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. 2014 Nov 5;91(6):149. doi: 10.1095/biolreprod.114.123794

Tissue-Specific Stem Cells in the Myometrium and Tumor-Initiating Cells in Leiomyoma1

Masanori Ono 3, Serdar E Bulun 4, Tetsuo Maruyama 3,2
PMCID: PMC4434985  PMID: 25376230

ABSTRACT

Tissue-specific (or somatic) stem cells constitute a subset of cells residing in normal adult tissues. By undergoing asymmetric division, they retain their ability to self-renew while producing daughter cells that go on to differentiate and play a role in tissue regeneration and repair. The human uterus consists primarily of endometrium and myometrium (the smooth muscle layer) that rapidly enlarges through its tremendous regenerative and remodeling capacity to accommodate the developing fetus. Such uterine enlargement and remodeling can take place repeatedly and cyclically over the course of a woman's reproductive life. These unique properties of the uterus suggest the existence of endometrial and myometrial stem cell systems. In addition, like somatic cells, tumor stem cells or tumor-initiating cells, a subset of cells within a tumor, retain the ability to reconstitute tumors. Uterine smooth muscle cells are thought to be the origin of leiomyomas that are the most common type of gynecologic tumor. Recent work has identified, isolated, and characterized putative stem/progenitor cells in the myometrium and in leiomyomas. Here, we review current studies of myometrial and leiomyoma stem/progenitor cells and provide a new paradigm for understanding myometrial physiology and pathology and how these cells might contribute to uterine remodeling during pregnancy and the formation of leiomyomas. The role of the WNT/CTNNB1 pathway in the pathogenesis of leiomyoma is also discussed.

Keywords: leiomyoma, myometrium, pregnancy, regeneration, tissue-specific stem cells, tumor-initiating cells

INTRODUCTION

After completion of embryonic development, undifferentiated tissue-specific adult somatic stem cells persist throughout the body [1, 2]. Tissue-specific stem cells are a subset of cells residing in normal adult tissues that retain their ability to self-renew while producing daughter cells that play a role in tissue regeneration and repair [3, 4]. Analogously, tumor-initiating cells are a subset of cells within a tumor cell population that retain the ability to reconstitute tumors through asymmetric division [5]. Leiomyomas are thought to be monoclonal tumors arising from the myometrium [6, 7]. However, the myometrial cell population that gives rise to these tumors has not been identified [6, 7]. Several recurrent genetic aberrations, such as chromosome 12 trisomy, deletions in 7q, and mutations in genes encoding mediator complex subunit 12 (MED12) or high mobility group AT-hook 2 (HMGA2) have been reported in leiomyomas [8–11]. As in other diseases, these genetic abnormalities occurring in tumor stem cells are thought to play pivotal roles in the tumorigenesis of leiomyomas.

Tissue-specific stem cells have been identified in a wide range of tissues and organs. In this review, we briefly summarize myometrial physiology and then review current studies of myometrial and leiomyoma stem/progenitor cells. We conclude by discussing the possible roles of these cells in myometrial function and the pathogenesis of leiomyomas.

MYOMETRIAL PHYSIOLOGY

The myometrium has two primary roles [12]. First, it protects the growing fetus from stresses, including labor, through its capacity for growth and stretching. Second, delivery is achieved through its forceful muscular contractions. It is currently believed that myometrial functions are regulated by endocrine, paracrine, and mechanical pathways. However, the underlying biochemical and genetic mechanisms are not fully understood [12]. Unlike other smooth muscles, myometrial smooth muscles have receptors for progesterone and estrogen. When these receptors are activated, they control cell growth and quiescence during gestation, as well as activation of the myometrial muscles during labor and delivery [13–15]. Moreover, a range of bioactive substances regulates the contractility of the myometrium, including contraction-associated proteins (e.g., gap junction protein), receptors for agonists such as oxytocin and stimulatory prostaglandins, and Na+ and Ca2+ ion channels that control myometrial excitability [12].

