Identification of Label-Retaining Cells in Mouse Endometrium

Chan, Rachel; Gargett, Caroline E.

doi:10.1634/stemcells.2005-0411

Cited by 240 publications

(295 citation statements)

References 50 publications

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“…The potential of singly dissociated endometrial cells to reconstitute the endometrial tissue raises a possibility that endometrial stem/progenitor cells present in the functionalis layer also may participate in the physiological regeneration of the endometrium through their recycle and reuse. Our hypothesis seems to be supported by the recent report that label-retaining cells, which are thought to be tissue stem/ progenitor cells, are present not only at the endometrialmyometrial junction but also in luminal epithelium and stroma adjacent to luminal epithelium and near blood vessels in mice (19).…”

Section: Discussionsupporting

confidence: 82%

Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γ _c ^null immunodeficient mice

Masuda

Maruyama²,

Hiratsu

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

146

164

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Human uterine endometrium exhibits unique properties of cyclical regeneration and remodeling throughout reproductive life and also is subject to endometriosis through ectopic implantation of retrogradely shed endometrial fragments during menstruation. Here we show that functional endometrium can be regenerated from singly dispersed human endometrial cells transplanted beneath the kidney capsule of NOD/SCID/␥ c null immunodeficient mice. In addition to the endometrium-like structure, hormonedependent changes, including proliferation, differentiation, and tissue breakdown and shedding (menstruation), can be reproduced in the reconstructed endometrium, the blood to which is supplied predominantly by human vessels invading into the mouse kidney parenchyma. Furthermore, the hormone-dependent behavior of the endometrium regenerated from lentivirally engineered endometrial cells expressing a variant luciferase can be assessed noninvasively and quantitatively by in vivo bioluminescence imaging. These results indicate that singly dispersed endometrial cells have potential applications for tissue reconstitution, angiogenesis, and human-mouse chimeric vessel formation, providing implications for mechanisms underlying the physiological endometrial regeneration during the menstrual cycle and the establishment of endometriotic lesions. This animal system can be applied as the unique model of endometriosis or for other various types of neoplastic diseases with the capacity of noninvasive and real-time evaluation of the effect of therapeutic agents and gene targeting when the relevant cells are transplanted beneath the kidney capsule.animal model ͉ bioluminescence imaging ͉ endometriosis ͉ menstruation ͉ angiogenesis H uman endometrium lines the uterus and comprises luminal and glandular epithelial cells, stromal fibroblasts, vascular smooth muscle cells, endothelial cells, and immune competent cells. These cell components coordinately participate in the cyclical changes of human endometrium, including proliferation, differentiation, and tissue breakdown and shedding under the influence of estrogen and progesterone during the menstrual cycle. This unique system of cyclic tissue regeneration also depends on the cyclical growth and regression of the blood vessels that supply the endometrium (1). In addition, angiogenesis is deeply involved in the pathogenesis of endometriumderived disorders such as endometriosis (2). Endometriosis, one of the most common gynecological diseases, is characterized by the presence of functional endometrial-like tissue outside the uterine cavity. It is an estrogen-dependent disorder associated with substantial morbidity; however, the etiology and pathophysiology are not well elucidated (3). To study the physiology of normal endometrium and the pathogenesis of endometriosis, a variety of in vivo models using small animals has been developed by using the transplantation of autologous or heterologous endometrial cells/tissues or endometriotic tissues (4).In the present study, taking advantage of newly de...

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Section: Discussionsupporting

confidence: 82%

Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γ _c ^null immunodeficient mice

Masuda

Maruyama²,

Hiratsu

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

146

164

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“…This concept is not new and was elegantly described in primate models 38,39 and supported by clonogenicity studies of human derived uterine cells. 16 More recent mouse studies utilizing pulse chase experiments to provide evidence of label retaining cells in the uterus 40,41 provide additional functional evidence to support this idea. Still, others have identified SP cells in benign endometrium.…”

Section: Discussionmentioning

confidence: 94%

Functional analyses of the cancer stem cell-like properties of human endometrial tumor initiating cells

Friel¹,

Sergent²,

Patnaude³

et al. 2008

Cell Cycle

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Recent data suggest that rare stem cell populations with the capacity to self renew and drive tumor formation are a feature of solid tumors. Several investigators have identified putative stem cells from solid tumors and cancer cell lines following isolation of a side population (SP) defined by dye exclusion. We investigated this parameter in our efforts to identify an endometrial cancer (EnCa) stem cell population. Multiple EnCa cell lines were assessed and verapamil sensitive SP and non-SP cells were isolated from two human EnCa cell lines. The functional significance of the SP and non-SP derived from AN3CA was evaluated in vitro and in vivo. SP cells proliferated at a significantly slower rate than the non-SP fraction, and a larger proportion of the SP cells were in the G 1 phase of the cell cycle as compared to the non-SP fraction. The SP fraction was more resistant to the chemotherapeutic agent paclitaxel. The SP comprised ~0.02% of the initial AN3CA cell population and this proportion of SP cells was maintained within the larger heterogeneous population following repeated passages of purified SP cells. These findings suggest that SP cells derived from the AN3CA cell line have the stem cell properties of low proliferative activity, chemoresistance and self-renewal. We also tested relative tumor formation activity of the SP and non-SP fractions. Only the SP fraction was tumorigenic. Additionally, we identified SP fractions in primary EnCa. Together these results are consistent with the hypothesis that EnCa contain a subpopulation of tumor initiating cells with stem like properties.

