Identification of embryo-derived implantation-inducing factors (embryonic signals) and their clinical application

• Project/Area Number: 26293358
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Kanazawa University
• Principal Investigator: Hiroshi Fujiwara 金沢大学, 医学系, 教授 (30252456)
• Co-Investigator(Kenkyū-buntansha): 高倉 正博 金沢大学, 大学病院, 准教授 (20313661) ; 京 哲 島根大学, 医学部, 教授 (50272969) ; 服部 明 京都大学, 薬学研究科(研究院), 准教授 (50300893) ; 河崎 洋志 金沢大学, 脳・肝インターフェースメディシン研究センター, 教授 (50303904) ; 荒木 慶彦 順天堂大学, 医学(系)研究科(研究院), 准教授 (70250933) ; 大黒 多希子 金沢大学, 学際科学実験センター, 教授 (30767249)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2016: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 胚シグナル / 透明帯 / HCG / Laeverin / 免疫寛容 / 着床 / laeverin

Outline of Final Research Achievements

We found that maternal immune systems change their function to induce corpus luteum and endometrial differentiation, leading to embryo implantation. This project further demonstrated the importance of zona pellucida and HCG as embryonal signals and proposed that laeverin, which is specifically produced by human extravillous trophoblast, is a new candidate for embryonal signas. We hope that these findings will contribute to developing a new therapy for patients with repeated implantation failure.