During pregnancy, the human uterus can increase its capacity from 500- to 1000-fold and increase its weight more than 20-fold [16–18]. Over a woman's reproductive life, these changes can reportedly occur more than 20 times. Both in humans and rodents, it is likely that myometrial hyperplasia and hypertrophy assist in the expansion of the gravid uterus [17, 19]. Pregnancy-associated growth of human myometrium is largely achieved by stretch-induced hypertrophy. During the initial period of pregnancy, myometrial hyperplasia also contributes. At this time, hyperplasia might be a more important factor for growth than hypertrophy in humans [19].

Five distinct phases have been identified in the development of the gravid rat uterus [17, 20]. In the initial (proliferative) phase, myocytes increase in cell number (hyperplasia). Next, myocytes increase in cell size and synthesize the interstitial matrix and remodel focal adhesions. Then, the contractile phenotype emerges with upregulation of contractile proteins and downregulation of myometrial inhibitory pathways. In labor, contraction-associated proteins accumulate, and uterotonic agonists are synthesized, leading to contractions. Last, there is postpartum uterine involution, during which expression levels of genes associated with apoptosis, wound repair, and tissue regeneration are upregulated. This permits the rat uterus to return to its normal condition [12]. Thus, the myometrium supports pregnancy through alterations in its biochemistry and functionality. Although the mechanisms underlying these changes have been studied, they remain poorly characterized [12].

Although the foregoing changes are remarkable, it does not seem likely that repeated expansion of the uterus could be due entirely to cycles of hyperplasia and hypertrophy of differentiated myocytes. For example, during postpartum involution, there is widespread myocyte apoptosis [17]. This observation necessitates replacement of the myometrial cells that were lost. In other words, new myometrial cells must be generated if the uterus is to return to its normal state after pregnancy. Precisely how this is achieved remains poorly understood. New smooth muscle cells might develop from differentiated cells. Alternatively, they might be generated by primitive stem cells. We, in fact, believe that remodeling of the uterus in response to these stimuli and its return to a basal state require adult stem/progenitor cells that reside in myometrial compartments. Furthermore, we suspect that several pathological conditions, such as endometrial cancer, adenomyosis, and leiomyoma, can be attributed to dysregulation of these stem cells. Indeed, both adenomyosis and endometrial gland hyperplasia were occasionally observed in some mice in which the Ctnnb1 gene was selectively activated in uterine mesenchyme [21]. Alternatively, these conditions could be derived from committed cells that acquire stem cell-like features. These possibilities are discussed below.

MYOMETRIAL STEM CELLS

Regeneration and remodeling of the female reproductive tract suggests the existence of myometrial and endometrial stem cell systems. However, the characteristics and functions of these stem cells are not understood in great detail. To confirm the presence and elucidate the possible roles of stem cells in nongravid human myometrium, we isolated side population (SP) cells. Human SP cells are characterized by the capacity to remove intracellular DNA-binding dyes via expression of the ATP-binding cassette, subfamily G, member 2 (ABCG2) protein [22]. Dissociated human myometrial cells were stained with Hoechst dye and subjected to flow cytometric sorting to isolate myometrial SP (myoSP) cells. Flow cytometric analysis revealed that the stained cells included a small fraction of myoSP. The expression level of ABCG2 mRNA was significantly higher in the myoSP fraction than in the main population (non-SP) of myometrial cells (myoMP) [22]. MyoSP also had very low expression levels of estrogen receptor α and progesterone receptor, as well as smooth muscle cell-specific markers such as calponin and smoothelin [22]. Subsequently, we demonstrated that transcripts of POU5F1 (previously known as OCT4), an embryonic stem cell marker, are more abundant in myoSP than in myoMP [23]. These results collectively suggested that myoSP represented an immature or undifferentiated population.

