Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women

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In a new report, Tilly and colleagues now perfect the purification of mouse OSCs and, using this technique, they show that similar cells exist in women of reproductive age. They also show that the mouse and human OSCs are able to give rise to oocytes in vivo (in the case of the human cells after xenotransplantation into NOD-SCID mice), while also showing that the mouse OSCs can give rise to embryos after in vitro fertilization. Germline stem cells that produce oocytes in vitro and fertilization-competent eggs in vivo have been identified in and isolated from adult mouse ovaries. Here we describe and validate a fluorescence-activated cell sorting-based protocol that can be used with adult mouse ovaries and human ovarian cortical tissue to purify rare mitotically active cells that have a gene expression profile that is consistent with primitive germ cells. Once established in vitro, these cells can be expanded for months and can spontaneously generate 35- to 50-μm oocytes, as determined by morphology, gene expression and haploid (1n) status. Injection of the human germline cells, engineered to stably express GFP, into human ovarian cortical biopsies leads to formation of follicles containing GFP-positive oocytes 1–2 weeks after xenotransplantation into immunodeficient female mice. 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USA; citation_title=Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies; citation_author=K Selesniemi, H-J Lee, A Muhlhauser, JL Tilly; citation_volume=108; citation_publication_date=2011; citation_pages=12319-12324; citation_doi=10.1073/pnas.1018793108; citation_id=CR48"/> <meta name="citation_reference" content="citation_journal_title=Biol. Reprod.; citation_title=Preliminary experience with subcutaneous human ovarian cortex transplantation in the NOD-SCID mouse; citation_author=A Weissman; citation_volume=60; citation_publication_date=1999; citation_pages=1462-1467; citation_doi=10.1095/biolreprod60.6.1462; citation_id=CR49"/> <meta name="citation_reference" content="citation_journal_title=Nat. Genet.; citation_title=Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals; citation_author=T Matikainen; citation_volume=28; citation_publication_date=2001; citation_pages=355-360; citation_doi=10.1038/ng575; citation_id=CR50"/> <meta name="citation_author" content="White, Yvonne A R"/> <meta name="citation_author_institution" content="Massachusetts General Hospital Vincent Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, USA"/> <meta name="citation_author_institution" content="Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, USA"/> <meta name="citation_author" content="Woods, Dori C"/> <meta name="citation_author_institution" content="Massachusetts General Hospital Vincent Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, USA"/> <meta name="citation_author_institution" content="Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, USA"/> <meta name="citation_author" content="Takai, Yasushi"/> <meta name="citation_author_institution" content="Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Saitama, Japan"/> <meta name="citation_author" content="Ishihara, Osamu"/> <meta name="citation_author_institution" content="Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Saitama, Japan"/> <meta name="citation_author" content="Seki, Hiroyuki"/> <meta name="citation_author_institution" content="Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Saitama, Japan"/> <meta name="citation_author" content="Tilly, Jonathan L"/> <meta name="citation_author_institution" content="Massachusetts General Hospital Vincent Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, USA"/> <meta name="citation_author_institution" content="Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, USA"/> <meta name="access_endpoint" content="https://www.nature.com/platform/readcube-access"/> <meta name="twitter:site" content="@naturemedicine"/> <meta name="twitter:card" content="summary_large_image"/> <meta name="twitter:image:alt" content="Content cover image"/> <meta name="twitter:title" content="Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women"/> <meta name="twitter:description" content="Nature Medicine - In 2004, a team led by Jonathan Tilly reported that mice contained oogonial stem cells (OSCs), suggesting that females may be able to generate new oocytes in adulthood—a..."/> <meta name="twitter:image" content="https://media.springernature.com/full/springer-static/image/art%3A10.1038%2Fnm.2669/MediaObjects/41591_2012_Article_BFnm2669_Fig1_HTML.jpg"/> <meta property="og:url" content="https://www.nature.com/articles/nm.2669"/> <meta property="og:type" content="article"/> <meta property="og:site_name" content="Nature"/> <meta property="og:title" content="Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women - Nature Medicine"/> <meta property="og:description" content="In 2004, a team led by Jonathan Tilly reported that mice contained oogonial stem cells (OSCs), suggesting that females may be able to generate new oocytes in adulthood—a concept that was, and still is, quite controversial even though those findings have since been replicated by others. In a new report, Tilly and colleagues now perfect the purification of mouse OSCs and, using this technique, they show that similar cells exist in women of reproductive age. They also show that the mouse and human OSCs are able to give rise to oocytes in vivo (in the case of the human cells after xenotransplantation into NOD-SCID mice), while also showing that the mouse OSCs can give rise to embryos after in vitro fertilization."