Research Products

• [Journal Article] Platelet-derived microparticles and soluble factors differentially regulate human endometrial epithelial cell movement (2017)
  • Author(s): Suginami K, Sato Y, Horie A, Matsumoto H, Tani H, Mizumoto Y, Ono M, Matsuoka A, Kyo S, Araki Y, Konishi I, Fujiwara H
  • Journal Title: Am J Reprod Immunol Volume: Feb 7 Issue: 4 Pages: 12641-12641
  • DOI: 10.1111/aji.12641
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Acquired hemophilia A manifesting as plasma transfusion-uncontrolled severe bleeding 2 weeks after chorioamnionitis-induced abortion (2016)
  • Author(s): Matsuoka A, Sasaki H, Sugimori C, Hirabuki S, Hoshiba T, Fujiwara H.
  • Journal Title: J Obstet Gynaecol Res Volume: Feb 2 Issue: 4 Pages: 13270-13270
  • DOI: 10.1111/jog.13270
  • Peer Reviewed
• [Journal Article] FDG-PET-positive ovarian thecoma with GLUT5 expression: Five cases (2016)
  • Author(s): Bono Y, Mizumoto Y, Nakamura M, Iwadare J, Obata T, Fujiwara H
  • Journal Title: J Obstet Gynaecol Res Volume: 43 Issue: 3 Pages: 599-603
  • DOI: 10.1111/jog.13243
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Platelets are a possible regulator of human endometrial re-epithelialization during menstruation (2016)
  • Author(s): Suginami K, Sato Y, Horie A, Matsumoto H, Kyo S, Araki Y, Konishi I, Fujiwara H
  • Journal Title: Am J Reprod Immunol Volume: 77 Issue: 1 Pages: 12609-12609
  • DOI: 10.1111/aji.12609
  • Peer Reviewed
• [Journal Article] CD9 suppresses human extravillous trophoblast invasion (2016)
  • Author(s): Matsumoto H, Sato Y, Horie A, Suginami K, Tani H, Hattori A, Araki Y, Kagami K, Konishi I, Fujiwara H
  • Journal Title: Placenta Volume: 47 Pages: 105-112
  • DOI: 10.1016/j.placenta.2016.09.014
  • Peer Reviewed
• [Journal Article] Synchronous endometrioid adenocarcinomas in the uterine cervix and corpus (2016)
  • Author(s): Obata T, Nakamura M, Mizumoto Y, Matsumoto T, Takakura M, Fujiwara H
  • Journal Title: J Obstet Gynaecol Res Volume: 42 Issue: 10 Pages: 1390-1394
  • DOI: 10.1111/jog.13049
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of an anti-sperm auto-monoclonal antibody (Ts4)-recognized molecule in the mouse sperm acrosomal region and its inhibitory effects on fertilization in vitro. (2016)
  • Author(s): Yoshitake H., Oda R., Yanagida M., Kawasaki Y., Sakuraba M., Takamori K., Hasegawa A., Fujiwara H., Araki Y.
  • Journal Title: J.Reprod.Immunol. Volume: 115 Pages: 6-13
  • DOI: 10.1016/j.jri.2016.04.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Familial discrepancy of clinical outcomes associated with fibrinogen Dorfen: A case of huge genital hematoma after episiotomy (2016)
  • Author(s): Kagami K, Yamazaki R, Minami T, Okumura N, Morishita E, Fujiwara H
  • Journal Title: J Obstet Gynaecol Res Volume: 42 Issue: 6 Pages: 722-725
  • DOI: 10.1111/jog.12972
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dual Positive Regulation of Embryo Implantation by Endocrine and Immune Systems - Step-by-Step Maternal Recognition of the Developing Embryo. (2016)
  • Author(s): Fujiwara H, Araki Y, Imakawa K, Saito S, Daikoku T, Shigeta M, Kanzaki H, Mori T.
  • Journal Title: Am J Reprod Immunol. Volume: 75 Issue: 3 Pages: 281-9
  • DOI: 10.1111/aji.12478
  • NAID: 120005743891
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Detection of hypermutated human papillomavirus type 16 genome by Next-Generation Sequencing. (2015)
  • Author(s): Wakae K, Aoyama S, Wang Z, Kitamura K, Liu G, Monjurul AM, Koura M, Imayasu M, Sakamoto N, Nakamura M, Kyo S, Kondo S, Fujiwara H, Yoshizaki T, Kukimoto I, Yamaguchi K, Shigenobu S, Nishiyama T, Muramatsu M.
  • Journal Title: Virology Volume: 485 Pages: 460-466
  • DOI: 10.1016/j.virol.2015.08.017
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Tamoxifen-induced ovarian hyperstimulation during premenopausal hormonal therapy for breast cancer in Japanese women. (2015)
  • Author(s): Yamazaki R, Inokuchi M, Ishikawa S, Myojo S, Iwadare J, Bono Y, Mizumoto Y, Nakamura M,Takakura M, Iizuka T, Ohta T, Fujiwara H.
  • Journal Title: Springerplus Volume: 4 Issue: 1 Pages: 425-429
  • DOI: 10.1186/s40064-015-1223-0
  • NAID: 120005743892
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Chemical characterization of N-linked oligosaccharide as the antigen epitope recognized by an anti-sperm auto-monoclonal antibody, Ts4. (2015)
  • Author(s): Yoshitake H, Hashii N, Kawasaki N, Endo S, Takamori K, Hasegawa A, Fujiwara H, Araki Y.