Although human myoSP cells did not proliferate in vitro in a normoxic (20% O2) environment, they did grow efficiently in vitro under a 2% oxygen tension [22]. There is growing evidence that low-oxygen conditions permit tissue-specific stem cell survival and growth in vitro [24]. Those data indicate that such stem cells are well suited for survival and growth in a hypoxic environment in vivo. Indeed, myoSP cells prefer a hypoxic environment for proliferation and spontaneous differentiation into smooth muscle cells. The results also suggest that human myoSP cells participate in the enlargement of the uterus. Using a biochemical probe that detects hypoxia, Shynlova et al. [25] showed that during pregnancy in the rat, hypoxia in the myometrium could be induced by mechanical stretching of the uterine wall. They also reported that activation of caspases in rat myometrium was caused by hypoxia. It is well known that hypoxia regulates the proliferation, differentiation, and function of trophoblasts and placenta [26]. Hypoxia promotes the proliferation of putative endometrial stem/progenitor cells like myoSP [27]. Therefore, oxygen tension, through its effects on the trophoblast, placenta, and uterus, may be a critical determinant of a successful pregnancy. It is, therefore, conceivable that pregnancy-induced mechanical stretching leads to hypoxia and may promote the proliferation of human myoSP. In this way, human myoSP could contribute to uterine enlargement and remodeling during pregnancy (Fig. 1) [28, 29].

FIG. 1.

FIG. 1

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Proposed model for the possible role of putative myometrial stem cells in pregnancy-induced uterine enlargement and pathogenesis of leiomyoma.

LEIOMYOMA STEM CELLS

Uterine leiomyomas occur in almost 70% of Caucasian women and more than 80% of African-American women by age 50 [30]. Clinically relevant leiomyomas are detectable by transvaginal sonography in approximately 50% to 80% of African-American women and 25% to 70% of Caucasian women [10, 30–33]. Leiomyomas cause excessive uterine bleeding, anemia, recurrent pregnancy loss, preterm labor, pelvic discomfort, and urinary incontinence in approximately 15% to 30% of cases [34, 35]. They are the most common indication for hysterectomy [34, 36]. Despite their high prevalence, the cellular and molecular origins of uterine leiomyomas are not well understood. Recent studies suggest the involvement of epigenetic mechanisms such as DNA methylation and micro-RNA and histone modification in leiomyoma [37–42]. At the genetic level, several mutations, such as germline mutations causing fumarate hydratase deficiency, have been associated with leiomyoma formation [43].

Recently, recurrent somatic mutations in MED12 were identified through exome sequencing of 18 uterine leiomyomas from Finnish patients [9]. Further analysis of a total of 225 tumors from 80 patients revealed that a striking 70% of uterine leiomyomas display MED12 mutations, making it the most frequently altered gene in leiomyomas. All the identified mutations clustered in an evolutionarily conserved region of the gene, in exon 2 and in the intron 1-exon 2 junction. This finding has been validated in several studies representing various ethnic groups [44–50]. These data suggest that aberrant functioning of the encoded region contributes to tumorigenesis. In the MED12 mutation study, leiomyoma size inversely correlated with the presence of MED12 mutations [9, 44, 51]. Most leiomyomas contain specific genetic mutations, as in MED12, suggesting that transformation of normal myocytes into abnormal myocytes is required at some point during the genesis of a leiomyoma [9]. MED12 encodes a subunit of the mediator complex that consists of at least 26 subunits and regulates transcription initiation and elongation by bridging regulatory elements in gene promoters to the RNA polymerase II initiation complex [9].

An elevated incidence of chromosomal abnormalities in leiomyomas due to translocations, deletions, and duplications of chromosomes 6, 7, 12, and 14 has been reported [52]. These data were confirmed by whole-genome sequencing, suggesting that the rearrangements in leiomyoma have a common origin [53]. Leiomyoma SP (LMSP) cells comprise 1% of tumor cells and display tumor-initiating stem cell characteristics [54]. The growth of LMSP cells in vivo drives tumor expansion, and such growth is estrogen- and progesterone-dependent even though they express remarkably lower estrogen/progesterone receptor levels than mature myometrial or leiomyoma cells [55]. Leiomyomas are thought to be monoclonal tumors [6, 7]. It has been proposed that each leiomyoma originates from a single transformed tissue-specific stem cell of the myometrium in an ovarian steroid-dependent manner [56]. However, this hypothesis has not been definitively proven. Estrogen/progesterone-dependent in vivo growth of human leiomyoma tissue requires the presence of these multipotent tissue-specific stem cells [54, 57]. Their growth requires the presence of mature myometrial or leiomyoma cells with higher levels of steroid receptors and their ligands. This is based on the postulate that steroid hormone action on leiomyoma stem cells is mediated by mature myometrial cells (tumor initiation) or mature leiomyoma cells (growth maintenance) in a paracrine fashion. It is likely that paracrine interaction with surrounding ESR1- and/or PGR-positive niche cells supports self-renewal of the leiomyoma stem cells.

