BackgroundThe human endometrium undergoes cyclical regeneration throughout a woman's reproductive life. Ectopic implantation of endometrial cells through retrograde menstruation gives rise to endometriotic lesions which affect approximately 10% of reproductive-aged women. The high regenerative capacity of the human endometrium at eutopic and ectopic sites suggests the existence of stem/progenitor cells and a unique angiogenic system. The objective of this study was to isolate and characterize putative endometrial stem/progenitor cells and to address how they might be involved in the physiology of endometrium.Methodology/Principal FindingsWe found that approximately 2% of the total cells obtained from human endometrium displayed a side population (SP) phenotype, as determined by flow cytometric analysis of Hoechst-stained cells. The endometrial SP (ESP) cells exhibited preferential expression of several endothelial cell markers compared to endometrial main population (EMP) cells. A medium specific for endothelial cell culture enabled ESP cells to proliferate and differentiate into various types of endometrial cells, including glandular epithelial, stromal and endothelial cells in vitro, whereas in the same medium, EMP cells differentiated only into stromal cells. Furthermore, ESP cells, but not EMP cells, reconstituted organized endometrial tissue with well-delineated glandular structures when transplanted under the kidney capsule of severely immunodeficient mice. Notably, ESP cells generated endothelial cells that migrated into the mouse kidney parenchyma and formed mature blood vessels. This potential for in vivo angiogenesis and endometrial cell regeneration was more prominent in the ESP fraction than in the EMP fraction, as the latter mainly gave rise to stromal cells in vivo.Conclusions/SignificanceThese results indicate that putative endometrial stem cells are highly enriched in the ESP cells. These unique characteristics suggest that ESP cells might drive physiological endometrial regeneration and be involved in the pathogenesis of endometriosis.

Over the course of pregnancy, the human uterus undergoes a 500-to 1,000-fold increase in volume and a 24-fold increase in weight. The uterine smooth muscle layer or myometrium is remodeled, and both cell hypertrophy and hyperplasia are evident. The origin of the new smooth muscle cells, however, is unclear. They may arise from existing smooth muscle cells, or they may be the product of stem cell differentiation. This study describes a subset of myometrial cells isolated from nonpregnant human myometrium that represents the myometrial stem cell population. This was characterized as side population of myometrial cells (myoSP) by a distinct Hoechst dye efflux pattern. In contrast to the main population of myometrial cells (myoMP), myoSP resided in quiescence, underexpressed or lacked myometrial cell markers, and could proliferate and eventually differentiate into mature myometrial cells in vitro only under low oxygen concentration. Although myoMP displayed mature myometrial phenotypes before and after in vitro cultivation, only myoSP, not myoMP, generated functional human myometrial tissues efficiently when transplanted into the uteri of severely immunodeficient mice. Finally, myoSP were multipotent and made to differentiate into osteocytes and adipocytes in vitro under the appropriate differentiation-inducing conditions. Thus, myoSP exhibited phenotypic and functional characteristics of myometrial stem cells. Study of myoSP will improve the understanding of myometrial physiology and the pathogenesis of myometrium-derived diseases such as leiomyoma. myoSP may also represent a novel source of biological material that could be used in the reconstruction of not only the human uterus but also other organs as well.pregnancy ͉ uterus ͉ hypoxia ͉ oxytocin receptor ͉ ATP-binding cassette transporter T he human uterus, which is composed mainly of myometrial cells, exhibits a 20-fold expansion in size over the course of pregnancy. Both myometrial hyperplasia (an increase in cell number) and hypertrophy (an increase in cell size) contribute to the dramatic growth of the pregnant uterus (1, 2). In humans, most growth results from stretch-induced myometrial hypertrophy. Uterine growth during the first weeks of pregnancy, however, is accomplished by myometrial hyperplasia with a smaller contribution from hypertrophy (1). Similarly in rats, myometrial hyperplasia is high during early gestation and decreases dramatically later; and myometrial hypertrophy is low at the beginning of pregnancy but increases as gestation progresses (2). These changes repeat with each successive pregnancy. The presence of stem cells in other areas of the body that undergo continual renewal such as the bone marrow, gut, and skeletal muscle (3) suggests that the changes in the uterus may not be attributable to the hypertrophy and hyperplasia of existing myometrial cells alone. We hypothesize that the myometrium harbors a population of stem cells that enable the repeatable enlargement of the pregnant uterus. In support of this hypothesis we isolated putat...

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