positve cells whose stem cell-like properties are verified in vivo as well as in vitro [59].

Laboratories isolating endometrial SP cells are not in complete agreement with regard to the cells’ properties [4750]. While the endometrial SP cells share some properties, they appear different in regard to their expression of surface markers, clonal efficiency, culture requirements, and location within the normal endometrium. Thus, it is not clear whether there are multiple types of stem cells in the human endometrium or whether these differences are the result of subtle variations in laboratory techniques. In any event, it is an open question whether the endometrium contains populations of precursor cells differing in phenotype and function. If this is indeed the case, it is important to determine their hierarchical relationship.

To better define the nature of endometrial stem cells, our laboratory established a novel in vivo endometrial stem cell assay [51]. This approach has a number of advantages, the most important of which is that we could follow multipotential differentiation through use of cell tracking in combination with in vivo model of human endometrial regeneration [5160]. We found that the efficiency with which endometrial SP cells reconstituted the endometrium increased when unfractionated endometrial cells were included as support cells. These data clearly showed the importance of the microenvironment in supporting primitive undifferentiated cells [51]. When SP and non-SP cells were labeled with a fluorescent marker by lentiviral labeling, we found that endometrial SP cells had a greater capacity to differentiate into vascular, glandular, and stromal structures in vivo compared with non-SP endometrial cells [51]. These experiments verified that endometrial precursors possess a range of differentiation potentials. This newly developed in vivo endometrial stem cell assay [51] should prove useful for the identification and analysis of human endometrial stem/progenitor cells.

4.3.4.2 Properties of Endometriosis-Initiating Cells

Based upon the pathogenesis of endometriosis, we can readily predict that endometriosis-initiating cells should possess three sets of properties. In the first case, recall that the functional layer sheds during menstruation and is partially refluxed into the peritoneal cavity through the fallopian tubes. The retrograde menstruation (implantation) theory requires large numbers of endometriosis-initiating cells in the functional layer. In agreement, our data have shown that endometrial SP cells are present in both the basalis and functional layers [49]. However, it has been postulated that stem cells present solely within the basal layer which are not shed during menstruation will then give rise to the new functional layer [6162]. There is evidence that fragments of the shed endometrial basalis are found more frequently in the menstrual blood of women with endometriosis than in that of healthy control subjects [63]. Importantly, the expression of stem cell-related markers such as SSEA-1 by endometriotic cells and basal layer cells is similar [64]. The data of the two studies suggest that endometriosis may originate from the basal layer, which, however, does not exclude a possibility that endometrial stem cells such as endometrial SP cells present in the functional layer may also contribute to the cyclic renewal and regeneration of eutopic endometrium and also the establishment of endometriosis.

Second, attachment, migration, and angiogenesis are essential for the implantation and survival of endometriosis-initiating cells at ectopic site(s). These cells, therefore, should have migratory potential and angiogenic capability. Third, to give rise to endometriotic lesion(s) containing glandular structures, endometriosis-initiating cells should demonstrate multi-differentiation potentials to produce a variety of endometrial cell components.

In summary, several groups have shown that endometrial SP cells satisfy most of the predicted properties of endometriosis-initiating cells. That is, endometrial SP cells are present in both the functional and basal layers and have migratory, angiogenic, and stem cell-like properties [4950]. These findings strengthen the stem cell theory of endometriosis and support the retrograde menstruation theory.

4.3.5 The Strength and Weakness of the Stem Cell Model

The stem cell theory can account for the weakness of the implantation theory. It can also address the unique characteristics and behavior of endometriosis.

The retrograde menstruation theory has a number of weaknesses. Specifically, it has been extremely difficult to detect the initial pathological steps, i.e., the attachment of endometrial tissue to the peritoneum and its secondary proliferation and invasion [6567]. A modified version of the stem cell theory explains this shortcoming. This theory posits that endometriosis arises from EmSCs and/or progenitor cells in the implanted endometrial fragments. In other words, EmSCs and/or progenitor cells are both necessary and sufficient for the establishment of endometriosis and can be initiated by a single or very few cells. In this scenario, EmSCs and/or progenitor cells (and not endometrial tissues) implant and give rise to endometriotic lesions. As such, it would be almost impossible to detect the initial attachment and proliferation events of these cells. Thus, endometriotic lesions would only become microscopically detectable after completion of initial events. Note that non-stem/progenitor cells in the endometrium (the bulk of endometrial cells) will not give rise to “persistent” endometriosis even when a large numbers are present ectopically.

