UCSF

Human endometrium is a dynamic tissue that responds to the circulating ovarian steroid hormones estradiol (E2) and progesterone (P4), and regenerates in the absence of pregnancy on a cyclic basis [1]. The regenerative capacity of the endometrium is remarkable, and this process occurs nearly 400 times during a women's reproductive lifetime. It has been proposed that endometrial stem cells (SC)/progenitor cells mediate endometrial regeneration. Recently, a clonogenic stem cell-like population co-expressing CD146 and platelet-derived growth factor-receptor ß (PDGF-Rß) has been found in the endometrium [2, 3, 4, 5]. It has been proposed that abnormal functioning of this endometrial stem cell-like population is involved in the initiation and progression of disorders associated with abnormal endometrial proliferation [6]. The concept that a stem cell-like population is responsible for disease progression has been previously postulated in the cancer stem cell model [7]. This model states that tumors contain a subset of cells that both self-renew and give rise to differentiated progeny and are responsible for the tumor's growth [7].

There are several disorders of the endometrium whose etiologies are not well understood and that may have their origins in the endometrial stem/progenitor population, including endometrial hyperplasias, endometrial cancers and endometriosis. Endometriosis is a chronic benign gynecological disorder characterized by the presence of endometrial glands and stroma outside the uterine cavity [8]. It has been established that the eutopic endometrium of women with endometriosis does not appropriately respond to progesterone (P4) [8, 9]. We hypothesize that, gynecological disorders such as endometriosis may be driven by a subset of cells, namely SC, that have some unique characteristics that distinguish them from those of SC in normal endometrium, and while not predisposing to uncontrolled growth as in cancers, do predispose to the persistent proliferative phenotype seen in endometriosis.

Herein, we propose experiments to 1) characterize the SC populations in eutopic endometrium from women with versus without endometriosis, both molecularly and functionally to help elucidate the role of these cells in the development and maintenance of normal endometrium and endometriosis, and 2) to determine whether the aberrant response to P4 in endometriosis can be observed in the SC precursor/progenitor cells.