The Identification and Characterization of Stem/Progenitor Cells in the Ovarian Surface Epithelium

Abstract

When a follicle ovulates, the ovarian surface epithelium (OSE), which covers the surface of the ovary, is ruptured and then rapidly regenerates. Because of this cycle of wound and repair, we determined if the OSE contains a stem/progenitor cell population. We identified a population of OSE cells with progenitor cell characteristics that express the stem cell marker Stem Cell Antigen-1 (SCA-1). We determined the size of the SCA-1 expressing (SCA-1+) progenitor cell population is regulated by at least two ovulation associated factors present in the follicular fluid: Transforming Growth Factor beta 1 (TGFB1) and Leukaemia-Inhibitory Factor. Ovulation triggers an epithelial-to mesenchymal transition (EMT) in the OSE surrounding the ovulatory wound. Because TGFB1 is a known inducer of the EMT, and because the EMT plays a role in expanding stem cell populations in other epithelia, we determined if TGFB1 expands the SCA-1+ OSE progenitor cell population by triggering an EMT. Treatment with TGFB1 and overexpression of the EMT master gene, SNAIL, caused the OSE cells to undergo an EMT, but unlike TGFB1 treatment, SNAIL overexpression did not expand the SCA-1+ OSE population. Interestingly, EMT induced by SNAIL overexpression increased sphere formation by OSE cells, which indicated that it increased specific stem cell capabilities of the OSE. Because BRCA1 controls the size of the progenitor cell population in mammary epithelium, we determined if the OSE progenitor cell population is regulated by BRCA1. OSE with inactivated Brca1 were more stem-like and expressed higher mRNA levels of the known stem cell markers CD44, CD117, CD133 and Sca-1 compared to OSE with functional Brca1. Inactivation of Brca1 also increased the number of OSE cells with surface expression of SCA-1. In addition, TGFB1 and SNAIL-overexpression decreased BRCA1 protein expression compared to controls. Besides providing the first report of a surface maker for OSE with stem-like properties, the results suggest that these cells may play a role in ovulatory wound healing as they are regulated by the EMT, and in ovarian cancer initiation as their numbers increase when BRCA1 is dysfunctional.