Molecular basis in endometrial cell differentiation induced by progesterone

2017 Fiscal Year Annual Research Report

• Project/Area Number: 16H05469
• Research Institution: The University of Tokyo
• Principal Investigator: 大須賀 穣 東京大学, 医学部附属病院, 教授 (80260496)
• Co-Investigator(Kenkyū-buntansha): 廣田 泰 東京大学, 医学部附属病院, 講師 (40598653) ; 平池 修 東京大学, 医学部附属病院, 准教授 (20529060) ; 甲賀 かをり 東京大学, 医学部附属病院, 准教授 (10396723) ; 平田 哲也 東京大学, 医学部附属病院, 講師 (30431860) ; 原田 美由紀 東京大学, 医学部附属病院, 講師 (70451812)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 妊娠 / 子宮 / プロゲステロン / 細胞老化 / リモデリング / マクロファージ

Outline of Annual Research Achievements

老化細胞は生理的に妊娠子宮に出現することが知られており、分娩後も子宮に存在することが考えられる。老化細胞の独特の性質を考えると、老化細胞の除去は産褥子宮の機能回復に重要であることが推測される。しかし、産褥子宮における老化細胞の動態や、それが過剰に蓄積した際の子宮機能障害の詳細は明らかになっていない。本研究では、産褥子宮における老化細胞の挙動とその除去機構を検討した。老化細胞は産褥子宮間質に存在し、徐々に減少して分娩後約1か月で消失した。また、Cd11b陽性細胞、NK細胞、T細胞、及び好中球は産褥子宮に認められなかった一方で、F4/80陽性マクロファージが老化細胞周囲に集積し、老化細胞のクリアランスを促進していることが示された。さらに、産褥子宮に老化細胞が過剰に蓄積するマウスモデルを用いて、老化細胞の過剰な蓄積を引き起こす子宮内微小環境の詳細を解析した。LPS誘導性早産p53-loxP/Pgr-Creマウス子宮では老化細胞のクリアランスの遅延、F4/80陽性マクロファージの減少、分娩直後の妊娠率の顕著な低下、向炎症因子の発現増加、プロゲステロン・シグナリングの亢進とエストロゲン・シグナリングの減弱が認められた。本研究により、産褥子宮には老化細胞が存在し、F4/80陽性マクロファージによって除去されること、子宮内に老化細胞が過剰に蓄積することにより妊娠障害が誘起されるほか、子宮内の炎症やプロゲステロン・シグナリング減弱によって老化細胞除去機構の障害が引き起こされることが示唆された。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

マウスおよびヒト検体を用いた研究が順調に行われており、その成果として本年度はプロジェクトに関連した論文を複数の英文誌に発表することができた。これらの成果をさらに発展させ、最終年度の研究進展が期待できる。