We emphasize that endometrial SP cells, the most likely candidate for endometrial stem cells, constitute only ~2 % of the endometrial cell population [49]. Consequently, the chances are low that endometrial stem/progenitor cells will find an ectopic supportive microenvironment and initiate an endometriotic lesion. This might explain the apparent discrepancy between the incidence of endometriosis and the frequent occurrence of retrograde menstruation.

The stem cell theory of endometriosis is weakened by the fact that the characteristics of endometrial and endometriosis stem cells are not universally accepted. Without such consensus, the theory necessarily remains an attractive hypothesis.

4.4 Conclusions

The stem cell theory for the pathogenesis of endometriosis seems to account for many aspects of the pathophysiology of this disease. The theory provides testable hypotheses and suggests new approaches to the development of novel diagnostic tests and treatments. The theory, however, largely depends on determining unequivocally the existence, identity, and function of EmSCs. Such evidence is growing. However, a consensus has not yet been established. Once EmSC populations are defined, significant progress in understanding the pathophysiology of the disease and new clinical approaches can be anticipated.

Acknowledgements

I thank Hirotaka Masuda, Masanori Ono, Kaoru Miyazaki, Takashi Kajitani, Hiroshi Uchida, and the other members of my research group for their generous assistance and discussion and Hideyuki Okano and Yumi Matsuzaki for their collaboration with the endometrial and endometriotic stem cell project. We acknowledge the secretarial assistance of Rika Shibata. This work was partly supported by Grant-in-Aid from the Japan Society for the Promotion of Science (to T.M and Y.Y.), Grant-in-Aid from Keio University Sakaguchi-Memorial Medical Science Fund (to T.M.), and Grant-in-Aid from the Japan Medical Association (to T.M.).

References

1.

Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–99.PubMedCrossRef

2.

Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–79.PubMedCrossRef

3.

Jubanyik KJ, Comite F. Extrapelvic endometriosis. Obstet Gynecol Clin North Am. 1997;24(2):411–40.PubMedCrossRef

4.

Robboy SJ, Anderson MC, Russell P. Endometriosis. In: Robboy SJ, Anderson MC, Russell P, editors. Pathology of the female reproductive tract. London: Churchill Livingstone; 2002. p. 445–73.

5.

Anaf V, Simon P, Fayt I, Noel J. Smooth muscles are frequent components of endometriotic lesions. Hum Reprod. 2000;15(4):767–71.PubMedCrossRef

6.

Taylor RN, Yu J, Torres PB, Schickedanz AC, Park JK, Mueller MD, Sidell N. Mechanistic and therapeutic implications of angiogenesis in endometriosis. Reprod Sci. 2009;16(2):140–6.PubMedCentralPubMedCrossRef

7.

Medina MG, Lebovic DI. Endometriosis-associated nerve fibers and pain. Acta Obstet Gynecol Scand. 2009;88(9):968–75.PubMedCrossRef

8.

Varma R, Rollason T, Gupta JK, Maher ER. Endometriosis and the neoplastic process. Reproduction. 2004;127(3):293–304. doi:10.​1530/​rep.​1.​00020.PubMedCrossRef

9.

Jimbo H, Hitomi Y, Yoshikawa H, Yano T, Momoeda M, Sakamoto A, Tsutsumi O, Taketani Y, Esumi H. Evidence for monoclonal expansion of epithelial cells in ovarian endometrial cysts. Am J Pathol. 1997;150(4):1173–8.PubMedCentralPubMed

10.

Tamura M, Fukaya T, Murakami T, Uehara S, Yajima A. Analysis of clonality in human endometriotic cysts based on evaluation of X chromosome inactivation in archival formalin-fixed, paraffin-embedded tissue. Lab Invest. 1998;78(2):213–8.PubMed

11.

Wu Y, Basir Z, Kajdacsy-Balla A, Strawn E, Macias V, Montgomery K, Guo SW. Resolution of clonal origins for endometriotic lesions using laser capture microdissection and the human androgen receptor (HUMARA) assay. Fertil Steril. 2003;79 Suppl 1:710–7.PubMedCrossRef

12.

Nabeshima H, Murakami T, Yoshinaga K, Sato K, Terada Y, Okamura K. Analysis of the clonality of ectopic glands in peritoneal endometriosis using laser microdissection. Fertil Steril. 2003;80(5):1144–50.PubMedCrossRef

13.

