003. ENDOMETRIUM: CINDERELLA TISSUE IN A STEM CELL WORLD

Abstract

Despite human endometrium undergoing more than 400 cycles of regeneration, differentiation and shedding during a woman's reproductive years, and that in non-menstruating species (eg rodents) there are cycles of endometrial growth and apoptosis, endometrial stem/progenitor cells have only recently been identified. Since there are no specific stem cell markers, initial studies using functional approaches identified candidate epithelial and stromal endometrial stem/progenitor cells as colony forming cells/units (CFU) (1). Further evaluation of key stem cell properties of individual CFU demonstrated that rare EpCAM⁺ epithelial cells and EpCAM^- stromal cells underwent self renewal by serial subcloning >3 times and underwent >30 population doublings in culture. Clonally-derived epithelial cells differentiated into cytokeratin⁺ gland-like structures. Single stromal cells were multipotent as they differentiated into 4 mesodermal lineages; myogenic, adipogenic, osteoblastic and chondrogenic, suggesting that human endometrium contains a rare population of epithelial progenitor cells and mesenchymal stem cells (MSC) (2). Transplantation of freshly isolated human endometrial cells into immunocompromised mice reconstructed endometrial tissue that responded to estrogen and progesterone (3). Endometrial MSC can be prospectively isolated by co-expression of CD146 and PDGFRβ (4), but not Stro-1, a bone marrow MSC marker (5). Currently there are no known markers of endometrial epithelial progenitor cells. Endometrial cancer tissue harbours a small subpopulation of clonogenic, self-renewing, tumour-initiating cells, producing tumours that recapitulate parent tumours in histoarchitecture and differentiation markers (ERα, PR, cytokeratin, vimentin) when xenografted into mice, suggesting they are cancer stem cells. Candidate epithelial and stromal stem/progenitor cells have been identified in mouse endometrium as label retaining cells (LRC) in the luminal epithelium and perivascular cells at the endometrial-myometrial junction, respectively (6). It is likely that endometrial stem/progenitor cells play key roles in the development of gynecological diseases associated with abnormal endometrial proliferation such as endometriosis and endometrial cancer (7).