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Molecular Analysis of Spermatogonial Stem Cell Aging

Research Project

Project/Area Number 18H05281
Research Category

Grant-in-Aid for Scientific Research (S)

Allocation TypeSingle-year Grants
Review Section Broad Section I
Research InstitutionKyoto University

Principal Investigator

Shinohara Takashi  京都大学, 医学研究科, 教授 (30322770)

Project Period (FY) 2018-06-11 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥193,440,000 (Direct Cost: ¥148,800,000、Indirect Cost: ¥44,640,000)
Fiscal Year 2022: ¥37,960,000 (Direct Cost: ¥29,200,000、Indirect Cost: ¥8,760,000)
Fiscal Year 2021: ¥37,960,000 (Direct Cost: ¥29,200,000、Indirect Cost: ¥8,760,000)
Fiscal Year 2020: ¥37,960,000 (Direct Cost: ¥29,200,000、Indirect Cost: ¥8,760,000)
Fiscal Year 2019: ¥37,960,000 (Direct Cost: ¥29,200,000、Indirect Cost: ¥8,760,000)
Fiscal Year 2018: ¥41,600,000 (Direct Cost: ¥32,000,000、Indirect Cost: ¥9,600,000)
Keywords精子形成 / 顕微授精 / 老化 / 幹細胞 / 精子幹細胞
Outline of Final Research Achievements

We found that spermatogonial stem cells use glutamine for producing glutathione to protect themselves from damages by reactive oxygen species (ROS) produced by Nox1. They also possess stronger base excision repair activity than embryonic stem cells or somatic cells to minimize mutations. We also discovered that ROS induce Nox1 expression via translocation of BCL6B into the nucleus, which creates a postive feedback loop. In the course of our study to analyze the impact of long-term SSC culture, we accidentally found that in vitro fertilization and intrancytoplasmic sperm injection, both of which are widely used for human infertility treatment, can cause implantation failure and congenital abnormalities in F2 offspring.

Academic Significance and Societal Importance of the Research Achievements

現在、我が国では14人に一人が生殖補助医療により生まれている。特に顕微授精はウサギ2匹、ウシ1匹が生まれたのみで臨床応用されたことからヒトに対する十分な安全性は検討されていない。今回の研究により我々が得た精子幹細胞のもつ強い老化抵抗性の分子機構の知見は今後の臨床応用に有益なものであるが、その応用を進める一方で現在の生殖補助医療の安全性に対する再検討を呼びかける必要がある。

Assessment Rating
Ex-post Assessment Comments (Rating)

A: In light of the aim of introducing the research area into the research categories, expected outcomes of research have been produced.

Assessment Rating
Interim Assessment Comments (Rating)

A: In light of the aim of introducing the research area into the research categories, the expected progress has been made in research.

Report

(11 results)
  • 2023 Ex-post Assessment (Comments) ( PDF )
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Abstract (Interim Assessment) ( PDF )   Annual Research Report   Interim Assessment (Comments) ( PDF )
  • 2019 Annual Research Report
  • 2018 Abstract ( PDF )   Comments on the Screening Results ( PDF )   Annual Research Report
  • Research Products

    (28 results)

All 2023 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (17 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 17 results,  Open Access: 12 results) Presentation (8 results) (of which Int'l Joint Research: 3 results,  Invited: 7 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 2 results)

  • [Int'l Joint Research] ピッツバーグ大学(米国)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Glutamine protects mouse spermatogonial stem cells against NOX1-derived ROS for sustaining self-renewal division in vitro.2023

    • Author(s)
      Miyazaki T, Kanatsu-Shinohara M, Ogonuki N, Matoba S, Ogura A, Yabe-Nishimura C, Zhang H, Pommier Y, Trumpp A, Shinohara T.
    • Journal Title

      Development

      Volume: 150 Issue: 20

    • DOI

      10.1242/dev.201157

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Adenovirus-mediated gene delivery restores fertility in congenitally infertile female mice2022

    • Author(s)
      Kanatsu-Shinohara M, Lee J, Miyazaki T, Morimoto H, Shinohara T.
    • Journal Title

      Journal of Reproduction and Development

      Volume: 68 Issue: 6 Pages: 369-376

    • DOI

      10.1262/jrd.2022-090

    • ISSN
      0916-8818, 1348-4400
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulation of male germline transmission patterns by the Trp53-Cdkn1a pathway2022