/> <meta property="og:image" content="https://media.springernature.com/m685/springer-static/image/art%3A10.1038%2Fnm.2669/MediaObjects/41591_2012_Article_BFnm2669_Fig1_HTML.jpg"/> <script> window.eligibleForRa21 = 'true'; </script> </head> <body class="article-page"> <noscript><iframe src="https://www.googletagmanager.com/ns.html?id=GTM-MRVXSHQ" height="0" width="0" style="display:none;visibility:hidden"></iframe></noscript> <div class="position-relative cleared z-index-50 background-white" data-test="top-containers"> <a class="c-skip-link" href="#content">Skip to main content</a> <div class="c-grade-c-banner u-hide"> <div class="c-grade-c-banner__container"> <p>Thank you for visiting nature.com. 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c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Yvonne_A_R-White-Aff1-Aff2" data-author-popup="auth-Yvonne_A_R-White-Aff1-Aff2" data-author-search="White, Yvonne A R">Yvonne A R White</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Dori_C-Woods-Aff1-Aff2" data-author-popup="auth-Dori_C-Woods-Aff1-Aff2" data-author-search="Woods, Dori C">Dori C Woods</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Yasushi-Takai-Aff3" data-author-popup="auth-Yasushi-Takai-Aff3" data-author-search="Takai, Yasushi">Yasushi Takai</a><sup class="u-js-hide"><a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Osamu-Ishihara-Aff3" data-author-popup="auth-Osamu-Ishihara-Aff3" data-author-search="Ishihara, Osamu">Osamu Ishihara</a><sup class="u-js-hide"><a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Hiroyuki-Seki-Aff3" data-author-popup="auth-Hiroyuki-Seki-Aff3" data-author-search="Seki, Hiroyuki">Hiroyuki Seki</a><sup class="u-js-hide"><a href="#Aff3">3</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 6 authors for this article" title="Show all 6 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Jonathan_L-Tilly-Aff1-Aff2" data-author-popup="auth-Jonathan_L-Tilly-Aff1-Aff2" data-author-search="Tilly, Jonathan L" data-corresp-id="c1">Jonathan L Tilly<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/nm" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature Medicine</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 18</b>, <span class="u-visually-hidden">pages </span>413–421 (<span data-test="article-publication-year">2012</span>)<a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">16k <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">352 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/nm.2669/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> <div class="u-js-hide" data-component="article-subject-links"> <h3 class="c-article__sub-heading">Subjects</h3> <ul class="c-article-subject-list"> <li class="c-article-subject-list__subject"><a href="/subjects/germ-cells" data-track="click" data-track-action="view subject" data-track-label="link">Germ cells</a></li><li class="c-article-subject-list__subject"><a href="/subjects/regenerative-medicine" data-track="click" data-track-action="view subject" data-track-label="link">Regenerative medicine</a></li><li class="c-article-subject-list__subject"><a href="/subjects/reproductive-biology" data-track="click" data-track-action="view subject" data-track-label="link">Reproductive biology</a></li><li class="c-article-subject-list__subject"><a href="/subjects/stem-cells" data-track="click" data-track-action="view subject" data-track-label="link">Stem cells</a></li> </ul> </div> </div> <div class="c-article-body"> <section aria-labelledby="Abs2" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs2">Abstract</h2><div class="c-article-section__content" id="Abs2-content"><p>Germline stem cells that produce oocytes <i>in vitro</i> and fertilization-competent eggs <i>in vivo</i> have been identified in and isolated from adult mouse ovaries. Here we describe and validate a fluorescence-activated cell sorting-based protocol that can be used with adult mouse ovaries and human ovarian cortical tissue to purify rare mitotically active cells that have a gene expression profile that is consistent with primitive germ cells. Once established <i>in vitro</i>, these cells can be expanded for months and can spontaneously generate 35- to 50-μm oocytes, as determined by morphology, gene expression and haploid (1<i>n</i>) status. Injection of the human germline cells, engineered to stably express GFP, into human ovarian cortical biopsies leads to formation of follicles containing GFP-positive oocytes 1–2 weeks after xenotransplantation into immunodeficient female mice. Thus, ovaries of reproductive-age women, similar to adult mice, possess rare mitotically active germ cells that can be propagated <i>in vitro</i> as well as generate oocytes <i>in vitro</i> and <i>in vivo</i>.</p></div></div></section> <noscript> <div class="c-nature-box c-nature-box--side " data-component="entitlement-box"> <div class="js-access-button"> <a href="https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fnm.2669" class="c-article__button" data-test="ra21"> <svg class="u-icon" width="18" height="18" aria-hidden="true" focusable="false"><use href="#icon-institution"></use></svg> <span class="c-article__button-text">Access through your institution</span> </a> </div> <div class="js-buy-button"> <a href="#access-options" class="c-article__button c-article__button--inverted" data-test="ra21"> <span>Buy or subscribe</span> </a> </div> </div> </noscript> <div class="js-context-bar-sticky-point-mobile" data-track-context="article body"> </div> <div 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data-test="figure" data-container-section="figure" id="figure-2"><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 2: Isolation of OSCs from adult mouse and human ovaries.