Mechano-bio system in the uterus

• Project/Area Number: 19H03796
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Osuga Yutaka 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, 准教授 (40598653) ; 甲賀 かをり 東京大学, 医学部附属病院, 病院診療医(出向) (10396723) ; 平池 修 東京大学, 医学部附属病院, 准教授 (20529060) ; 原田 美由紀 東京大学, 医学部附属病院, 准教授 (70451812) ; 平田 哲也 東京大学, 医学部附属病院, 届出研究員 (30431860)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 胚着床 / 着床不全 / マウスモデル / 胚接着 / 胚浸潤 / LIF-STAT3 / HIF / EZH2-PRC2-H3K27me3 / 着床 / 子宮内膜 / EZH2 / ヒストン修飾 / 着床能 / バイオマーカー / 子宮 / メカニカルストレス / シネMRI / 3次元培養 / RB / STAT3 / 上皮 / 間質 / ネクロトーシス / 細胞増殖 / LIF / 黄体ホルモン

Outline of Research at the Start

本研究では、子宮内膜細胞を三次元培養し、種々の自発的内部力学場および動的な外部力学刺激を与えた上で、受精卵を接着浸潤させる着床モデルへの影響を解析し、メカノバイオロジーの観点からの着床の機序およびその異常によって起こる不妊のメカニズムを解明することを目的とする。本研究は、メカノバイオロジーの観点からの不妊メカニズム解析を行い、着床障害の診断・治療や避妊法の開発という臨床応用のための学術的基盤創出につながるものとして期待できる。

Outline of Final Research Achievements

Embryo implantation is established through the process of embryo attachment and embryo invasion. This study revealed the following findings:
(1) High-dose progestin induces a decrease in endometrial LIF and impairs embryo attachment. (2) STAT3, a transcription factor downstream of LIF, regulates different pathways in the endometrial epithelium and stroma to regulate embryo attachment. (3) HIF2a in the endometrial stroma induces epithelial detachment from the stroma and governs embryo invasion. (4) EZH2-PRC2-H3K27me3 pathway epigenetically regulating gene transcription controls embryo invasion through the cell cycle and the terminal differentiation of the endometrial stroma. These findings newly clarified the detail mechanisms of embryo implantation.

Academic Significance and Societal Importance of the Research Achievements

受精卵（胚）が子宮内膜へ生着する着床という妊娠開始の現象が成立する仕組みは未だ不明のままであり、生殖医療という臨床的な観点だけでなく基礎生物学・発生学の観点からも研究が必要とされていた。本研究では、マウスモデルやヒト臨床検体を用いて、不妊症のうち、胚移植の反復不成功で定義される着床不全が起こる機序を示すことができた。研究を通じて、新たな着床不全の診断法・治療法や新たな避妊法の開発のための学術的基盤を確立することができた。