  • Journal Title: PLoS One Volume: 10 Issue: 7 Pages: e0133784-e0133784
  • DOI: 10.1371/journal.pone.0133784
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nerve-sparing abdominal radical trachelectomy: a novel concept to preserve uterine branches of pelvic nerves. (2015)
  • Author(s): Kyo S, Mizumoto Y, Takakura M, Nakamura M, Sato E, Katagiri H, Ishikawa M, Nakayama K, Fujiwara H.
  • Journal Title: Eur J Obstet Gynecol Reprod Biol. Volume: 193 Pages: 5-9
  • DOI: 10.1016/j.ejogrb.2015.06.029
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] APOBEC3A and 3C decrease human papillomavirus 16 pseudovirion infectivity. (2015)
  • Author(s): Ahasan MM, Wakae K, Wang Z, Kitamura K, Liu G, Koura M, Imayasu M, Sakamoto N, Hanaoka K, Nakamura M, Kyo S, Kondo S, Fujiwara H, Yoshizaki T, Mori S, Kukimoto I, Muramatsu M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 457 Issue: 3 Pages: 295-9
  • DOI: 10.1016/j.bbrc.2014.12.103
  • Peer Reviewed / Open Access
• [Journal Article] Concurrent estrogen action was essential for maximal progestin effect in oral contraceptives. (2014)
  • Author(s): Bono Y, Kyo S, Kiyono T, Mizumoto Y, Nakamura M, Maida Y, Takakura M, Fujiwara H.
  • Journal Title: Fertil Steril Volume: 101 Pages: 1337-43
  • Peer Reviewed
• [Journal Article] Invovement of VCAM-1 in the bovine conceptus adhesion to the uterine endometrium. (2014)
  • Author(s): Bai, bai, Kuse, Ideta, Aoyagi, Fujiwara, Okuda, Imakawa and Sakurai
  • Journal Title: Reproduction Volume: 147 Issue: 2 Pages: 119-127
  • DOI: 10.1530/rep-13-0655
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Extravillous trophoblast cell invasion is promoted by the CD44-hyaluronic acid interaction (2014)
  • Author(s): Hironori Takahashi, Takami Takizawa, Shigeki Matsubara, Akihide Ohkuchi, Tomoyuki Kuwata, Rie Usui, Hisanori Matsumoto, Yukiyasu Sato, Hiroshi Fujiwara, Aikou Okamoto, Mitsuaki Suzuki, Toshihiro Takizawa
  • Journal Title: Placenta Volume: 35 Issue: 3 Pages: 163-170
  • DOI: 10.1016/j.placenta.2013.12.009
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Imatinib sensitizes endometrial cancer cells to cisplatin by targeting CD117-positive growth-competent cells. (2014)
  • Author(s): Zhang X, Kyo S, Nakamura M, Mizumoto Y, Maida Y, Bono Y, Takakura M, Fujiwara H.
  • Journal Title: Cancer Lett. Volume: 345 Issue: 1 Pages: 106-114
  • DOI: 10.1016/j.canlet.2013.11.020
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 母体による胚の認識機構 - 胚の着床（寄生）と感染症は表裏一体か - (2015)
  • Author(s): 藤原 浩
  • Organizer: 第30回日本生殖免疫学会学術講演会オープニングレクチャー
  • Place of Presentation: 熊本
  • Year and Date: 2015-11-21
  • Invited
• [Presentation] 末梢血循環細胞による胚着床誘導機構 (2015)
  • Author(s): 藤原 浩
  • Organizer: 金沢大学学際科学実験サンタ-シンポジウム
  • Place of Presentation: 金沢
  • Year and Date: 2015-11-13
  • Invited
• [Presentation] Possible involvement of Eph-ephrin system in the initial step of embryo implantation (2015)
  • Author(s): Fujiwara H.
  • Organizer: IFFS/JSRM International Meeting 2015
  • Place of Presentation: Yokohama
  • Year and Date: 2015-04-26
  • Int'l Joint Research / Invited
• [Presentation] 血球系細胞の着床への作用機序 (2015)
  • Author(s): 藤原
  • Organizer: 第６０回日本生殖医学会学術講演会 シンポジウム４「妊娠認識と着床」
  • Place of Presentation: 横浜
  • Year and Date: 2015-04-26
  • Invited
• [Presentation] Positive contribution of immune cells to endometrial receptivity and embryo implantation. (2015)
  • Author(s): Hiroshi Fujiwara
  • Organizer: International Congress On“Embryo Implantation: Intricacies and Strategies for its Success”
  • Place of Presentation: National Institute of Immunology, New Delhi, India
  • Year and Date: 2015-03-09 – 2015-03-11
  • Invited
• [Presentation] 婦人科腫瘍学と生殖医学の接点 －胚着床に対応する生殖臓器の機能再建を目指して－ (2015)
  • Author(s): 藤原浩
  • Organizer: 第6回統合産婦人科学研究合同シンポジウム
  • Place of Presentation: 東北大学大学院医学系研究科附属 創生応用医学研究センター（宮城県仙台市）
  • Year and Date: 2015-03-03
  • Invited
• [Presentation] 胚着床に対応する生殖臓器の機能を考慮した再建術を目指して (2014)
  • Author(s): 藤原浩
  • Organizer: 第217回熊本産科婦人科学術講演会
  • Place of Presentation: 熊本地域医療センター（熊本県熊本市）
  • Year and Date: 2014-10-19
  • Invited
• [Presentation] 絨毛外トロホブラスト研究の課題と展望 (2014)
  • Author(s): 藤原浩
  • Organizer: 第22回日本胎盤学会
  • Place of Presentation: 京都大学医学部構内芝蘭会館 （京都府京都市）
  • Year and Date: 2014-10-04
  • Invited
• [Book] A novel concept of fundus-ovary-salpinx-para-aorta implantation promoting unit during human embryo implantation (2015)
  • Author(s): Fujiwara H, Araki Y, Saito S, Imakawa K, Kyo S, Shigeta M, Shiotani M, Horie A, Mori T.
  • Publisher: In Tech