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><picture><source type="image/webp" srcset="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnm.2669/MediaObjects/41591_2012_Article_BFnm2669_Fig2_HTML.jpg?as=webp"><img src="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnm.2669/MediaObjects/41591_2012_Article_BFnm2669_Fig2_HTML.jpg" alt="" loading="lazy" width="312" height="212"></picture></div></div></figure></div><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3"><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 3: Mouse OSCs generate functional eggs after intraovarian transplantation.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><picture><source type="image/webp" srcset="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnm.2669/MediaObjects/41591_2012_Article_BFnm2669_Fig3_HTML.jpg?as=webp"><img src="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fnm.2669/MediaObjects/41591_2012_Article_BFnm2669_Fig3_HTML.jpg" alt="" loading="lazy" width="312" height="199"></picture></div></div></figure></div><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4"><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 4: Evaluation of mouse- and human-ovary–derived OSCs in defined cultures.</b></figcaption><div 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Prickett-Rice and K. Folz-Donahue of the Harvard Stem Cell Institute Flow Cytometry Core Facility and J. Groeneweg for expert technical assistance. We also thank J.R. Mann and K.J. MacLaughlin for the provision of TgOG2 transgenic mice. This work was supported by a Method to Extend Research in Time (MERIT) Award from the US National Institute on Aging (NIH R37-AG012279), the Henry and Vivian Rosenberg Philanthropic Fund, the Sea Breeze Foundation and Vincent Memorial Hospital Research Funds. This work was conducted while D.C.W. was supported in part by a Ruth L. Kirschstein National Research Service Award (NIH F32-AG034809).</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><span class="c-article-author-information__subtitle u-visually-hidden" id="author-notes">Author notes</span><ol class="c-article-author-information__list"><li class="c-article-author-information__item" id="na1"><p>Yvonne A R White and Dori C Woods: These authors contributed equally to this work.</p></li></ol><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Massachusetts General Hospital Vincent Department of Obstetrics and Gynecology, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, Massachusetts, USA</p><p class="c-article-author-affiliation__authors-list">Yvonne A R White, Dori C Woods & Jonathan L Tilly</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts, USA</p><p class="c-article-author-affiliation__authors-list">Yvonne A R White, Dori C Woods & Jonathan L Tilly</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Saitama, Japan</p><p class="c-article-author-affiliation__authors-list">Yasushi Takai, Osamu Ishihara & Hiroyuki Seki</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Yvonne_A_R-White-Aff1-Aff2"><span class="c-article-authors-search__title u-h3 js-search-name">Yvonne A R White</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Yvonne%20A%20R%20White" class="c-article-button" data-track="click" data-track-action="author link - 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Y.A.R.W. and D.C.W. conducted the experiments. Y.T., O.I. and H.S. collected, cryopreserved and provided human ovarian cortical tissue. J.L.T. directed the project. All authors reviewed and approved the final manuscript for submission.</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:jtilly@partners.org">Jonathan L Tilly</a>.</p></div></div></section><section data-title="Ethics declarations"><div class="c-article-section" id="ethics-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="ethics">Ethics declarations</h2><div class="c-article-section__content" id="ethics-content"> <h3 class="c-article__sub-heading">Competing interests</h3> <p>J.L.T. declares interest in intellectual property described in US Patent 7,955,846 and is a co-founder of OvaScience, Inc., and Y.A.R.W. and D.C.W. are scientific consultants for OvaScience, Inc.</p> </div></div></section><section data-title="Supplementary information"><div class="c-article-section" id="Sec26-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec26">Supplementary information</h2><div class="c-article-section__content" id="Sec26-content"><div data-test="supplementary-info"><div id="figshareContainer" class="c-article-figshare-container" data-test="figshare-container"></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM14"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="supplementary text and figures" href="https://static-content.springer.com/esm/art%3A10.1038%2Fnm.2669/MediaObjects/41591_2012_BFnm2669_MOESM14_ESM.pdf" data-supp-info-image="">Supplementary Text and Figures</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>Supplementary Methods, Supplementary Tables 1 and 2 and Supplementary Figures 1–5 (PDF 1403 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