Ovarian Surface Stem Cell Population Identified in Mice

Approximately once a month, pre-menopausal women undergo ovulation. During ovulation, a mature graafian follicle is ejected from a rupture in the surface of the ovary. How does the ovary repair itself each month? Many have suspected that the ovary contains its own resident stem cell population that divides and heals the ovary after each ovulation. However, demonstrating the presence of this stem cell population and isolating the ovarian stem cells responsible for this feat have proven difficult.

Now, Nick Barker and colleagues from the University of Edinburgh have identified a cell surface protein called a “Leucine-rich-repeat-containing G protein coupled receptor 5” (LGR5) that is expressed on the surfaces of cells in the ovary surface layer. These LGR5-expressing cells seem to be the stem cell population that contributes to the ovary and oviduct covering during the formation of these organs, and then persist to repair and maintain the ovary surface layer in adults.

LGR5 is also expressed in the cells that cover several other organs. Experiments in mice have shown that LGR5+ cells are in the developing ovary from embryonic day 13.5 onwards. These LGR5-expressing cells are first detected in the ovary surface and lower layers, but later only in the surface of the ovaries of newborn mice. In adult ovaries, LGR5-expressing cells are found only in the layer of cells at the ovary surface, and in the cells that cover the far reaches of the oviduct, and in the cells that line the mesovarium ligament. These LGR5+ cells are found throughout the ovary surface, but they are most prominent in ovulating regions where the ovary surface ruptures. Barker and others also showed that in undamaged regions of the ovary, only a small proportion of dividing cells were LGR5+, but in ovaries that suffered ovulation-induced damage, cycling LGR5+ cells comprised a higher proportion (~50%) of the total percentage of ovary surface cells. These observations do not prove, but are wholly consistent with LGR5-expressing cells playing a seminal role in ovary tissue repair.

Lineage studies with marked cells in embryonic and fetal mice showed that the LGR5+ cells present during ovary development contributed to adult LGR5+ cells that are part of the ovary covering. These lineage studies show that the embryonic and fetal LGR5+ cells are the source of adult stem cells that maintain the ovary surface.

Lineage studies in adult females showed that those cells closer to damaged areas of the ovary underwent more cell divisions. Also, the marked cells on the ovary surface were not only capable of self-renewal, but they could also differentiate into more than one cell type (epithelia of the mesovarian ligament and oviduct/fimbria); this is a key characteristic that defines a stem cell population.

This Barker’s study not only more precisely maps the location of the ovarian stem cell population, but it also suggests that this stem cell population might be the source of ovarian cancers. LGR5-expressing cells might be the source of malignancies of the reproductive tract, which makes these cells important from a clinical perspective. With respect to harvesting these cells and exploiting them for regenerative strategies, it is simply too early at this point to know if this is a realistic possibility, but perhaps this will be the next phase of Barker’s very interesting research.