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Ovary and fimbrial stem cells: biology, niche and cancer origins

Nature Reviews Molecular Cell Biology volume 16, pages 625–638 (2015)Cite this article

Subjects

Key Points

  • Cyclic rupture and repair of the ovarian surface epithelium during ovulation, and repeated exposure of the fimbrial epithelium to the mechanics of follicular rupture, suggests the existence of stem cells that fuel cellular regeneration in these tissues.

  • Stem-like epithelial cells have been identified in the ovary and fimbria; however, only the Leu-rich repeat-containing G protein-coupled receptor 5 (LGR5)-expressing cells at the ovary surface have been formally shown to contribute to lifelong epithelial homeostasis and post-ovulatory repair in vivo. These Lgr5+ stem cells are concentrated at interfollicular clefts and at the hilum region.

  • Stem cells reside within instructive niches that dictate their function; candidate ovary niche sources encompass the mature epithelial progeny and underlying follicular and stromal cells.

  • Epithelial ovarian cancers, which form the majority of ovarian cancers in humans, are believed to originate from the ovary or (more recently) fimbria.

  • The discovery of a transformation-prone stem cell niche at the ovary hilum in mice, and the presence of transitional epithelia at the ovarian fimbriae in humans, has raised the interesting possibility that mutations in these stem cells may contribute to ovarian carcinogenesis.

Abstract

The mammalian ovary is covered by a single-layered epithelium that undergoes rupture and remodelling following each ovulation. Although resident stem cells are presumed to be crucial for this cyclic regeneration, their identity and mode of action have been elusive. Surrogate stemness assays and in vivo fate-mapping studies using recently discovered stem cell markers have identified stem cell pools in the ovary and fimbria that ensure epithelial homeostasis. Recent findings provide insights into intrinsic mechanisms and local extrinsic cues that govern the function of ovarian and fimbrial stem cells. These discoveries have advanced our understanding of stem cell biology in the ovary and fimbria, and lay the foundations for evaluating the contribution of resident stem cells to the initiation and progression of human epithelial ovarian cancer.

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Figure 1: The adult human and mouse ovary and associated tissues.
Figure 2: Locations and characteristics of epithelial stem and stem-like cells in the ovarian surface epithelium (OSE) and the fimbria.
Figure 3: Putative ovarian surface epithelium (OSE) and fimbrial niche locations and signals.
Figure 4: Proposed model of stem cell-driven epithelial ovarian cancer (EOC) carcinogenesis.

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Acknowledgements

The authors would like to thank all laboratory members in the group for their support and critical reading of the manuscript.

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  1. A* STAR Institute of Medical Biology, 8A Biomedical Grove, 06-06 Immunos, 138648, Singapore

    Annie Ng & Nick Barker

  2. MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK

    Nick Barker

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Glossary

Fimbria

The most distal part of the fallopian tube (or oviduct in non-primates). The fimbria comprises finger-like fringes that collect the released oocyte from the surface of the ovary and transport it into the uterus for fertilization.

Ovary

A reproductive organ that is responsible for the production and cyclic release of oocytes. In mammals, the ovary is present as a pair of glands that are attached to the uterus by the ovary ligaments.

Follicular fluid

A growth factor-enriched liquid that fills the ovarian follicle. The composition of the follicular fluid dramatically changes during folliculogenesis, as well as during the various stages of the oestrus cycle.

Niche

The supportive local environment in which stem cells reside. The stem cell niche supplies all the extrinsic signalling cues that dictate stem cell maintenance and proliferative activity.

DNA label retention

Introduction of a nucleotide analogue (for example, 5-bromo-2′-deoxyuridine (BrdU) or 5-iodo-2′-deoxyuridine (IdU)) or labelling by genetic means (for example, using histone 2B–GFP) for a short period, followed by a prolonged period in the absence of the labelling reagent. After several rounds of cell division, fast-cycling cells rapidly dilute the label, whereas quiescent cells retain most of the original label. These cells are termed label-retaining cells.

Side-population enrichment

A flow-cytometry assay that discriminates for and enriches cell populations that efflux fluorescent dyes (for example, Hoechst 33342) at a higher pace, owing to the expression of ATP-binding cassette transporter proteins within the cell membrane.

Fate-mapping

Permanent labelling of a cell type with a reporter marker (LacZ or a fluorescent protein) that is inherited by its progeny upon cellular division, thus facilitating analyses of its cell-fate decisions and behaviour. Also known as lineage tracing.

Cellular quiescence

A reversible, non-dividing cell state. Some stem cells are quiescent under steady state, a property that is believed to sustain lifelong tissue maintenance and preservation of the stem cell compartment.

Organoids

Three-dimensional cell culture structures that recapitulate the multipotent cellular differentiation and functional complexity of the native tissue of origin.

Corpus luteum

The vascularized by-product of a recently ruptured follicle. Over time, the corpus luteum regresses into the centre of the ovary to become stromal or interstitial tissue.

Epithelial–mesenchymal transition

(EMT). A biological process by which epithelial cells dissolve their tight junctions with one another and convert into a free, migratory form.

Cancer cell of origin

The cell that sustains the first cancer-promoting mutation or mutations that initiate tumour development.

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Ng, A., Barker, N. Ovary and fimbrial stem cells: biology, niche and cancer origins. Nat Rev Mol Cell Biol 16, 625–638 (2015). https://doi.org/10.1038/nrm4056

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