WNT/CTNNB1 PATHWAY AND THE MOUSE MODEL OF LEIOMYOMA

Among different pathways that transduce WNT receptor activation, the canonical WNT/CTNNB1 cascade is best understood. Once bound by one of the WNT ligands, the FZD/LRP5/6 coreceptor complex activates the canonical signaling pathway [58]. The key effector of the canonical WNT cascade is CTNNB1, a cytoplasmic protein whose stability is regulated by the destruction complex. The tumor suppressor protein AXIN functions as the scaffold of this complex as it directly interacts with all other components: CTNNB1, the tumor suppressor protein APC and the two kinase families (CSNK1A1 and GSK3A/B) [58]. When WNT receptor complexes are not engaged, CSNK1A1 and GSK3A/B phosphorylate CTNNB1 at a number of residues, leading to its ubiquitination and destruction [58]. Activation of the canonical WNT/CTNNB1 pathway via binding of a WNT family member to its cell surface receptor leads to translocation of intact CTNNB1 to the nucleus. There, it binds to the T-cell factor/lymphoid-enhancing factor (TCF/LEF) transcription factors, resulting in the expression of specific target genes [58,59]. Because many CTNNB1 target genes, such as MYC, WISP1, and CCND1 are involved in cell proliferation, CTNNB1 signaling plays an important role in cell development and neoplasia [58].

Selective overexpression of the Ctnnb1 gene in uterine mesenchyme during embryonic development and in adults gives rise to leiomyoma-like tumors in the uteri of female mice [21]. In those mutant mouse uteri, Tanwar et al. [21] observed dysplastic lesions in the myometrium, with 100% penetrance, and they appeared to increase in size and number with age and parity. In contrast, parity may protect humans from leiomyomas [60, 61]. For this reason, there must be a significant difference between the mouse model and human disease. Nonetheless, signaling by WNT/CTNNB1 plays a role in tissue-specific stem cell function in the myometrium and in uterine leiomyoma tissue. Selective deletion of the murine Ctnnb1 gene from the uterine mesenchyme during embryonic development significantly reduced uterine size and led to the replacement of myometrial cells by adipocytes, thus completely disrupting normal myometrial smooth muscle differentiation and regeneration [62]. These findings collectively suggest that signaling by WNT/CTNNB1 plays a role in tissue-specific stem cell function in the myometrium and in uterine leiomyoma tissue. These findings indicate that CTNNB1 plays a key role in stem cell renewal and in differentiation to the smooth muscle phenotype observed in myometrial and leiomyoma tissues [3]. Moreover, activated CTNNB1 induces expression of transforming growth factor-beta 3 (TGFB3), which was shown to induce proliferation and extracellular matrix (ECM) formation in human leiomyoma tissue [21, 63]. Because the frequency of tumors is greater in multiparous mice, it appears that development of the tumors is hormonally driven. Alternatively, it is possible that changes in the uterus (both during pregnancy and after delivery) might be injurious. Thus, repair mechanisms might stimulate tumorigenesis from stem/progenitor cells that otherwise do not express constitutively activated CTNNB1. Additionally, adenomyosis and endometrial gland hyperplasia are occasionally observed in some mice. These results suggest that there might be pleiotropic effects on uterine function and tumorigenesis resulting from dysregulated stromal and myometrial WNT/CTNNB1 signaling [21].

