Roles of uterine hypoxia inducible factor in embryo implantation

• Project/Area Number: 15K15596
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• 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): FUJITA Tomoko 東京大学, 医学部附属病院, 特別研究員 (60375441)
• Research Collaborator: HARAGUCHI Hirofumi 東京大学, 大学院医学系研究科, 大学院生 ; MATSUMOTO Leona 東京大学, 大学院医学系研究科, 大学院生 ; EGASHIRA Mahiro 東京大学, 農学生命科学研究科, 大学院生 ; MATSUO Mitsunori 東京大学, 大学院医学系研究科, 大学院生 ; HIRAOKA Takehiro 東京大学, 大学院医学系研究科, 大学院生
• Project Period (FY): 2015-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: 着床 / 低酸素 / HIF / マウスモデル / 子宮 / 子宮内膜 / HIF2α / 脱落膜化 / 妊娠 / 胚受容能 / 胎盤

Outline of Final Research Achievements

Roles of uterine hypoxia inducible factor (HIF) in early pregnancy remain unknown. In this study, we found that mice with conditional deletion of uterine Hif2a are infertile, and have the dislocation of implantation sites and defective decidualization. We also found that supplementation of progesterone markedly improve decidualization but can not recover full pregnancy in Hif2a conditional knockout mice. These findings suggest that HIF in the periimplantation uterus may support successful implantation and decidualization.