Gaetje R, Kotzian S, Herrmann G, Baumann R, Starzinski-Powitz A. Invasiveness of endometriotic cells in vitro. Lancet. 1995;346(8988):1463–4.PubMedCrossRef

14.

Podberezin M, Wen J, Chang CC. Cancer stem cells: a review of potential clinical applications. Arch Pathol Lab Med. 2013;137(8):1111–6. doi:10.​5858/​arpa.​2012-0494-RA.PubMedCrossRef

15.

Sugihara E, Saya H. Complexity of cancer stem cells. Int J Cancer. 2013;132(6):1249–59. doi:10.​1002/​ijc.​27961.PubMedCrossRef

16.

Sasson IE, Taylor HS. Stem cells and the pathogenesis of endometriosis. Ann N Y Acad Sci. 2008;1127:106–15.PubMedCentralPubMedCrossRef

17.

Gargett CE, Masuda H. Adult stem cells in the endometrium. Mol Hum Reprod. 2010;16(11):818–34.PubMedCrossRef

18.

Maruyama T, Yoshimura Y. Stem cell theory for the pathogenesis of endometriosis. Front Biosci. 2012;E4:2754–63.CrossRef

19.

Maruyama T, Masuda H, Ono M, Kajitani T, Yoshimura Y. Human uterine stem/progenitor cells: their possible role in uterine physiology and pathology. Reproduction. 2010;140(1):11–22.PubMedCrossRef

20.

Scheel C, Weinberg RA. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin Cancer Biol. 2012;22(5–6):396–403. doi:10.​1016/​j.​semcancer.​2012.​04.​001.PubMedCrossRef

21.

Shiozawa Y, Nie B, Pienta KJ, Morgan TM, Taichman RS. Cancer stem cells and their role in metastasis. Pharmacol Ther. 2013;138(2):285–93. doi:10.​1016/​j.​pharmthera.​2013.​01.​014.PubMedCentralPubMedCrossRef

22.

Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8. doi:10.​1172/​JCI39104.PubMedCentralPubMedCrossRef

23.

Uchida H, Maruyama T, Nishikawa-Uchida S, Oda H, Miyazaki K, Yamasaki A, Yoshimura Y. Studies using an in vitro model show evidence of involvement of epithelial-mesenchymal transition of human endometrial epithelial cells in human embryo implantation. J Biol Chem. 2012;287(7):4441–50. doi:10.​1074/​jbc.​M111.​286138.PubMedCentralPubMedCrossRef

24.

Dinulescu DM, Ince TA, Quade BJ, Shafer SA, Crowley D, Jacks T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med. 2005;11(1):63–70.PubMedCrossRef

25.

Matsuzaki S, Darcha C. Epithelial to mesenchymal transition-like and mesenchymal to epithelial transition-like processes might be involved in the pathogenesis of pelvic endometriosis. Hum Reprod. 2012;27(3):712–21. doi:10.​1093/​humrep/​der442.PubMedCrossRef

26.

Demir AY, Demol H, Puype M, de Goeij AF, Dunselman GA, Herrler A, Evers JL, Vandekerckhove J, Groothuis PG. Proteome analysis of human mesothelial cells during epithelial to mesenchymal transitions induced by shed menstrual effluent. Proteomics. 2004;4(9):2608–23. doi:10.​1002/​pmic.​200300827.PubMedCrossRef

27.

Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med. 1996;183(4):1797–806.PubMedCrossRef

28.

Challen GA, Little MH. A side order of stem cells: the SP phenotype. Stem Cells. 2006;24(1):3–12.PubMedCrossRef

29.

Kato K, Takao T, Kuboyama A, Tanaka Y, Ohgami T, Yamaguchi S, Adachi S, Yoneda T, Ueoka Y, Kato K, Hayashi S, Asanoma K, Wake N. Endometrial cancer side-population cells show prominent migration and have a potential to differentiate into the mesenchymal cell lineage. Am J Pathol. 2010;176(1):381–92.PubMedCentralPubMedCrossRef

30.

Forte A, Schettino MT, Finicelli M, Cipollaro M, Colacurci N, Cobellis L, Galderisi U. Expression pattern of stemness-related genes in human endometrial and endometriotic tissues. Mol Med. 2009;15(11–12):392–401.PubMedCentralPubMed

31.

Chang JH, Au HK, Lee WC, Chi CC, Ling TY, Wang LM, Kao SH, Huang YH, Tzeng CR. Expression of the pluripotent transcription factor OCT4 promotes cell migration in endometriosis. Fertil Steril. 2013;99(5):1332–9.e5.PubMedCrossRef

32.