    • Author(s)
      Kanatsu-Shinohara Mito、Naoki Honda、Tanaka Takashi、Tatehana Misako、Kikkawa Takako、Osumi Noriko、Shinohara Takashi
    • Journal Title

      Stem Cell Reports

      Volume: 17 Issue: 9 Pages: 1924-1941

    • DOI

      10.1016/j.stemcr.2022.07.007

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adeno-associated-virus-mediated gene delivery to ovaries restores fertility in congenital infertile mice.2022

    • Author(s)
      Kanatsu-Shinohara M, Lee J, Miyazaki T, Morimoto H, Shinohara T.
    • Journal Title

      Cell Rep Med

      Volume: 3 Issue: 5 Pages: 100606-100606

    • DOI

      10.1016/j.xcrm.2022.100606

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Spermatogonial stem cell transplantation into nonablated mouse recipient testes2022

    • Author(s)
      Hiroko Morimoto, Narumi Ogonuki, Mito Kanatsu-Shinohara , Shogo Matoba , Atsuo Ogura , Takashi Shinohara
    • Journal Title

      Stem cell reports

      Volume: 16 Issue: 7 Pages: 1832-1844

    • DOI

      10.1016/j.stemcr.2021.05.013

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genomic stability of mouse spermatogonial stem cells in vitro.2021

    • Author(s)
      Chuma S, Kanatsu-Shinohara M, Katanaya A, Hosokawa M, Shinohara T.
    • Journal Title

      Sci Rep

      Volume: 11 Issue: 1 Pages: 24199-24199

    • DOI

      10.1038/s41598-021-03658-1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cdc42 is required for male germline niche development in mice.2021

    • Author(s)
      Mori Y, Takashima S, Kanatsu-Shinohara M, Yi Z, Shinohara T.
    • Journal Title

      Cell Rep

      Volume: 36 Issue: 7 Pages: 109550-109550

    • DOI

      10.1016/j.celrep.2021.109550

    • NAID

      120007141735

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] OGG1 protects mouse spermatogonial stem cells from reactive oxygen species in culture2021

    • Author(s)
      Mori Y, Ogonuki N, Hasegawa A, Kanatsu-Shinohara M, Ogura A, Wang Y, McCarrey JR, Shinohara T.
    • Journal Title

      Biol Reprod

      Volume: 104 Issue: 3 Pages: 706-716

    • DOI

      10.1093/biolre/ioaa216

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] An interplay of NOX1-derived ROS and oxygen determines the spermatogonial stem cell self-renewal efficiency under hypoxia.2021

    • Author(s)
      Hiroko Morimoto, Takuya Yamamoto, Takehiro Miyazaki, Harumi Ogonuki, Atsuo Ogura, Takashi Tanaka, Mito Kanatsu-Shinohara , Chihiro Yabe-Nishimura, Hongliang Zhang, Yves Pommier, Andreas Trumpp, Takashi Shinohara
    • Journal Title

      Genes Dev.

      Volume: 35(3-4) Issue: 3-4 Pages: 250-260

    • DOI

      10.1101/gad.339903.120

    • NAID

      120006951673

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CD2 is a surface marker for mouse and rat spermatogonial stem cells.2020

    • Author(s)
      Kanatsu-Shinohara M, Chen G, Morimoto H, Shinohara T.
    • Journal Title

      J Reprod Dev.

      Volume: Mar 26. Issue: 4 Pages: 1-32

    • DOI

      10.1262/jrd.2020-019

    • NAID

      130007888738

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression and functional analyses of EPHA2 in mouse spermatogonial stem cells.2020

    • Author(s)
      Morimoto, H., Kanatsu-Shinohara, M., Orwig, K. E. and Shinohara, T.
    • Journal Title

      Biol. Reprod.