Given that WNT signaling controls cell fate decisions throughout development and in adult stem cells, we further posit that the relevant target of CTNNB1-mediated tumorigenesis is a progenitor cell that gives rise to leiomyomas, rather than a mature smooth muscle cell. Thus, a paracrine role of WNT ligand is suggested. The WNT ligand probably originates from mature myometrial or leiomyoma smooth muscle cells in response to estrogen/progesterone. The WNT ligand acts on adjacent leiomyoma stem-like tumor-initiating cells to stimulate self-renewal and proliferation, eventually leading to tumor growth (Fig. 2).

FIG. 2.

FIG. 2

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Interactions among ovarian hormones, CTNNB1 and TGFB3 pathways, and MED12 in leiomyoma cells. Expression levels of ESR1 and PGR are remarkably high in mature myometrial and leiomyoma niche cells compared to that of stem cells. Thus, estrogen and progesterone signals reach leiomyoma stem cells through hormone receptors in mature niche cells in a paracrine fashion. Estrogen and progesterone might increase secretion of WNT ligands from the surrounding ESR1- and/or PGR-positive niche cells. In both cell types, WNT, acting through the FZD family of receptors, activates the TCF pathway, subsequently inducing the production of TGFB3 in mature niche cells and leading to excessive formation of extracellular matrix. In stem cells, wild-type MED12 might act as a physiologic modifier of CTNNB1 action, whereas the MED12 mutant (or the absence of MED12) might lead to the failure of this function. Parts of this figure were modified from Bulun [32]. Modified with permission from the New England Journal of Medicine.

CELLULAR ORIGINS AND ROLE OF THE WNT/CTNNB1 PATHWAY IN THE PATHOGENESIS OF LEIOMYOMAS IN HUMANS

The cellular origin of uterine leiomyomas remains undefined. Several observations support the notion that each leiomyoma originates from the transformation of a single tissue-specific stem cell within the myometrium [28, 29] (Fig. 1). Early genetic studies suggested that leiomyomas are monoclonal tumors [56]. Human and mouse myometrial tissues contain multipotent tissue-specific stem cells [56]. By means of asymmetric division, this subset of tissue cells undergoes self-renewal and produces daughter cells under the influence of reproductive hormones (possibly ovarian hormones), a process responsible for tumor growth [62]. Human uterine leiomyoma tissue contains fewer stem cells than normal myometrium [54, 64]. However, stem cells derived from leiomyoma tissue, not the myometrium, carry MED12 mutations. This finding suggests that at least one genetic hit initially transforms a myometrial stem cell that subsequently interacts with the surrounding myometrial tissue to give rise to a leiomyoma tumor. There is increasing evidence that steroid hormones are the most important regulators affecting the growth of leiomyomas [65]. Growth of leiomyoma stem cells requires the presence of myometrial cells with higher levels of estrogen and progesterone receptors and their ligands, suggesting that the action of steroid hormones on leiomyoma stem cells is mediated by myometrial cells in a paracrine fashion [54, 57]. It is likely that this paracrine interaction with the surrounding cells supports the self-renewal of leiomyoma stem cells (Fig. 2).

Complex mechanisms regulate the biologic functions of CTNNB1. Secreted WNT proteins bind to cell surface receptors of the FZD family, causing activation of a cascade of proteins that leads to decreased CTNNB1 degradation in the cytosol and ultimately changes the amount of CTNNB1 that reaches the nucleus [37]. Leiomyoma tissue-derived TGFB3 might also suppress the expression of local anticoagulant factors in adjacent endometrial cells, resulting in prolonged menstrual bleeding associated with leiomyoma [66]. These observations indicate that there are critical interactions among activated WNT-CTNNB1 and TGFB3 pathways, estrogen/progesterone, and stem cell renewal and that these interactions may ultimately give rise to the clonal formation of uterine leiomyoma tumors (Fig. 2).

MED12 protein binds directly to CTNNB1 and regulates canonical WNT signaling [67]. Recently, it was reported that MED12 mutations in leiomyoma disrupt the interaction between MED12 and cyclin C (CCNC)-CDK8/CDK19, resulting in diminished CDK activity [68]. Turunen et al. [68] used affinity purification, mass spectrometry, and immunoprecipitation and Western blotting to identify wild-type proteins that became bound differently from mutant MED12 proteins. A significant decrease in CCNC-CDK8/CDK19 was observed in MED12 mutants. MED12 mutations seem to disrupt the binding interface between MED12 and CCNC, which is necessary to activate CCNC-dependent CDK8 kinase activity.