Matsuzaki S, Darcha C. Adenosine triphosphate-binding cassette transporter G2 expression in endometriosis and in endometrium from patients with and without endometriosis. Fertil Steril. 2012;98(6):1512–20.e3.PubMedCrossRef

33.

Silveira CG, Abrao MS, Dias Jr JA, Coudry RA, Soares FA, Drigo SA, Domingues MA, Rogatto SR. Common chromosomal imbalances and stemness-related protein expression markers in endometriotic lesions from different anatomical sites: the potential role of stem cells. Hum Reprod. 2012;27(11):3187–97. doi:10.​1093/​humrep/​des282.PubMedCrossRef

34.

Sterneckert J, Hoing S, Scholer HR. Concise review: Oct4 and more: the reprogramming expressway. Stem Cells. 2012;30(1):15–21. doi:10.​1002/​stem.​765.PubMedCrossRef

35.

Krishnamurthy P, Schuetz JD. Role of ABCG2/BCRP in biology and medicine. Annu Rev Pharmacol Toxicol. 2006;46:381–410. doi:10.​1146/​annurev.​pharmtox.​46.​120604.​141238.PubMedCrossRef

36.

Mayr D, Amann G, Siefert C, Diebold J, Anderegg B. Does endometriosis really have premalignant potential? A clonal analysis of laser-microdissected tissue. FASEB J. 2003;17(6):693–5.PubMed

37.

Chan RW, Ng EH, Yeung WS. Identification of cells with colony-forming activity, self-renewal capacity, and multipotency in ovarian endometriosis. Am J Pathol. 2011;178(6):2832–44. doi:10.​1016/​j.​ajpath.​2011.​02.​025.PubMedCentralPubMedCrossRef

38.

Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril. 1997;68(4):585–96.PubMedCrossRef

39.

Seli E, Berkkanoglu M, Arici A. Pathogenesis of endometriosis. Obstet Gynecol Clin North Am. 2003;30(1):41–61.PubMedCrossRef

40.

Nap AW, Groothuis PG, Demir AY, Evers JL, Dunselman GA. Pathogenesis of endometriosis. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):233–44.PubMedCrossRef

41.

Brosens I, Benagiano G. Is neonatal uterine bleeding involved in the pathogenesis of endometriosis as a source of stem cells? Fertil Steril. 2013. doi:10.​1016/​j.​fertnstert.​2013.​04.​046.PubMed

42.

Brosens I, Puttemans P, Benagiano G. Endometriosis: a life cycle approach? Am J Obstet Gynecol. 2013. doi:10.​1016/​j.​ajog.​2013.​03.​009.PubMed

43.

Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2004;292(1):81–5.PubMedCrossRef

44.

Ikoma T, Kyo S, Maida Y, Ozaki S, Takakura M, Nakao S, Inoue M. Bone marrow-derived cells from male donors can compose endometrial glands in female transplant recipients. Am J Obstet Gynecol. 2009;201(e601):8.

45.

Du H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007;25(8):2082–6.PubMedCrossRef

46.

Bratincsak A, Brownstein MJ, Cassiani-Ingoni R, Pastorino S, Szalayova I, Toth ZE, Key S, Nemeth K, Pickel J, Mezey E. CD45-positive blood cells give rise to uterine epithelial cells in mice. Stem Cells. 2007;25(11):2820–6.PubMedCrossRef

47.

Kato K, Yoshimoto M, Kato K, Adachi S, Yamayoshi A, Arima T, Asanoma K, Kyo S, Nakahata T, Wake N. Characterization of side-population cells in human normal endometrium. Hum Reprod. 2007;22(5):1214–23.PubMedCrossRef

48.

Tsuji S, Yoshimoto M, Takahashi K, Noda Y, Nakahata T, Heike T. Side population cells contribute to the genesis of human endometrium. Fertil Steril. 2008;90(4 Suppl):1528–37.PubMedCrossRef

49.

Masuda H, Matsuzaki Y, Hiratsu E, Ono M, Nagashima T, Kajitani T, Arase T, Oda H, Uchida H, Asada H, Ito M, Yoshimura Y, Maruyama T, Okano H. Stem cell-like properties of the endometrial side population: implication in endometrial regeneration. PLoS One. 2010;5(4):e10387.PubMedCentralPubMedCrossRef

50.