      Volume: 102 Issue: 1 Pages: 220-232

    • DOI

      10.1093/biolre/ioz156

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Transgenesis and genome editing of mouse spermatogonial stem cells by lentivirus pseudotyped with Sendai virus F protein.2020

    • Author(s)
      Shinohara, T. and Kanatsu-Shinohara, M.
    • Journal Title

      Stem Cell Reports

      Volume: 14 Issue: 3 Pages: 447-461

    • DOI

      10.1016/j.stemcr.2020.02.001

    • NAID

      120006936408

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ROS amplification drives mouse spermatogonial stem cell self-renewal.2019

    • Author(s)
      Morimoto H, Kanatsu-Shinohara M, Ogonuki N, Kamimura S, Ogura A, Yabe-Nishimura C, Mori Y, Morimoto T, Watanabe S, Otsu K, Yamamoto T, *Shinohara T.
    • Journal Title

      Life Sci Alliance

      Volume: 2 Issue: 2 Pages: 2-2

    • DOI

      10.26508/lsa.201900374

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation.2019

    • Author(s)
      Kanatsu-Shinohara, M., Yamamoto, T., Toh, H., Kazuki, Y., Kazuki, K., Imoto, J., Ikeo, K., Oshima, M., Shirahige, K., Iwama, A., Nabeshima, Y., Sasaki, H. and Shinohara, T.
    • Journal Title

      PNAS

      Volume: 116 Issue: 33 Pages: 16404-16409

    • DOI

      10.1073/pnas.1904980116

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sendai virus-mediated transduction of mammalian spermatogonial stem cells.2019

    • Author(s)
      Watanabe S., Kanatsu-Shinohara, M., Shinohara T.
    • Journal Title

      Biol. Reprod.

      Volume: 100 Issue: 2 Pages: 523-534

    • DOI

      10.1093/biolre/ioy192

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Reversible inhibition of the blood-testis barrier protein improves stem cell homing in mouse testes2018

    • Author(s)
      Kanatsu-Shinohara M, Morimoto H, Watanabe S, Shinohara T.
    • Journal Title

      Journal of Reproduction and Development

      Volume: 64 Issue: 6 Pages: 511-522

    • DOI

      10.1262/jrd.2018-093

    • NAID

      130007530501

    • ISSN
      0916-8818, 1348-4400
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] In vivo genetic manipulateon of spermatogonial stem cells and their microenvironment by adeno-associated viruses.2018

    • Author(s)
      Watanabe S., Kanatsu-Shinohara, M., Ogonuki N., Matoba S., Ogura A., Shinohara T.
    • Journal Title

      Stem Cell Reports

      Volume: S2213-6711 (18) Issue: 5 Pages: 30132-2

    • DOI

      10.1016/j.stemcr.2018.03.005

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 不妊症の遺伝子治療2022

    • Author(s)
      篠原隆司
    • Organizer
      生殖細胞と減数分裂研究の過去、現在、未来"およびサテライトシンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 不妊症の遺伝子治療2021

    • Author(s)
      篠原隆司
    • Organizer
      理研バイオリソースセンター設立20周年記念シンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Effect of spermatogonial manipulation on offspring2021

    • Author(s)
      Takashi Shinohara
    • Organizer
      Molecular and cellular mechanisms of brain systems generating individuality
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 宇宙環境が精子幹細胞に及ぼす影響についての解析2019

    • Author(s)
      篠原隆司
    • Organizer
      日本宇宙生物科学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 精子幹細胞の老化メカニズム2019

    • Author(s)
      篠原隆司
    • Organizer
      若手支援技術講習会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Aging of spermatogonial stem cells. Long Lie spermatogonial stem cells!2019

    • Author(s)
      Takashi Shinohara
    • Organizer
      Brinster Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 精子幹細胞の移植による妊孕性の回復2019

    • Author(s)
      篠原隆司
    • Organizer
      日本アンドロロジー学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Tight junction and the fate of transplanted spermatogonial stem cells2018

    • Author(s)
      Takashi Shinohara
    • Organizer
      Gordon research conference on Mammalian Reproduction
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Patent(Industrial Property Rights)] 1.Method of introducing polynucleotide into cell in testis2019

    • Inventor(s)
      篠原隆司、渡邉哲史
    • Industrial Property Rights Holder
      篠原隆司、渡邉哲史
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-004529
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 雄性生殖細胞またはセルトリ細胞にポリヌクレオチドを導入する方法2019

    • Inventor(s)
      篠原隆司、渡邉哲史
    • Industrial Property Rights Holder
      京都大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2018 Annual Research Report
    • Overseas

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Published: 2018-06-12   Modified: 2024-03-28  

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