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“…In many hormonally responsive epithelia, stem cells either lack hormone receptor expression (41) or active signaling (38,40). Murine uterine epithelial label-retaining cells were found to be ERα-negative (12), suggesting these progenitors may have quiescent hormone-receptor transcription machinery. Because type II tumors are resistant to hormonal therapy and are predominantly ER-/PR-negative, they may arise from endometrial stem cells.…”

Section: Discussionmentioning

confidence: 99%

“…In response to fluctuating levels of estrogen and progesterone, mouse and human endometria undergo cyclic apoptosis/shedding and regrowth during the estrous and menstrual cycle, respectively (12,13). Endometrial estrogen-and progesterone-mediated effects are thought to occur in a paracrine manner from adjacent stroma (14,15).…”

Section: Dissociated Endometrial Glands Were Highly Enriched For Epitmentioning

confidence: 99%

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Memarzadeh¹,

Zong

Janzen³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial-specific activation of the PI3-kinase pathway is the most common genetic alteration in type I endometrial cancer. In the majority of these tumors, PTEN expression is lost in the epithelium but maintained in tumor stroma. Currently reported PTEN knockout mouse models initiate type I endometrial cancer concomitant with loss of PTEN in both uterine epithelium and stroma. Consequently, the biologic outcome of selectively activating the PI3-kinase pathway in the endometrial epithelium remains unknown. To address this question, we established a malleable in vivo endometrial regeneration system from dissociated murine uterine epithelium and stroma. Regenerated endometrial glands responded to pharmacologic variations in hormonal milieu similar to the native endometrium. Cellautonomous activation of the PI3-kinase pathway via biallelic loss of PTEN or activation of AKT in adult uterine epithelia in this model was sufficient to initiate endometrial carcinoma. AKT-initiated tumors were serially transplantable, demonstrating permanent genetic changes in uterine epithelia. Immunohistochemistry confirmed loss of PTEN or activation of AKT in regenerated hyperplastic glands that were surrounded by wild-type stroma. We demonstrate that cell-autonomous activation of the PI3-kinase pathway is sufficient for the initiation of endometrial carcinoma in naive adult uterine epithelia. This in vivo model provides an ideal platform for testing the response of endometrial carcinoma to targeted therapy against this common genetic alteration.tissue regeneration model | progesterone receptor | uterine cancer E ndometrial cancer, the most common gynecologic cancer in the United States (1), is a hormonally regulated tumor arising from epithelial cells lining the uterine cavity. Effective targeted therapy is unavailable, partly because of lack of knowledge regarding basic biologic pathways and cellular compartments that can initiate this malignancy. Women diagnosed with endometrial cancer are treated in a similar manner irrespective of the heterogeneity of this disease, with surgery or combinations of radiation and chemotherapy. Although endometrial cancer can be cured in early stages, side effects associated with the current therapy can have lifelong debilitating effects on some patients. The majority of women diagnosed with late-stage or metastatic disease die, despite undergoing radical treatments.Endometrial cancer can be divided into two distinct subtypes (2). Type I tumors occur in younger patients exposed to high levels of estrogen unopposed by progesterone. They are typically localized with better response to hormonal therapy. Type II tumors occur in older patients independent of hormonal status. These tumors are more invasive, have a greater propensity for metastatic spread, and are refractory to hormonal treatment. Activation of distinct biologic pathways has been reported in type I vs. type II cancers. Type I tumors are associated with activation of the PI3-kinase pathway, activating mutations of KRAS, mutant β-catenin, an...

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Identification of Label-Retaining Cells in Mouse Endometrium

Cited by 240 publications

References 50 publications

Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γ _c ^null immunodeficient mice

Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γ _c ^null immunodeficient mice

Functional analyses of the cancer stem cell-like properties of human endometrial tumor initiating cells

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

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Identification of Label-Retaining Cells in Mouse Endometrium

Cited by 240 publications

References 50 publications

Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γ c null immunodeficient mice

Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γ c null immunodeficient mice

Functional analyses of the cancer stem cell-like properties of human endometrial tumor initiating cells

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

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Product

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Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γ _c ^null immunodeficient mice

Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γ _c ^null immunodeficient mice