Lgr5 marks stem/progenitor cells in ovary and tubal epithelia

The ovary surface epithelium (OSE) undergoes ovulatory tear and remodelling throughout life. Resident stem cells drive such tissue homeostasis in many adult epithelia, but their existence in the ovary has not been definitively proven. Lgr5 marks stem cells in multiple epithelia. Here we use reporter mice and single-molecule fluorescent in situ hybridization to document candidate Lgr5+ stem cells in the mouse ovary and associated structures. Lgr5 is broadly expressed during ovary organogenesis, but becomes limited to the OSE in neonate life. In adults, Lgr5 expression is predominantly restricted to proliferative regions of the OSE and mesovarian–fimbria junctional epithelia. Using in vivo lineage tracing, we identify embryonic and neonate Lgr5+ populations as stem/progenitor cells contributing to the development of the OSE cell lineage, as well as epithelia of the mesovarian ligament and oviduct/fimbria. Adult Lgr5+ populations maintain OSE homeostasis and ovulatory regenerative repair in vivo. Thus, Lgr5 marks stem/progenitor cells of the ovary and tubal epithelia.

[1]  N. Auersperg.  The Origin of Ovarian Carcinomas: A Unifying Hypothesis , 2011, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[2]  P. Leung,et al.  Ovarian surface epithelium: biology, endocrinology, and pathology. , 2001, Endocrine reviews.

[3]  H. Clevers,et al.  Identification of stem cells in small intestine and colon by marker gene Lgr5 , 2007, Nature.

[4]  M. Taketo,et al.  RSPO1/β-Catenin Signaling Pathway Regulates Oogonia Differentiation and Entry into Meiosis in the Mouse Fetal Ovary , 2011, PloS one.

[5]  Hans Clevers,et al.  Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts , 2011, Nature.

[6]  Hans Clevers,et al.  Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. , 2010, Cell stem cell.

[7]  R. Farookhi,et al.  β-catenin/Tcf-signaling appears to establish the murine ovarian surface epithelium (OSE) and remains active in selected postnatal OSE cells , 2012, BMC Developmental Biology.

[8]  A. Oudenaarden,et al.  Single-molecule transcript counting of stem-cell markers in the mouse intestine , 2011, Nature Cell Biology.

[9]  Hans Clevers,et al.  Lgr5 marks cycling, yet long-lived, hair follicle stem cells , 2008, Nature Genetics.

[10]  R. Fodde,et al.  Identification of Quiescent, Stem-Like Cells in the Distal Female Reproductive Tract , 2012, PloS one.

[11]  Hans Clevers,et al.  Crypt stem cells as the cells-of-origin of intestinal cancer , 2009, Nature.

[12]  G. Enikolopov,et al.  Ovarian surface epithelium at the junction area contains cancer-prone stem cell niche , 2013, Nature.

[13]  G. Camerino,et al.  Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. , 2008, Human molecular genetics.

[14]  B. Vanderhyden,et al.  The Mouse Ovarian Surface Epithelium Contains a Population of LY6A (SCA-1) Expressing Progenitor Cells That Are Regulated by Ovulation-Associated Factors1 , 2012, Biology of reproduction.

[15]  D. Connolly.  Development of Mouse Models to Study Ovarian Cancer Biology and Response Therapy. , 2012 .

[16]  H. Clevers,et al.  Differentiated Troy + Chief Cells Act as Reserve Stem Cells to Generate All Lineages of the Stomach Epithelium , 2013, Cell.

[17]  N. Auersperg.  The origin of ovarian cancers--hypotheses and controversies. , 2013, Frontiers in bioscience.

[18]  S. Memarzadeh,et al.  Stem‐Like Epithelial Cells Are Concentrated in the Distal End of the Fallopian Tube: A Site for Injury and Serous Cancer Initiation , 2012, Stem cells.

[19]  J. Fleming,et al.  Proliferating Cell Nuclear Antigen Immunoreactivity in the Ovarian Surface Epithelium of Mice of Varying Ages and Total Lifetime Ovulation Number Following Ovulation1 , 2004, Biology of reproduction.

[20]  K. Brennand,et al.  Normal ovarian surface epithelial label-retaining cells exhibit stem/progenitor cell characteristics , 2008, Proceedings of the National Academy of Sciences.

[21]  H. Clevers,et al.  Lgr5(+ve) stem/progenitor cells contribute to nephron formation during kidney development. , 2012, Cell reports.

[22]  P. V. van Diest,et al.  Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer , 2001, The Journal of pathology.

[23]  H. Clevers,et al.  Slide preparation for single-cell–resolution imaging of fluorescent proteins in their three-dimensional near-native environment , 2011, Nature Protocols.

[24]  J. Pačes,et al.  Troy, a tumor necrosis factor receptor family member, interacts with lgr5 to inhibit wnt signaling in intestinal stem cells. , 2013, Gastroenterology.

[25]  Hans Clevers,et al.  Lineage Tracing Reveals Lgr5+ Stem Cell Activity in Mouse Intestinal Adenomas , 2012, Science.

[26]  Hans Clevers,et al.  Negative Feedback Loop of Wnt Signaling through Upregulation of Conductin/Axin2 in Colorectal and Liver Tumors , 2002, Molecular and Cellular Biology.

[27]  M. Muto,et al.  Serous tubal intraepithelial carcinoma: its potential role in primary peritoneal serous carcinoma and serous cancer prevention. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  S. Kilen,et al.  Gonadotropin-induced superovulation drives ovarian surface epithelia proliferation in CD1 mice. , 2006, Endocrinology.