Strategy for Future Research Activity

順調に進展し成果を上げているため、今後の研究は進展が認められる研究計画を中心に進める予定とする。

Research Products

• [Journal Article] Activation of Nrf2 might reduce oxidative stress in human granulosa cells (2018)
  • Author(s): Akino Nana、Wada-Hiraike Osamu、Terao Hiromi、Honjoh Harunori、Isono Wataru、Fu Houju、Hirano Mana、Miyamoto Yuichiro、Tanikawa Michihiro、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Koga Kaori、Oda Katsutoshi、Kawana Kei、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Mol Cell Endocrinol Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1016/j.mce.2017.10.002
  • Peer Reviewed
• [Journal Article] ジエノゲストの子宮腺筋症患者における臨床評価 - 多施設共同ランダム化プラセボ対照二重盲検並行群間用量反応比較試験 - (2017)
  • Author(s): 大須賀穣, 渡邉学, 萩野篤司
  • Journal Title: 薬理と治療 Volume: 45 Pages: 907～920
  • Peer Reviewed
• [Journal Article] Oil-Soluble Contrast Medium (OSCM) for Hysterosalpingography Modulates Dendritic Cell and Regulatory T Cell Profiles in the Peritoneal Cavity: A Possible Mechanism by Which OSCM Enhances Fertility (2017)
  • Author(s): Izumi Gentaro、Koga Kaori、Takamura Masashi、Bo Wang、Nagai Miwako、Miyashita Mariko、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Yoshino Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: J Immunol Volume: 198 Pages: 4277～4284
  • DOI: 10.4049/jimmunol.1600498
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] F4/80+ Macrophages Contribute to Clearance of Senescent Cells in the Mouse Postpartum Uterus (2017)
  • Author(s): Egashira Mahiro、Hirota Yasushi、Shimizu-Hirota Ryoko、Saito-Fujita Tomoko、Haraguchi Hirofumi、Matsumoto Leona、Matsuo Mitsunori、Hiraoka Takehiro、Tanaka Tomoki、Akaeda Shun、Takehisa Chiaki、Saito-Kanatani Mayuko、Maeda Kei-ichiro、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Endocrinology Volume: 158 Pages: 2344～2353
  • DOI: 10.1210/en.2016-1886
  • Peer Reviewed
• [Journal Article] Autotaxin‐lysophosphatidic acid‐LPA3 signaling at the embryo‐epithelial boundary controls decidualization pathways (2017)
  • Author(s): Aikawa Shizu、Kano Kuniyuki、Inoue Asuka、Wang Jiao、Saigusa Daisuke、Nagamatsu Takeshi、Hirota Yasushi、Fujii Tomoyuki、Tsuchiya Soken、Taketomi Yoshitaka、Sugimoto Yukihiko、Murakami Makoto、Arita Makoto、Kurano Makoto、Ikeda Hitoshi、Yatomi Yutaka、Chun Jerold、Aoki Junken
  • Journal Title: EMBO J Volume: 36 Pages: 2146～2160
  • DOI: 10.15252/embj.201696290
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nomenclature of primary amenorrhea: A proposal document of the Japan Society of Obstetrics and Gynecology committee for the redefinition of primary amenorrhea (2017)
  • Author(s): Shozu Makio、Ishikawa Hiroshi、Horikawa Reiko、Sakakibara Hideya、Izumi Shun-ichiro、Ohba Takashi、Hirota Yasushi、Ogata Tsutomu、Osuga Yutaka、Kugu Koji
  • Journal Title: J Obstet Gynaecol Res Volume: 43 Pages: 1738～1742
  • DOI: 10.1111/jog.13442
  • Peer Reviewed
• [Journal Article] Activation of Endoplasmic Reticulum Stress in Granulosa Cells from Patients with Polycystic Ovary Syndrome Contributes to Ovarian Fibrosis (2017)
  • Author(s): Takahashi Nozomi、Harada Miyuki、Hirota Yasushi、Nose Emi、Azhary Jerilee MK、Koike Hiroshi、Kunitomi Chisato、Yoshino Osamu、Izumi Gentaro、Hirata Tetsuya、Koga Kaori、Wada-Hiraike Osamu、Chang R. Jeffrey、Shimasaki Shunichi、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Sci Rep Volume: 7 Pages: 10824
  • DOI: 10.1038/s41598-017-11252-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced HIF2α expression during human trophoblast differentiation into syncytiotrophoblast suppresses transcription of placental growth factor (2017)
  • Author(s): Fujii Tatsuya、Nagamatsu Takeshi、Morita Kazuki、Schust Danny J.、Iriyama Takayuki、Komatsu Atsushi、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: Sci Rep Volume: 7 Pages: 12455
  • DOI: 10.1038/s41598-017-12685-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of the efficacy and safety of dienogest in the treatment of painful symptoms in patients with adenomyosis: a randomized, double-blind, multicenter, placebo-controlled study (2017)
  • Author(s): Osuga Yutaka、Fujimoto-Okabe Haruka、Hagino Atsushi