Research Products

• [Journal Article] A gene network of uterine luminal epithelium organizes mouse blastocyst implantation (2022)
  • Author(s): Aikawa Shizu、Hirota Yasushi、Fukui Yamato、Ishizawa Chihiro、IIda Rei、Kaku Tetsuaki、Hirata Tomoyuki、Akaeda Shun、Hiraoka Takehiro、Matsuo Mitsunori、Osuga Yutaka
  • Journal Title: Reproductive Medicine and Biology Volume: 21 Issue: 1
  • DOI: 10.1002/rmb2.12435
  • Peer Reviewed / Open Access
• [Journal Article] Constant Activation of STAT3 Contributes to the Development of Adenomyosis in Females (2022)
  • Author(s): Hiraoka Takehiro、Hirota Yasushi、Aikawa Shizu、Iida Rei、Ishizawa Chihiro、Kaku Tetsuaki、Hirata Tomoyuki、Fukui Yamato、Akaeda Shun、Matsuo Mitsunori、Shimizu-Hirota Ryoko、Takeda Norihiko、Osuga Yutaka
  • Journal Title: Endocrinology Volume: 163 Issue: 5
  • DOI: 10.1210/endocr/bqac044
  • Peer Reviewed
• [Journal Article] Establishment of a novel mouse model of adenomyosis suitable for longitudinal and quantitative analysis and perinatal outcome studies (2022)
  • Author(s): Elsherbini Mohammed、Koga Kaori、Hiraoka Takehiro、Kumasawa Keiichi、Maki Eiko、Satake Erina、Taguchi Ayumi、Makabe Tomoko、Takeuchi Arisa、Izumi Gentaro、Takamura Masashi、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Wada-Hiraike Osamu、Osuga Yutaka
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 1-1
  • DOI: 10.1038/s41598-022-22413-8
  • Peer Reviewed / Open Access
• [Journal Article] Uterine Epithelial LIF Receptors Contribute to Implantation Chamber Formation in Blastocyst Attachment (2021)
  • Author(s): Fukui Yamato、Hirota Yasushi、Saito-Fujita Tomoko、Aikawa Shizu、Hiraoka Takehiro、Kaku Tetsuaki、Hirata Tomoyuki、Akaeda Shun、Matsuo Mitsunori、Shimizu-Hirota Ryoko、Takeda Norihiko、Ikawa Masahito、Osuga Yutaka
  • Journal Title: Endocrinology Volume: 162 Issue: 11
  • DOI: 10.1210/endocr/bqab169
  • Peer Reviewed
• [Journal Article] Uterine Receptivity is Reflected by LIF Expression in the Cervix (2021)
  • Author(s): Fukui Yamato、Hirota Yasushi、Aikawa Shizu、Ishizawa Chihiro、Iida Rei、Kaku Tetsuaki、Hirata Tomoyuki、Akaeda Shun、Hiraoka Takehiro、Matsuo Mitsunori、Osuga Yutaka
  • Journal Title: Reproductive Sciences Volume: 29 Issue: 5 Pages: 1457-1462
  • DOI: 10.1007/s43032-021-00816-8
  • Peer Reviewed
• [Journal Article] Temporal relationship between alterations in the gut microbiome and the development of polycystic ovary syndrome‐like phenotypes in prenatally androgenized female mice (2021)
  • Author(s): Kusamoto Akari、Harada Miyuki、Azhary Jerilee M. K.、Kunitomi Chisato、Nose Emi、Koike Hiroshi、Xu Zixin、Urata Yoko、Kaku Tetsuaki、Takahashi Nozomi、Wada‐Hiraike Osamu、Hirota Yasushi、Koga Kaori、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: The FASEB Journal Volume: 35 Issue: 11
  • DOI: 10.1096/fj.202101051r
  • Peer Reviewed
• [Journal Article] Assisted reproductive technology in Japan: A summary report for 2019 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology (2021)
  • Author(s): Katagiri Yukiko、Jwa Seung Chik、Kuwahara Akira、Iwasa Takeshi、Ono Masanori、Kato Keiichi、Kishi Hiroshi、Kuwabara Yoshimitsu、Harada Miyuki、Hamatani Toshio、Osuga Yutaka
  • Journal Title: Reproductive Medicine and Biology Volume: 21 Issue: 1
  • DOI: 10.1002/rmb2.12434
  • Peer Reviewed / Open Access
• [Journal Article] Retinoblastoma protein promotes uterine epithelial cell cycle arrest and necroptosis for embryo invasion (2021)
  • Author(s): Akaeda Shun、Hirota Yasushi、Fukui Yamato、Aikawa Shizu、Shimizu‐Hirota Ryoko、Kaku Tetsuaki、Gebril Mona、Hirata Tomoyuki、Hiraoka Takehiro、Matsuo Mitsunori、Haraguchi Hirofumi、Saito‐Kanatani Mayuko、Takeda Norihiko、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: EMBO reports Volume: 22 Issue: 2
