Uterine hypoxia inducible factor regulates embryo implantation

• Project/Area Number: 16H04679
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: The University of Tokyo
• Principal Investigator: HIROTA YASUSHI 東京大学, 医学部附属病院, 講師 (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): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 着床 / 低酸素誘導因子 / 子宮内膜 / 胚 / 間質 / 管腔上皮 / 着床障害 / マウスモデル / トロホブラスト / 低酸素 / HIF / 胎盤 / 子宮 / 胚浸潤 / 増殖因子 / AKT / 胚接着

Outline of Final Research Achievements

This study aimed to clarify functions of uterine HIF using transgenic mouse models. Mice with deletion of Hif2α in the whole uterus (Hif2α-uKO mice) showed infertility due to implantation failure. Histological analyses in Hif2α-uKO mice revealed persistence of the intact luminal epithelium, which blocked direct contact between stroma and embryo, inactivation of PI3K-AKT pathway, and failed embryo invasion. Mice with stromal deletion of Hif2α showed infertility with impaired embryo invasion and those with epithelial deletion of Hif2α showed normal fertility, suggesting the importance of stromal HIF2α in embryo invasion. These findings provide new insight that stromal HIF2α allows trophoblast invasion through detachment of the luminal epithelium and activation of an embryonic survival signal.

Academic Significance and Societal Importance of the Research Achievements

着床は胚が子宮内膜に入り込む過程（胚浸潤）を経て成立するが、その仕組みは不明であった。本研究で低酸素誘導因子HIF2aが子宮内膜で作用して胚浸潤を調節していること、子宮内膜間質のHIF2aが子宮内膜管腔上皮を剥離し間質を露出させ胚が子宮内に入り込むのを可能にし、間質が胚とじかに接することによって胚の生存シグナルが活性化すること、が明らかになった（J Clin Invest 2018）。これらの研究成果として胚浸潤の仕組みと胚浸潤の異常による着床障害の機序が世界で初めて解明された。低酸素誘導因子およびその下流因子をターゲットとした着床障害の診断・治療法の開発が期待される。