  • Journal Title: Fertil Steril Volume: 108 Pages: 673～678
  • DOI: 10.1016/j.fertnstert.2017.07.021
  • Peer Reviewed
• [Journal Article] Long-term use of dienogest in the treatment of painful symptoms in adenomyosis (2017)
  • Author(s): Osuga Yutaka、Watanabe Manabu、Hagino Atsushi
  • Journal Title: J Obstet Gynaecol Res Volume: 43 Pages: 1441～1448
  • DOI: 10.1111/jog.13406
  • Peer Reviewed
• [Journal Article] Development of endometrioma after cervical conization (2017)
  • Author(s): Takahashi Nozomi、Koga Kaori、Arakawa Ichiro、Harada Miyuki、Oda Katsutoshi、Kawana Kei、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Gynecol Endocrinol Volume: 34 Pages: 1～4
  • DOI: 10.1080/09513590.2017.1393660
  • Peer Reviewed
• [Journal Article] Drospirenone reduces inflammatory cytokines, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) expression in human endometriotic stromal cells (2017)
  • Author(s): Makabe Tomoko、Koga Kaori、Miyashita Mariko、Takeuchi Arisa、Sue Fusako、Taguchi Ayumi、Urata Yoko、Izumi Gentaro、Takamura Masashi、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Wada-Hiraike Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: J Reprod Immunol Volume: 119 Pages: 44～48
  • DOI: 10.1016/j.jri.2016.12.002
  • Peer Reviewed
• [Presentation] STAT3: A Key Transcriptional Factor Not Only in Embryo Implantation but also in Endometrial Regeneration (2018)
  • Author(s): Yasushi Hirota
  • Organizer: Society for Reproductive Investigation, 65th Annual Scientific Meeting, Endometrium Satellite Meeting
  • Int'l Joint Research / Invited
• [Presentation] Levonorgestrel Inhibits Embryo Implantation by Downregulation of Uterine LIF Expression (2018)
  • Author(s): Mitsunori Matsuo, Yasushi Hirota, Tomoko Saito-Fujita, Hirofumi Haraguchi, Shota Igaue, Leona Matsumoto, Takehiro Hiraoka, Shun Akaeda, Tomoki Tanaka, Tomoyuki Fujii, Yutaka Osuga
  • Organizer: Society for Reproductive Investigation, 65th Annual Scientific Meeting
  • Int'l Joint Research
• [Presentation] Diet and Supplements for Endometriosis (2017)
  • Author(s): Yutaka Osuga
  • Organizer: 6 th Asian Congress of Endometriosis
  • Int'l Joint Research / Invited
• [Presentation] Novel immune mechanism in the development of endometriosis (2017)
  • Author(s): Yutaka Osuga
  • Organizer: 19th World Congress on In Vitro Fertilization in conjunction with VI. Society of Reproductive Medicine and Surgery Congress
  • Int'l Joint Research / Invited
• [Presentation] Novel strategies for ART in patients with endometriosis, adenomyosis, and uterine fibroid. (2017)
  • Author(s): Yutaka Osuga
  • Organizer: The 11th Congress of the Pacific Society for Reproductive Medicine
  • Int'l Joint Research / Invited
• [Presentation] Current problems in infertile women associated with endometriosis. (2017)
  • Author(s): Yutaka Osuga
  • Organizer: 7th Congress of the Asia Pacific Initiative on Reproduction
  • Int'l Joint Research / Invited
• [Presentation] Results from a phase 2 study of Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, VS. placebo in women with endometriosis-associated pain. (2017)
  • Author(s): Yutaka Osuga
  • Organizer: World Congress of Endometriosis 2017
  • Int'l Joint Research / Invited
• [Presentation] Activated IL6-STAT3 pathway in adenomyosis (2017)
  • Author(s): Yasushi Hirota、Takehiro Hiraoka、Tomoko Saito-Fujita、Tomoyuki Fujii、Yutaka Osuga
  • Organizer: World Congress of Endometriosis 2017
  • Int'l Joint Research / Invited
• [Presentation] Uterine hypoxia inducible factor contributes to blastocyst invasion by clearance of luminal epithelium at the site of blastocyst attachment (2017)
  • Author(s): Yasushi Hirota, Tomoko Saito-Fujita, Leona Matsumoto, Hirofumi HaraguchiMitsunori Matsuo, Takehiro Hiraoka, Shun Akaeda, Tomoki Tanaka, Norihiko Takeda, Yutaka Osuga, Tomoyuki Fujii
  • Organizer: Society for the Study of Reproduction, 50th Annual Meeting
  • Int'l Joint Research
• [Presentation] Medical and Surgical Treatment in Adenomyosis (2017)
  • Author(s): Yasushi Hirota
  • Organizer: 18th APAGE Annual Congress 2017
  • Int'l Joint Research / Invited