Molecular mechanisms of uterine luminal epithelium disappearance in the process of embryo implantation

• Project/Area Number: 18K19601
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: HIROTA YASUSHI 東京大学, 医学部附属病院, 准教授 (40598653)
• Co-Investigator(Kenkyū-buntansha): 藤田 知子 東京大学, 医学部附属病院, 特任研究員 (60375441)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 着床 / 子宮内膜 / 胚浸潤 / 管腔上皮 / 間質 / 低酸素誘導因子 / 細胞周期 / 胚接着 / マウスモデル / 白血病阻止因子 / 受精卵

Outline of Final Research Achievements

Although disappearance of the endometrial luminal epithelium occurs during the embryo invasion, the mechanism of this event has been unclear. We newly found that hypoxia inducible factor HIF2α and cell cycle suppressor RB1 have essential roles in embryo invasion. Stromal HIF2α acts on the detachment of the endometrial luminal epithelium from the stroma via hypoxia-related signals. RB1 suppresses cell proliferation of the endometrial luminal epithelium and induces the fragmentation of epithelial cells and its trophoblast phagocytosis at the embryo attachment site.

Academic Significance and Societal Importance of the Research Achievements

本研究では胚浸潤の異常が起こる各種の遺伝子改変マウスを用いて、その異常の詳細を横断的に解析し、胚が子宮内膜に浸潤していく過程で起こる子宮内膜管腔上皮の消失のメカニズムを解析することを通して、胚浸潤という現象を分子細胞生物学的に理解することができた。ヒト着床障害の発症機序の解明につながる可能性があり、着床障害の診断・治療への応用が期待される。