Research Products

• [Int'l Joint Research] シンシナティ小児病院(米国)
• [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: in press
  • Peer Reviewed
• [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
• [Journal Article] Simultaneous Detection and Evaluation of Four Subsets of CD4+ T Lymphocyte in Lesions and Peripheral Blood in Endometriosis. (2015)
  • Author(s): Takamura, M., Koga, K., Izumi, G., Hirata, T., Harada, M., Hirota, Y., Hiraike, O., Fujii, T., Osuga, Y
  • Journal Title: American Journal of Reproductive Immunology Volume: 74 Issue: 6 Pages: 480-486
  • DOI: 10.1111/aji.12426
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evidence of the activation of unfolded protein response in granulosa and cumulus cells during follicular growth and maturation. (2015)
  • Author(s): Harada, M., Nose, E., Takahashi, N., Hirota, Y., Hirata, T., Yoshino, O., Koga, K., Fujii, T., Osuga, Y
  • Journal Title: Gynecological Endocrinology Volume: 31 Issue: 10 Pages: 783-787
  • DOI: 10.3109/09513590.2015.1062862
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Drospirenone induces decidualization in human eutopic endometrial stromal cells and reduces DNA synthesis of human endometriotic stromal cells. (2015)
  • Author(s): Miyashita, M., Koga, K., Izumi, G., Makabe, T., Hasegawa, A., Hirota, Y., Hirata, T., Harada, M., Fujii, T., Osuga, Y
  • Journal Title: Fertility and Sterility Volume: 104 Issue: 1 Pages: 217-24
  • DOI: 10.1016/j.fertnstert.2015.03.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Muscle Segment Homeobox Genes Direct Embryonic Diapause by Limiting Inflammation in the Uterus. (2015)
  • Author(s): Cha, J., Burnum-Johnson, K.E., Bartos, A., Li, Y., Baker, ES., Tilton, S.C., Webb-Robertson, B.J., Piehowski, P.D., Monroe, M.E., Jegga, A.G., Murata, S., Hirota, Y., Dey, S.K.
  • Journal Title: The Journal of Biological Chemistry Volume: 290 Issue: 24 Pages: 15337-15349
  • DOI: 10.1074/jbc.m115.655001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cyclic Stretch Augments Production of Neutrophil Chemokines, Matrix Metalloproteinases, and Activin A in Human Endometrial Stromal Cells. (2015)
  • Author(s): Izumi G, Koga K, Takamura M, Osuga Y.
  • Journal Title: Am J Reprod Immunol Volume: epub Issue: 6 Pages: 501-506
  • DOI: 10.1111/aji.12359
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] How does Progesterone Support Embryo Implantation? (2015)
  • Author(s): Hiraoka T, Saito-Fujita T, Hirota Y.
  • Journal Title: J Mamm Ova Res Volume: 32 Issue: 3 Pages: 87-94
  • DOI: 10.1274/jmor.32.87
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 着床における黄体ホルモンの作用 (2015)
  • Author(s): 平岡毅大、廣田泰
  • Journal Title: 産科と婦人科 Volume: 82 Pages: 740-745
• [Journal Article] 子宮内膜における着床制御因子 プロゲステロン・シグナルを中心に (2015)
  • Author(s): 藤田知子、廣田泰
  • Journal Title: HORMONE FRONTIER IN GYNECOLOGY Volume: 22 Pages: 176-179
• [Journal Article] 種差からみた着床 ヒトとの共通点と相違点 (2015)
  • Author(s): 江頭真宏、廣田泰
  • Journal Title: HORMONE FRONTIER IN GYNECOLOGY Volume: 22 Pages: 183-189
• [Presentation] プロゲステロンと子宮の機能～着床から分娩まで (2016)
  • Author(s): 廣田泰
  • Organizer: 第5回プロゲスチン研究会
  • Place of Presentation: ホテル椿山荘東京（東京都文京区）
  • Year and Date: 2016-02-23
  • Invited
• [Presentation] MicroRNA-200a impairs progesterone signaling in the cervix, disturbing embryo implantation. (2016)
  • Author(s): Yasushi Hirota, Hirofumi Haraguchi, Tomoko Saito-Fujita, Mahiro Egashira, Leona Matsumoto, Mitsunori Matsuo, Takehiro Hiraoka, Sudhansu K. Dey, Yutaka Osuga, Tomoyuki Fujii.
  • Organizer: International Symposium on Epigenome Dynamics and Regulation in Germ Cells
  • Place of Presentation: 京都大学百周年時計台記念館（京都府京都市）
  • Year and Date: 2016-02-18
  • Int'l Joint Research
• [Presentation] Endometrial regeneration in the mouse model of decellularized matrix transplantation. (2016)
  • Author(s): Takehiro Hiraoka, Yasushi Hirota.
  • Organizer: International Symposium on Epigenome Dynamics and Regulation in Germ Cells
  • Place of Presentation: 京都大学百周年時計台記念館（京都府京都市）
  • Year and Date: 2016-02-18
  • Int'l Joint Research
• [Presentation] Endometrial regeneration in the mouse model of decellularized matrix transplantation. (2016)
  • Author(s): Takehiro Hiraoka, Yasushi Hirota.
  • Organizer: 平成２７年度「がん研究分野の特性等を踏まえた支援活動」冬期シンポジウム
  • Place of Presentation: 一橋講堂 学術総合センター（東京都千代田区）
  • Year and Date: 2016-02-07
• [Presentation] Endometrial regeneration in the mouse model of decellularized matrix transplantation. (2015)
  • Author(s): Takehiro Hiraoka, Yasushi Hirota, Tomoko Saito-Fujita, Tomoki Tanaka, Mitsunori Matsuo, Mahiro Egashira, Leona Matsumoto, Hirofumi Haraguchi, Katsuko S. Furukawa, Yutaka Osuga, Tomoyuki Fujii.
  • Organizer: 第38回日本分子生物学会年会 (BMB 2015)
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-02
• [Presentation] 子宮の低酸素誘導因子HIF2αは妊娠成立に必須である (2015)
  • Author(s): 松本玲央奈、廣田泰、藤田知子、原口広史、江頭真宏、松尾光徳、平岡毅大、田中智基、武田憲彦、大須賀穣、藤井知行
  • Organizer: 第33回日本受精着床学会総会・学術講演会
  • Place of Presentation: TFTホール（東京都江東区）
  • Year and Date: 2015-11-27
• [Presentation] 松本玲央奈、廣田泰、藤田知子、原口広史、江頭真宏、松尾光徳、平岡毅大、田中智基、武田憲彦、大須賀穣、藤井知行 (2015)
  • Author(s): 着床における低酸素誘導因子HIFの意義
  • Organizer: 第30回日本生殖免疫学会
  • Place of Presentation: くまもと県民交流館パレア（熊本県熊本市）
  • Year and Date: 2015-11-21
• [Presentation] 黄体ホルモンが調節する子宮内膜の胚受容能 (2015)
  • Author(s): 廣田泰
  • Organizer: 第6回金沢大学学際科学実験センターシンポジウム
  • Place of Presentation: 金沢大学附属医学図書館（石川県金沢市）
  • Year and Date: 2015-11-13
  • Invited
• [Presentation] The presence of ovarian hormone-independent endometrial epithelial growth in endometrial remodeling and regeneration. (2015)
  • Author(s): Hiraoka T, Hirota Y.
  • Organizer: The Second International Meeting for Epithelial Tubulology
  • Place of Presentation: 北海道大学医学部学友会館（北海道札幌市）
  • Year and Date: 2015-08-22
  • Int'l Joint Research / Invited
• [Presentation] Crucial role of hypoxia inducible factor 2α in the pregnant uterus. (2015)
  • Author(s): Leona Matsumoto, Yasushi Hirota, Tomoko Saito-Fujita, Hirofumi Haraguchi, Mahiro Egashira, Mitsunori Matsuo, Takehiro Hiraoka, Kaori Koga, Sudhansu K. Dey, Tomoyuki Fujii, Yutaka Osuga.
  • Organizer: 31st ESHRE Annual Meeting (ESHRE 2015)
  • Place of Presentation: FIL International Lisbon Fair （Portugal, Lisbon）
  • Year and Date: 2015-06-15
  • Int'l Joint Research
• [Presentation] 黄体ホルモンによる妊娠成立・維持のしくみ (2015)
  • Author(s): 廣田泰
  • Organizer: 第38回東京成長ホルモン成長因子セミナー
  • Place of Presentation: 新宿住友ホール（東京都新宿区）
  • Year and Date: 2015-05-22
  • Invited
• [Presentation] 子宮におけるプロゲステロン受容体シグナルと着床 (2015)
  • Author(s): 廣田泰
  • Organizer: 第60回日本生殖医学会学術講演会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-04-27
  • Invited
• [Presentation] The presence of cellular senescence and its possible roles in the postpartum uterus. (2015)
  • Author(s): Mahiro Egashira, Yasushi Hirota, Tomoko Saito-Fujita, Hirofumi Haraguchi, Leona Matsumoto, Mitsunori Matsuo, Takehiro Hiraoka, Yutaka Osuga, Tomoyuki Fujii.
  • Organizer: IFFS/JSRM International Meeting 2015
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-04-26
  • Int'l Joint Research
• [Presentation] MicroRNA controls receptivity to the embryo by regulating progesterone signaling in the cervix and uterus. (2015)
  • Author(s): Hirofumi Haraguchi, Yasushi Hirota, Tomoko Saito-Fujita, Mahiro Egashira, Leona Matsumoto, Mitsunori Matsuo, Takehiro Hiraoka, Kaori Koga, Sudhansu K. Dey, Yutaka Osuga, Tomoyuki Fujii.
  • Organizer: IFFS/JSRM International Meeting 2015
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-04-26
  • Int'l Joint Research
• [Book] Uterine Endometrial Function (2016)
  • Author(s): Hirota Y
  • Publisher: Springer
• [Remarks] Researchmap：廣田泰
  • URL: http://researchmap.jp/yhirota-tky/