  • DOI: 10.15252/embr.202050927
  • Peer Reviewed / Open Access
• [Journal Article] CD206+?macrophage is an accelerator of endometriotic-like lesion via promoting angiogenesis in the endometriosis mouse model (2021)
  • Author(s): Ono Yosuke、Yoshino Osamu、Hiraoka Takehiro、Sato Erina、Furue Akiko、Nawaz Allah、Hatta Hideki、Fukushi Yoshiyuki、Wada Shinichiro、Tobe Kazuyuki、Hirota Yasushi、Osuga Yutaka、Unno Nobuya、Saito Shigeru
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 853-853
  • DOI: 10.1038/s41598-020-79578-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD206+ M2-like Macrophages are Essential for Successful Implantation. (2020)
  • Author(s): Ono Y, Yoshino O, Ushijima A, Hiraoka T, Fukui Y, Nawaz A, Hirota Y, Wada S, Tobe K, Nakashima A, Osuga Y and Saito S.
  • Journal Title: Front Immunol. Volume: 11 Pages: 557184-557184
  • DOI: 10.3389/fimmu.2020.557184
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Uterine Epithelial Progesterone Receptor Governs Uterine Receptivity Through Epithelial Cell Differentiation (2020)
  • Author(s): Gebril Mona、Hirota Yasushi、Aikawa Shizu、Fukui Yamato、Kaku Tetsuaki、Matsuo Mitsunori、Hirata Tomoyuki、Akaeda Shun、Hiraoka Takehiro、Shimizu-Hirota Ryoko、Takeda Norihiko、Taha Tamer、Balah Osama Al、Elnoury Mohamed Amr H、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Endocrinology Volume: 161 Issue: 12 Pages: 12-12
  • DOI: 10.1210/endocr/bqaa195
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differential roles of uterine epithelial and stromal STAT3 coordinate uterine receptivity and embryo attachment (2020)
  • Author(s): Hiraoka Takehiro、Hirota Yasushi、Fukui Yamato、Gebril Mona、Kaku Tetsuaki、Aikawa Shizu、Hirata Tomoyuki、Akaeda Shun、Matsuo Mitsunori、Haraguchi Hirofumi、Saito-Kanatani Mayuko、Shimizu-Hirota Ryoko、Takeda Norihiko、Yoshino Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 15523-15523
  • DOI: 10.1038/s41598-020-72640-0
  • Peer Reviewed / Open Access
• [Journal Article] Acquired contractile ability in human endometrial stromal cells by passive loading of cyclic tensile stretch (2020)
  • Author(s): Kim Jeonghyun、Ushida Takashi、Montagne Kevin、Hirota Yasushi、Yoshino Osamu、Hiraoka Takehiro、Osuga Yutaka、Furuakwa Katsuko S.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 9014-9014
  • DOI: 10.1038/s41598-020-65884-3
  • Peer Reviewed / Open Access
• [Journal Article] KRAS mutations in uterine endometrium are associated with gravidity and parity. (2020)
  • Author(s): Inoue, S., Yoshida, E., Fukui, Y., Ueno, T., Kawazu, M., Takeyama, R., Ikemura, M., Osuga, Y., Terao, Y., Hirota, Y., Mano, H.
  • Journal Title: Cell Death Disease Volume: 11 Issue: 5 Pages: 347-347
  • DOI: 10.1038/s41419-020-2559-0
  • Peer Reviewed / Open Access
• [Journal Article] Androgens Increase Accumulation of Advanced Glycation End Products in Granulosa Cells by Activating ER Stress in PCOS (2020)
  • Author(s): Azhary Jerilee M K、Harada Miyuki、Kunitomi Chisato、Kusamoto Akari、Takahashi Nozomi、Nose Emi、Oi Nagisa、Wada-Hiraike Osamu、Urata Yoko、Hirata Tetsuya、Hirota Yasushi、Koga Kaori、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Endocrinology Volume: 161 Issue: 2 Pages: 1-13
  • DOI: 10.1210/endocr/bqaa015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ASK1 promotes uterine inflammation leading to pathological preterm birth (2020)
  • Author(s): Yoshikawa Midori、Iriyama Takayuki、Suzuki Kensuke、Sayama Seisuke、Tsuruga Tetsushi、Kumasawa Keiichi、Nagamatsu Takeshi、Homma Kengo、Naguro Isao、Osuga Yutaka、Ichijo Hidenori、Fujii Tomoyuki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1887-1887
  • DOI: 10.1038/s41598-020-58653-9
  • Peer Reviewed / Open Access