Cervello I, Gil-Sanchis C, Mas A, Delgado-Rosas F, Martinez-Conejero JA, Galan A, Martinez-Romero A, Martinez S, Navarro I, Ferro J, Horcajadas JA, Esteban FJ, O’Connor JE, Pellicer A, Simon C. Human endometrial side population cells exhibit genotypic, phenotypic and functional features of somatic stem cells. PLoS One. 2010;5(6):e10964.PubMedCentralPubMedCrossRef

51.

Miyazaki K, Maruyama T, Masuda H, Yamasaki A, Uchida S, Oda H, Uchida H, Yoshimura Y. Stem cell-like differentiation potentials of endometrial side population cells as revealed by a newly developed in vivo endometrial stem cell assay. PLoS One. 2012;7(12):e50749.PubMedCentralPubMedCrossRef

52.

Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004;95(4):343–53.PubMedCrossRef

53.

Timmermans F, Plum J, Yoder MC, Ingram DA, Vandekerckhove B, Case J. Endothelial progenitor cells: identity defined? J Cell Mol Med. 2009;13(1):87–102.PubMedCrossRef

54.

Deane JA, Gualano RC, Gargett CE. Regenerating endometrium from stem/progenitor cells: is it abnormal in endometriosis, Asherman’s syndrome and infertility? Curr Opin Obstet Gynecol. 2013;25(3):193–200. doi:10.​1097/​GCO.​0b013e32836024e7​.PubMedCrossRef

55.

Cervello I, Mas A, Gil-Sanchis C, Simon C. Somatic stem cells in the human endometrium. Semin Reprod Med. 2013;31(1):69–76. doi:10.​1055/​s-0032-1331800.PubMedCrossRef

56.

Schwab KE, Gargett CE. Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium. Hum Reprod. 2007;22(11):2903–11.PubMedCrossRef

57.

Schwab KE, Hutchinson P, Gargett CE. Identification of surface markers for prospective isolation of human endometrial stromal colony-forming cells. Hum Reprod. 2008;23(4):934–43.PubMedCrossRef

58.

Gargett CE, Schwab KE, Zillwood RM, Nguyen HP, Wu D. Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol Reprod. 2009;80(6):1136–45.PubMedCentralPubMedCrossRef

59.

Masuda H, Anwar SS, Buhring HJ, Rao JR, Gargett CE. A novel marker of human endometrial mesenchymal stem-like cells. Cell Transplant. 2012;21(10):2201–14. doi:10.​3727/​096368911X637362​.PubMedCrossRef

60.

Masuda H, Maruyama T, Hiratsu E, Yamane J, Iwanami A, Nagashima T, Ono M, Miyoshi H, Okano HJ, Ito M, Tamaoki N, Nomura T, Okano H, Matsuzaki Y, Yoshimura Y. Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γc nullimmunodeficient mice. Proc Natl Acad Sci U S A. 2007;104(6):1925–30.PubMedCentralPubMedCrossRef

61.

Padykula HA. Regeneration in the primate uterus: the role of stem cells. Ann N Y Acad Sci. 1991;622:47–56.PubMedCrossRef

62.

Padykula HA, Coles LG, Okulicz WC, Rapaport SI, McCracken JA, King Jr NW, Longcope C, Kaiserman-Abramof IR. The basalis of the primate endometrium: a bifunctional germinal compartment. Biol Reprod. 1989;40(3):681–90.PubMedCrossRef

63.

Leyendecker G, Herbertz M, Kunz G, Mall G. Endometriosis results from the dislocation of basal endometrium. Hum Reprod. 2002;17(10):2725–36.PubMedCrossRef

64.

Valentijn AJ, Palial K, Al-Lamee H, Tempest N, Drury J, Von Zglinicki T, Saretzki G, Murray P, Gargett CE, Hapangama DK. SSEA-1 isolates human endometrial basal glandular epithelial cells: phenotypic and functional characterization and implications in the pathogenesis of endometriosis. Hum Reprod. 2013. doi:10.​1093/​humrep/​det285.PubMed

65.

Redwine DB. Was Sampson wrong? Fertil Steril. 2002;78(4):686–93.PubMedCrossRef

66.

Redwine DB. Sampson revisited: a critical review of the development of Sampson’s theory of origin of endometriosis. In: Garcia-Velasco JA, Rizk BR, editors. Endometriosis: current management and future trends. New Delhi: Jaypee Brothers Medical Publishers; 2010.

67.

Katabuchi H. Endometriosis as an enigmatic pelvic disease [Japanese]. J Jpn Soc Endometriosis. 2008;29:22–31.