Cervical biomarkers to detect uterine endometrial receptivity

• Project/Area Number: 16K15701
• 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): 藤田 知子 東京大学, 医学部附属病院, 特別研究員 (60375441)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 子宮頸部 / 子宮内膜 / LIF / 着床 / 胚受容能 / 着床障害 / マウスモデル / 子宮頸部上皮 / 子宮頸部スメア / 着床能 / 子宮 / バイオマーカー

Outline of Final Research Achievements

The aim of this study is to establish a new diagnostic strategy for implantation failure. To identify cervical biomarkers for embryo implantation using mouse models of implantation failure, we employed laser capture microdissection system to dissect cervical tissues from three types of mouse models of drug-induced implantation failure, and control mice, and RNA-seq of these cervical tissues were performed. We identified 320 genes with implantation-dependent upregulation in the mouse cervical epithelium, which was shown by mouse models of drug-induced implantation failure. The selected genes are candidates of cervical biomarkers in uterine capacity of implantation. Cervical epithelium obtained by cervical smear may be a useful material to detect the implantation capacity of the uterus. Although our findings in the current study were achieved by the animal studies, we believe that our newly-established approaches in mice can be clinically applied to humans.

Research Products

• [Int'l Joint Research] Wayne State University/Cincinnati Children's Hospital/Augusta University(米国)
• [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: 1-9
  • DOI: 10.1016/j.mce.2017.10.002
  • Peer Reviewed / Open Access
• [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 Issue: 11 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 M, Hirota Y, Shimizu-Hirota R, Saito-Fujita T, Haraguchi H, Matsumoto L, Matsuo M, Hiraoka T, Tanaka T, Akaeda S, Takehisa C, Saito-Kanatani M, Maeda K, Fujii T, Osuga Y.
  • Journal Title: Endocrinology Volume: 印刷中 Issue: 7 Pages: 2344-2353
  • DOI: 10.1210/en.2016-1886
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 Issue: 14 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 Issue: 11 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 Issue: 1 Pages: 10824-10824
  • DOI: 10.1038/s41598-017-11252-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Potential Role for Endoplasmic Reticulum Stress in Progesterone Deficiency in Obese Women. (2017)
  • Author(s): Takahashi N, Harada M, Hirota Y, Zhao L, Azhary JM, Yoshino O, Izumi G, Hirata T, Koga K, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: Endocrinology Volume: 158 Pages: 84-97
  • DOI: 10.1210/en.2016-1511
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 T, Koga K, Miyashita M, Takeuchi A, Sue F, Taguchi A, Urata Y, Izumi G, Takamura M, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: J Reprod Immunol Volume: 119 Pages: 44-48
  • DOI: 10.1016/j.jri.2016.12.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] STAT3 accelerates uterine epithelial regeneration in a mouse model of decellularized uterine matrix transplantation. (2016)
  • Author(s): Hiraoka T, Hirota Y, Saito-Fujita T, Matsuo M, Egashira M, Matsumoto L, Haraguchi H, Dey SK, Furukawa KS, Fujii T, Osuga Y.
  • Journal Title: JCI Insight Volume: 1 Issue: 8
  • DOI: 10.1172/jci.insight.87591
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing. (2016)
  • Author(s): Deng W, Cha J, Yuan J, Haraguchi H, Bartos A, Leishman E, Viollet B, Bradshaw HB, Hirota Y, Dey SK.
  • Journal Title: J Clin Invest Volume: 126 Issue: 8 Pages: 2941-2954
  • DOI: 10.1172/jci87715
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dienogest reduces proliferation, NGF expression and nerve fiber density in human adenomyosis. (2016)
  • Author(s): Takeuchi A, Koga K, Miyashita M, Makabe T, Sue F, Harada M, Hirata T, Hirota Y, Fujii T, Osuga Y.
  • Journal Title: Eur J Obstet Gynecol Reprod Biol Volume: 207 Pages: 157-161
  • DOI: 10.1016/j.ejogrb.2016.10.053
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of ovarian cancer after excision of endometrioma. (2016)
  • 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.
  • Journal Title: Fertil Steril Volume: 106 Issue: 6 Pages: 1432-1437
  • DOI: 10.1016/j.fertnstert.2016.07.1077
  • Peer Reviewed
• [Journal Article] Mannose receptor is highly expressed by peritoneal dendritic cells in endometriosis. (2016)
  • Author(s): Izumi G, Koga K, Takamura M, Makabe T, Nagai M, Urata Y, Harada M, Hirata T, Hirota Y, Fujii T, Osuga Y.
  • Journal Title: Fertil Steril Volume: 107 Issue: 1 Pages: 167-173
  • DOI: 10.1016/j.fertnstert.2016.09.036
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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.
  • Journal Title: Am J Reprod Immunol Volume: 76 Issue: 3 Pages: 193-198
  • DOI: 10.1111/aji.12540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reduced homeobox protein MSX1 in human endometrial tissue is linked to infertility. (2016)
  • Author(s): Bolnick AD, Bolnick JM, Kilburn BA, Stewart T, Oakes J, Rodriguez-Kovacs J, Kohan-Ghadr HR, Dai J, Diamond MP, Hirota Y, Drewlo S, Dey SK, Armant DR; NICHD National Cooperative Reproductive Medicine Network.
  • 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
  • DOI: 10.1210/jc.2016-1515
  • 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] 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 / Invited
• [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] 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