• [Journal Article] Levonorgestrel Inhibits Embryo Attachment by Eliminating Uterine Induction of Leukemia Inhibitory Factor (2019)
  • Author(s): Matsuo Mitsunori、Hirota Yasushi、Fukui Yamato、Fujita Hidetoshi、Saito-Fujita Tomoko、Kaku Tetsuaki、Gebril Mona、Hirata Tomoyuki、Akaeda Shun、Hiraoka Takehiro、Tanaka Tomoki、Haraguchi Hirofumi、Saito-Kanatani Mayuko、Shimizu-Hirota Ryoko、Takeda Norihiko、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Endocrinology Volume: 161 Issue: 2
  • DOI: 10.1210/endocr/bqz005
  • Peer Reviewed / Open Access
• [Journal Article] Activation of endoplasmic reticulum stress mediates oxidative stress?induced apoptosis of granulosa cells in ovaries affected by endometrioma (2019)
  • Author(s): Kunitomi Chisato、Harada Miyuki、Takahashi Nozomi、Azhary Jerilee M K、Kusamoto Akari、Nose Emi、Oi Nagisa、Takeuchi Arisa、Wada-Hiraike Osamu、Hirata Tetsuya、Hirota Yasushi、Koga Kaori、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Molecular Human Reproduction Volume: 26 Issue: 1 Pages: 40-52
  • DOI: 10.1093/molehr/gaz066
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Uterine receptivity, embryo attachment, and embryo invasion: Multistep processes in embryo implantation (2019)
  • Author(s): Fukui Yamato、Hirota Yasushi、Matsuo Mitsunori、Gebril Mona、Akaeda Shun、Hiraoka Takehiro、Osuga Yutaka
  • Journal Title: Reproductive Medicine and Biology Volume: 18 Issue: 3 Pages: 234-240
  • DOI: 10.1002/rmb2.12280
  • Peer Reviewed / Open Access
• [Journal Article] A survey of public attitudes toward uterus transplantation, surrogacy, and adoption in Japan (2019)
  • Author(s): Nakazawa Akari、Hirata Tetsuya、Arakawa Tomoko、Nagashima Natsuki、Fukuda Shinya、Neriishi Kazuaki、Harada Miyuki、Hirota Yasushi、Koga Kaori、Wada-Hiraike Osamu、Koizumi Yoshio、Fujii Tomoyuki、Irahara Minoru、Osuga Yutaka
  • Journal Title: PLOS ONE Volume: 14 Issue: 10 Pages: 0223571-0223571
  • DOI: 10.1371/journal.pone.0223571
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations (2019)
  • Author(s): Inoue Satoshi、Hirota Yasushi、Ueno Toshihide、十人省略、Tanaka Yosuke、Sakata Seiji、Takeuchi Kengo、Muraoka Ayako、Osuka Satoko、Saito Tsuyoshi、Oda Katsutoshi、Osuga Yutaka、Terao Yasuhisa、Kawazu Masahito、Mano Hiroyuki
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41467-019-13708-y
  • Peer Reviewed / Open Access
• [Journal Article] Oral Gonadotropin-Releasing Hormone Antagonist Relugolix Compared With Leuprorelin Injections for Uterine Leiomyomas (2019)
  • Author(s): Osuga Yutaka、Enya Kazuaki、Kudou Kentarou、Tanimoto Masataka、Hoshiai Hiroshi
  • Journal Title: Obstetrics & Gynecology Volume: 133 Issue: 3 Pages: 423-433
  • DOI: 10.1097/aog.0000000000003141
  • Peer Reviewed
• [Journal Article] Expression of Nerve Injury-Induced Protein1 (Ninj1) in Endometriosis (2018)
  • Author(s): Miyashita Mariko、Koga Kaori、Takeuchi Arisa、Makabe Tomoko、Taguchi Ayumi、Urata Yoko、Izumi Gentaro、Takamura Masashi、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Wada-Hiraike Osamu、Yoshino Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Reproductive Sciences Volume: in press Issue: 8 Pages: 368-375
  • DOI: 10.1177/1933719118806395
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 子宮内膜症と反復着床障害～cine MRI 検査を通して～ (2021)
  • Author(s): 福井大和,廣田泰,賀来哲明,平田知之,飯田麗,石沢千尋,赤枝俊,平岡毅大,松尾光徳,大須賀穣
  • Organizer: 第66回日本生殖医学会学術講演会・シンポジウム
  • Invited
• [Presentation] Cox-1・Cox-2による胚着床機構の解明 (2021)
  • Author(s): 藍川志津,廣田泰,赤枝俊,松尾光徳,賀来哲明,福井大和,大須賀穣
  • Organizer: 第94回日本生化学会大会
• [Remarks] 不妊症患者向け情報提供ツール「治療の難しい不妊症のためのガイドブック」作成、研究を一部引用
• [Remarks] 【プレスリリース】子宮腺筋症と子宮内膜症併発に関連する遺伝子変異を発見―発症機構の解明に期待―
  • URL: https://www.ncc.go.jp/jp/information/pr_release/2019/1219/20191219.pdf