Because MED12 limits CTNNB1-dependent tissue growth during embryonic development, a critical question is whether absent or defective MED12 in uterine leiomyoma stem cells or differentiated cells causes CTNNB1 pathway-dependent tumor growth [69, 70]. Interestingly, expression of WNT4 is markedly elevated in leiomyomas with MED12 mutations compared to that in the gene without mutations [44]. These observations point to a mechanism involving MED12 mutations and WNT/CTNNB1 activation that supports stem cell renewal, proliferation, and fibrosis in uterine leiomyoma tissue [67, 71].

POSSIBLE THERAPEUTIC STRATEGIES FOR TREATMENT OF LEIOMYOMA BY TARGETING THE WNT/CTNNB1 PATHWAY

Leiomyomas are the most common indication for hysterectomy [32, 34, 36, 72]. Approximately 200 000 hysterectomies, 30 000 myomectomies, and thousands of selective uterine artery embolization and high-intensity, focused ultrasonography procedures are performed annually in the United States to remove or destroy uterine leiomyomas. The annual economic burden of these tumors has been estimated to be between $5.9 and $34.4 billion [32, 73]. Thus, there is a need to discover new treatment modalities.

The role of aberrant WNT signaling in the development and progression of tumors such as colorectal cancer has been studied extensively [74–76]. Thus, components of the WNT pathway, particularly the accessible plasma membrane FZD receptors, are prime targets for drug development. However, there are no current U. S. Food and Drug Administration-approved drugs that regulate WNT signaling at the level of the FZD receptors. It has been reported that niclosamide promotes FZD1 internalization and inhibits WNT/FZD function, suggesting that it might have antitumor effects [77]. It was also reported that XAV939, which inhibits the stabilization and nuclear accumulation of CTNNB1 by targeting tankyrase 1 and 2, down-regulates AXIN levels and blocks colorectal and lung cancer cell growth [78, 79]. These and other related compounds might serve as future leiomyoma therapy agents.

Ulipristal acetate has recently emerged as a promising drug that controls excessive bleeding due to leiomyoma and reduces the size of the tumor preoperatively [80]. Ulipristal acetate is equivalent to once monthly leuprolide acetate in controlling uterine bleeding and is significantly less likely to cause hot flashes [81]. Given that the reduction in fibroid volume was largely maintained even after cessation of ulipristal treatment, it is conceivable that ulipristal may negatively affect leiomyoma stem cells and/or their relevant WNT/CTNNB1 signaling pathways [82].

CONCLUSIONS AND PERSPECTIVES

Mounting evidence indicates that the myometrium in humans and rodents includes small populations of tissue-specific stem cells. The study of myometrial stem cells, however, is still in its early phase. Identification of specific markers for myometrial stem cells remains critically important. Thorough characterization of these cells is a prerequisite for understanding the mechanisms underlying the altered physiology and remodeling of the uterus. Analogously, better understanding of the pathogenesis of myometrium-derived tumors including leiomyomas, adenomyosis, leiomyosarcomas, and mixed Müllerian tumors is required. Defining their cellular and functional properties is a necessary first step to achieve this broad goal. We predict that increasing our understanding of myometrial and leiomyoma stem cells will shift the focus of therapeutic interventions to these defined cell populations and transform the field of uterine biology and medicine.

ACKNOWLEDGMENT

We thank members of the Departments of Obstetrics and Gynecology and Physiology, Keio University School of Medicine, and Northwestern University, for their help with this work.

Footnotes

1

Supported by grants-in-aid from the Japan Society for the Promotion of Science to T.M and M.O., a grant-in-aid from Keio University Sakaguchi-Memorial Medical Science Fund to T.M., a grant-in-aid from the Japan Medical Association to T.M., U.S. National Institutes of Technology grants CA060553 and P01-HD057877 to S.E.B., and a grant-in-aid from the Uehara Memorial Foundation to T.M.

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