Research Products

• [Int'l Joint Research] Southern Illinois University/Cincinnati Children's Hospital(米国)
• [Int'l Joint Research] シンシナティ小児病院(米国)
• [Journal Article] The effects of tokishakuyakusan, a traditional Japanese medicine (kampo), ferulic acid and paeoniflorin, on human endometriotic stromal cells and peritoneal macrophages (2020)
  • Author(s): Takeuchi Arisa、Koga Kaori、Tokita Yohei、Matsumoto Takashi、Satake Erina、Taguchi Ayumi、Makabe Tomoko、Miyashita Mariko、Takamura Masashi、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Wada-Hiraike Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: J Reprod Immunol Volume: 139 Pages: 103104-103104
  • DOI: 10.1016/j.jri.2020.103104
  • Peer Reviewed
• [Journal Article] Expression of ALDH1A Isozymes in Human Endometrium with and without Endometriosis and in Ovarian Endometrioma (2020)
  • Author(s): Ma Suke、Hirata Tetsuya、Arakawa Tomoko、Sun Hui、Neriishi Kazuaki、Fukuda Shinya、Nakazawa Akari、Wang Yu、Harada Miyuki、Hirota Yasushi、Koga Kaori、Wada-Hiraike Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Reproductive Sciences Volume: 27 Issue: 1 Pages: 443-452
  • DOI: 10.1007/s43032-019-00041-4
  • Peer Reviewed
• [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] Niclosamide suppresses macrophage-induced inflammation in endometriosis† (2020)
  • Author(s): Sekulovski Nikola、Whorton Allison E、Tanaka Tomoki、Hirota Yasushi、Shi Mingxin、MacLean James A、de Mola Julio Ricardo Loret、Groesch Kathleen、Diaz-Sylvester Paula、Wilson Teresa、Hayashi Kanako
  • Journal Title: Biol Reprod Volume: in press Issue: 5 Pages: 1011-1019
  • DOI: 10.1093/biolre/ioaa010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell Cycle Perturbation Induces Collagen Production in Fibroblasts (2019)
  • Author(s): Wake M, Takeda N, Isagawa T, Sato T, Nakagama Y, Morioka MS, Hirota Y, Asagiri M, Maemura K, Manabe I, Tanabe K, Komuro I.
  • Journal Title: International Heart Journal Volume: 60 Issue: 4 Pages: 958-963
  • DOI: 10.1536/ihj.18-710
  • NAID: 130007684138
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2019-07-30
  • 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 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] 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] 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] Accumulation of advanced glycation end products in follicles is associated with poor oocyte developmental competence (2019)
  • Author(s): Takahashi Nozomi、Harada Miyuki、Azhary Jerilee M K、Kunitomi Chisato、Nose Emi、Terao Hiromi、Koike Hiroshi、Wada-Hiraike Osamu、Hirata Tetsuya、Hirota Yasushi、Koga Kaori、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Molecular Human Reproduction Volume: 25 Issue: 11 Pages: 684-694
  • DOI: 10.1093/molehr/gaz050
  • Peer Reviewed / Open Access
• [Journal Article] Clinical aspects and management of inguinal endometriosis: A case series of 20 patients (2019)
  • Author(s): Arakawa Tomoko、Hirata Tetsuya、Koga Kaori、Neriishi Kazuaki、Fukuda Shinya、Ma Suke、Sun Hui、Nagashima Natsuki、Harada Miyuki、Hirota Yasushi、Wada‐Hiraike Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 45 Issue: 10 Pages: 2029-2036
  • DOI: 10.1111/jog.14059
  • Peer Reviewed
• [Journal Article] Placental expression of lysophosphatidic acid receptors in normal pregnancy and preeclampsia (2019)
  • Author(s): Fujii Tatsuya、Nagamatsu Takeshi、Schust Danny J.、Ichikawa Mayuko、Kumasawa Keiichi、Yabe Shinichiro、Iriyama Takayuki、Hirota Yasushi、Osuga Yutaka、Aoki Junken、Yatomi Yutaka、Fujii Tomoyuki
  • Journal Title: American Journal of Reproductive Immunology Volume: 82 Issue: 5
  • DOI: 10.1111/aji.13176
  • Peer Reviewed / Open Access
• [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] Role of oxidative stress in follicular fluid on embryos of patients undergoing assisted reproductive technology treatment (2019)
  • Author(s): Terao Hiromi、Wada‐Hiraike Osamu、Nagumo Aiko、Kunitomi Chisato、Azhary Jerilee M. K.、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Koga Kaori、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 45 Issue: 9 Pages: 1884-1891
  • DOI: 10.1111/jog.14040
  • Peer Reviewed
• [Journal Article] Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M. (2019)
  • Author(s): Abe H, Takeda N, Isagawa T, Semba H, Nishimura S, Morioka MS, Nakagama Y, Sato T, Soma K, Koyama K, Wake M, Katoh M, Asagiri M, Neugent ML, Kim JW, Stockmann C, Yonezawa T, Inuzuka R, Hirota Y, Maemura K, Yamashita T, Otsu K, Manabe I, Nagai R, Komuro I.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 2824-2833
  • DOI: 10.1038/s41467-019-10859-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endometriosis Triggers Excessive Activation of Primordial Follicles via PI3K-PTEN-Akt-Foxo3 Pathway (2019)
  • Author(s): Takeuchi Arisa、Koga Kaori、Satake Erina、Makabe Tomoko、Taguchi Ayumi、Miyashita Mariko、Takamura Masashi、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Yoshino Osamu、Wada-Hiraike Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: The Journal of Clinical Endocrinology & Metabolism Volume: 104 Issue: 11 Pages: 5547-5554
  • DOI: 10.1210/jc.2019-00281
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endothelial Cells in the Decidual Bed Are Potential Therapeutic Targets for Preterm Birth Prevention (2019)
  • Author(s): Deng Wenbo、Yuan Jia、Cha Jeeyeon、Sun Xiaofei、Bartos Amanda、Yagita Hideo、Hirota Yasushi、Dey Sudhansu K.
  • Journal Title: Cell Rep Volume: 27 Issue: 6 Pages: 1755-1768.e4