Research Products

• [Int'l Joint Research] シンシナティ小児病院(米国)
• [Int'l Joint Research] Wayne State University/Cincinnati Children's Hospital/Augusta University(米国)
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• [Journal Article] HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment (2018)
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  • Journal Title: Journal of Clinical Investigation Volume: 128 Issue: 7 Pages: 3186-3197
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• [Journal Article] Activation of Nrf2 might reduce oxidative stress in human granulosa cells (2018)
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• [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)
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• [Journal Article] F4/80+ macrophages contribute to clearance of senescent cells in the mouse postpartum uterus. (2017)
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  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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  • Author(s): Haraguchi H, Koga K, Takamura M, Makabe T, Sue F, Miyashita M, Urata Y, Izumi G, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Oda K, Kawana K, Fujii T, Osuga Y.
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  • Peer Reviewed
• [Journal Article] Neutrophil depletion reduces endometriotic lesion formation in mice. (2016)
  • Author(s): Takamura M, Koga K, Izumi G, Urata Y, Nagai M, Hasegawa A, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Fujii T, Osuga Y.
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  • Journal Title: Hum Reprod Volume: 31 Issue: 9 Pages: 2042-50
  • DOI: 10.1093/humrep/dew143
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of 1,25-dihydroxy vitamin D3 on endometriosis. (2016)
  • Author(s): Miyashita M, Koga K, Izumi G, Sue F, Makabe T, Taguchi A, Nagai M, Urata Y, Takamura M, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: J Clin Endocrinol Metab Volume: 101 Issue: 6 Pages: 2371-2379
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  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A potential role of endoplasmic reticulum stress in development of ovarian hyperstimulation syndrome. (2016)
  • Author(s): Takahashi N, Harada M, Hirota Y, Zhao L, Yoshino O, Urata Y, Izumi G, Takamura M, Hirata T, Koga K, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: Mol Cell Endocrinol Volume: 428 Pages: 161-169
  • DOI: 10.1016/j.mce.2016.03.032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Resveratrol Enhances Apoptosis in Endometriotic Stromal Cells. (2016)
  • Author(s): Taguchi, A., Koga, K., Kawana, K., Makabe, T., Sue, F., Miyashita, M., Yoshida, M., Urata, Y., Izumi, G., Takamura, M., Harada, M., Hirata, T., Hirota, Y., Wada-Hiraike, O., Fujii, T., Osuga, Y
  • Journal Title: American Journal of Reproductive Immunology Volume: 75 Issue: 4 Pages: 486-492
  • DOI: 10.1111/aji.12489
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Activated IL6-STAT3 pathway in adenomyosis (2017)
  • Author(s): Hirota Y, Hiraoka T, Saito-Fujita T, Harada M, Fujii T, Osuga Y.
  • Organizer: World Conference of Endometriosis 2017
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2017-05-20
  • Int'l Joint Research
• [Presentation] IL6-STAT3経路の活性化が子宮腺筋症の進展に寄与する (2017)
  • Author(s): 廣田泰、平岡毅大、大須賀穣
  • Organizer: 第90回日本内分泌学会学術総会 シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2017-04-21
  • Invited
• [Presentation] 着床障害の分子機構の解明に基づく着床能の診断法と革新的治療技術の開発 (2017)
  • Author(s): 廣田泰
  • Organizer: 第69回日本産科婦人科学会学術講演会 シンポジウム
  • Place of Presentation: 広島
  • Year and Date: 2017-04-15
  • Invited
• [Presentation] 子宮の線維化：子宮腺筋症～IL6／STAT3経路の関与～ (2017)
  • Author(s): 廣田泰
  • Organizer: 第1回Frontier in basic and clinical research of fibrosis
  • Place of Presentation: 名古屋
  • Year and Date: 2017-03-04
  • 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
• [Presentation] 生殖医学の最先端 不妊症治療におけるブレイクスルーを目指して 着床障害の分子機構の解明に基づく着床能の診断法と革新的治療技術の開発 (2017)
  • Author(s): 廣田泰
  • Organizer: 第69回日本産科婦人科学会学術講演会 シンポジウム
• [Presentation] 低酸素誘導因子HIF2αによる子宮内膜への胚浸潤の調節 (2017)
  • Author(s): 松本 玲央奈, 廣田泰, 藤田知子, 伊賀上翔太, 田中智基, 平岡毅大, 松尾光徳, 原口広史, 赤枝俊, 武田憲彦, 大須賀穣, 藤井知行
  • Organizer: 第62回日本生殖医学会学術講演会
• [Presentation] IL6-STAT3 signaling in adenomyosis (2016)
  • Author(s): Hirota Y.
  • Organizer: Asian Conference of Endometriosis 2016
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2016-09-23
  • Int'l Joint Research
• [Presentation] STAT3 promotes uterine regeneration in a mouse modelof decellularized uterine matrix transplantation (2016)
  • Author(s): Hirota Y.
  • Organizer: Gordon Research Conference on Mammalian Reproduction
  • Place of Presentation: Waterville Valley, NH, United States
  • Year and Date: 2016-08-24
  • Int'l Joint Research
• [Presentation] 黄体ホルモンによる子宮の胚受容能と着床の調節機構 (2016)
  • Author(s): 廣田泰
  • Organizer: 第5 回プロゲストーゲン研究会
  • Place of Presentation: 東京
  • Year and Date: 2016-06-04
  • Invited
• [Presentation] 天然型プロゲステロンが着床に与える影響 (2016)
  • Author(s): 廣田泰
  • Organizer: 第3回最適な不妊治療を考える会
  • Place of Presentation: 東京
  • Year and Date: 2016-05-28
  • Invited
• [Book] 研修ノート No99 流産のすべて (2018)
  • Author(s): 廣田泰
  • Total Pages: 81
  • Publisher: 日本産婦人科医会
• [Remarks] 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
• [Remarks] 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
• [Remarks] 東大産婦人科 廣田研究室
  • URL: https://plaza.umin.ac.jp/tkyobgyn/recruit/laboratory/hirota.html
• [Remarks] 【プレスリリース】転写因子STAT3を介した子宮内膜の再構築と子宮の再生の仕組み
  • URL: http://www.h.u-tokyo.ac.jp/vcms_lf/release_20160603-1.pdf