  • DOI: 10.1016/j.celrep.2019.04.049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Contralateral ovarian endometrioma recurrence after unilateral salpingo-oophorectomy (2019)
  • Author(s): Hidari Tokie、Hirata Tetsuya、Arakawa Tomoko、Koga Kaori、Neriishi Kazuaki、Fukuda Shinya、Nakazawa Akari、Nagashima Natsuki、Ma Suke、Sun Hui、Takamura Masashi、Harada Miyuki、Hirota Yasushi、Wada-Hiraike Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: BMC Women's Health Volume: 19 Issue: 1 Pages: 59-59
  • DOI: 10.1186/s12905-019-0760-z
  • Peer Reviewed / Open Access
• [Journal Article] Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality (2019)
  • Author(s): Haraguchi Hirofumi、Hirota Yasushi、Saito-Fujita Tomoko、Tanaka Tomoki、Shimizu-Hirota Ryoko、Harada Miyuki、Akaeda Shun、Hiraoka Takehiro、Matsuo Mitsunori、Matsumoto Leona、Hirata Tetsuya、Koga Kaori、Wada-Hiraike Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: The FASEB Journal Volume: 33 Issue: 2 Pages: 2610-2620
  • DOI: 10.1096/fj.201801401r
  • Peer Reviewed / Open Access
• [Journal Article] Activation of Nrf2/Keap1 pathway by oral Dimethylfumarate administration alleviates oxidative stress and age-associated infertility might be delayed in the mouse ovary (2019)
  • Author(s): Akino Nana、Wada-Hiraike Osamu、Isono Wataru、Terao Hiromi、Honjo Harunori、Miyamoto Yuichiro、Tanikawa Michihiro、Sone Kenbun、Hirano Mana、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Koga Kaori、Oda Katsutoshi、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Reproductive Biology and Endocrinology Volume: 17 Issue: 1 Pages: 2323-2323
  • DOI: 10.1186/s12958-019-0466-y
  • Peer Reviewed / Open Access
• [Journal Article] Progesterone governs endometrial proliferation-differentiation switching and blastocyst implantation (2019)
  • Author(s): Hirota Yasushi
  • Journal Title: Endocrine Journal Volume: 66 Issue: 3 Pages: 199-206
  • DOI: 10.1507/endocrj.EJ18-0431
  • NAID: 130007626244
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment (2018)
  • Author(s): Matsumoto Leona、Hirota Yasushi、Saito-Fujita Tomoko、Takeda Norihiko、Tanaka Tomoki、Hiraoka Takehiro、Akaeda Shun、Fujita Hidetoshi、Shimizu-Hirota Ryoko、Igaue Shota、Matsuo Mitsunori、Haraguchi Hirofumi、Saito-Kanatani Mayuko、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Journal of Clinical Investigation Volume: 128 Issue: 7 Pages: 3186-3197
  • DOI: 10.1172/jci98931
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endoplasmic Reticulum Stress Activated by Androgen Enhances Apoptosis of Granulosa Cells via Induction of Death Receptor 5 in PCOS (2018)
  • Author(s): Azhary Jerilee M K、Harada Miyuki、Takahashi Nozomi、Nose Emi、Kunitomi Chisato、Koike Hiroshi、Hirata Tetsuya、Hirota Yasushi、Koga Kaori、Wada-Hiraike Osamu、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Endocrinology Volume: 160 Issue: 1 Pages: 119-132
  • DOI: 10.1210/en.2018-00675
  • Peer Reviewed / Open Access
• [Journal Article] The efficacy of non-assisted reproductive technology treatment might be limited in infertile patients with advanced endometriosis in their 30s (2018)
  • Author(s): Isono Wataru、Wada-Hiraike Osamu、Akino Nana、Terao Hiromi、Harada Miyuki、Hirata Tetsuya、Hirota Yasushi、Koga Kaori、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 45 Issue: 2 Pages: 368-375
  • DOI: 10.1111/jog.13826
  • Peer Reviewed
• [Journal Article] A survey of public attitudes towards third-party reproduction in Japan in 2014 (2018)
  • Author(s): Yamamoto Naoko、Hirata Tetsuya、Izumi Gentaro、Nakazawa Akari、Fukuda Shinya、Neriishi Kazuaki、Arakawa Tomoko、Takamura Masashi、Harada Miyuki、Hirota Yasushi、Koga Kaori、Wada-Hiraike Osamu、Fujii Tomoyuki、Irahara Minoru、Osuga Yutaka
  • Journal Title: PLOS ONE Volume: 13 Issue: 10 Pages: 198499-198499
  • DOI: 10.1371/journal.pone.0198499
  • Peer Reviewed / Open Access
• [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: 470 Pages: 96
  • DOI: 10.1016/j.mce.2017.10.002
  • Peer Reviewed / Open Access
• [Journal Article] 【妊娠成立過程における最近のトピックス】胚接着、胚浸潤の分子機構に関する最新知見とその解明への展望 (2018)
  • Author(s): 福井大和、廣田泰
  • Journal Title: Hormone Frontier In Gynecology Volume: 25 Pages: 53-58
• [Presentation] Key regulators in embryo implantation: Lessons from mice (2018)
  • Author(s): Yasushi Hirota
  • Organizer: 75th Korean Society for Reproductive Medicine Annual Meeting 2018
  • Int'l Joint Research / Invited
• [Presentation] Progestin Therapy and Uterus-sparing Surgery for Adenomyosis (2018)
  • Author(s): Yasushi Hirota
  • Organizer: 2018 Taiwan Endometriosis Society Expert Meeting in Taipei
  • Int'l Joint Research / Invited
• [Presentation] Pathophysiology of Adenomyosis: Relationship to thrombophilia and uterine infection (2018)
  • Author(s): Yasushi Hirota
  • Organizer: 2018 Taiwan Endometriosis Society Expert Meeting in Taichung
  • Int'l Joint Research / Invited
• [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] 子宮内膜による胚の接着・浸潤の調節 (2018)
  • Author(s): 廣田泰
  • Organizer: 第15回日本A-PART学術講演会 シンポジウム「胚の着床機構について考える」
  • Invited
• [Presentation] 胚接着・浸潤過程を調節する仕組み～黄体ホルモンを取り巻く役者たち～ (2018)
  • Author(s): 廣田泰
  • Organizer: 第20回 横浜ART研究会
  • Invited
• [Presentation] 子宮内環境の適正化 (2018)
  • Author(s): 廣田泰
  • Organizer: 第135回関東連合産科婦人科学会学術集会 生殖シンポジウム non-ART vs ART
  • Invited
• [Presentation] 内分泌疾患と不妊治療の基礎と臨床：内分泌疾患と女性不妊症 (2018)
  • Author(s): 廣田泰
  • Organizer: 第91回日本内分泌学会学術総会
  • Invited
• [Book] Uterine Fibroids and Adenomyosis (2018)
  • Author(s): Yasushi Hirota
  • Total Pages: 173
  • Publisher: Springer
  • ISBN: 9789811071676
• [Remarks] 【プレスリリース】胚が子宮内膜に浸潤する着床のメカニズムを解明
  • URL: http://www.h.u-tokyo.ac.jp/vcms_lf/release_20180619.pdf