Analysis of reconstruction mechanism of endometrial epithelial cell sheet during human implantation

• Project/Area Number: 17K11251
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Keio University
• Principal Investigator: HIHARA Hanako 慶應義塾大学, 医学部(信濃町), 助教 (80626458)
• Co-Investigator(Kenkyū-buntansha): 丸山 哲夫 慶應義塾大学, 医学部(信濃町), 准教授 (10209702) ; 内田 浩 慶應義塾大学, 医学部(信濃町), 講師 (90286534) ; 升田 博隆 慶應義塾大学, 医学部(信濃町), 講師(非常勤) (80317198) ; 内田 明花 慶應義塾大学, 医学部(信濃町), 助教 (60445236)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 着床 / 子宮内膜上皮細胞 / 遠心性運動 / 求心性運動 / Hippo pathway / 生殖医学

Outline of Final Research Achievements

During human implantation, embryo have to adhere and migrate into maternal endometrial tissue. For successful pregnancy, construction of embryo-penetrating route in endometrial epithelial cell barrier is required. In in vitro implantation assay system, the unique and reasonable preparation of embryo-penetrating route is performed by massive efferent motion of endometrial epithelial cells in association with endometrial epithelial cell apoptosis. The characteristic efferent cell motion is regulated by ovarian steroid hormones and can be accelerated by a kind of histone deacetylase inhibitors. Moreover, the acceleration ratio is higher in cells near the embryo attachment point compared to cells far from the central point.

Academic Significance and Societal Importance of the Research Achievements

女性ホルモン剤投与による生殖補助医療の成功率上昇のメカニズムの一端を示している可能性がある。また、妊娠反応は認めても臨床的妊娠にはいたらないごくごく初期の流産（化学的流産）は、胚接着後間もない胚ー子宮内膜の相互反応の破綻ととらえることができるが、胚接着から胚陥入までの超初期段階の妊娠メカニズムとして子宮内膜上皮細胞の特異な細胞動態の解明は、今後の異常状態の理由（メカニズムのいかなる破綻か）の解明検討をあわせて臨床妊娠率向上にむけての新たな治療戦略の理論的基盤に発展していくことが期待される。

Research Products

• [Journal Article] The orientation of a decellularized uterine scaffold determines the tissue topology and architecture of the regenerated uterus in rats (2019)
  • Author(s): Miki Fumie、Maruyama Tetsuo、Miyazaki Kaoru、Takao Tomoka、Yoshimasa Yushi、Katakura Satomi、Hihara Hanako、Uchida Sayaka、Masuda Hirotaka、Uchida Hiroshi、Nagai Toshihiro、Shibata Shinsuke、Tanaka Mamoru
  • Journal Title: Biology of Reproduction Volume: - Issue: 5 Pages: 1215-1227
  • DOI: 10.1093/biolre/ioz004
  • Peer Reviewed / Open Access
• [Journal Article] ZEB1 expression is a potential indicator of invasive endometriosis (2017)
  • Author(s): Furuya M, Masuda H, Hara K, Uchida H, Sato K, Sato S, Asada H, Maruyama T, Yoshimura Y, Katabuchi H, Tanaka M, Saya H
  • Journal Title: Acta Obstet Gynecol Scand Volume: 96 Issue: 9 Pages: 1128-1135
  • DOI: 10.1111/aogs.13179
  • Peer Reviewed
• [Journal Article] Impact of borderline-subclinical hypothyroidism on subsequent pregnancy outcome in women with unexplained recurrent pregnancy loss (2017)
  • Author(s): Uchida S, Maruyama T, Kagami M, Miki F, Hihara H, Katakura S, Yoshimasa Y, Masuda H, Uchida H, Tanaka M
  • Journal Title: J Obstet Gynaecol Res Volume: 43 Issue: 6 Pages: 1014-1020
  • DOI: 10.1111/jog.13319
  • Peer Reviewed
• [Presentation] Differential epithelial-mesenchymal transition status between types of endometriosis and adenomyosis (2017)
  • Author(s): Hirotaka Masuda, Masataka Furuya, Tetsuo Maruyama, Hironori Asada, Hidetaka Katabuchi, Hideyuki Saya, Mamoru Tanaka
  • Organizer: 33rd Annual Meeting of European Society of Human Reproduction and Embryology (ESHRE2017)
  • Int'l Joint Research
• [Presentation] Differential status of epithelial-mesenchymal transition in each endometriotic lesion: ZEB1 as a potential indicator of endometriotic invasiveness (2017)
  • Author(s): Hirotaka Masuda, Masataka Fuyuya, Tetsuo Maruyama, Hironori Asada, Hideyuki Saya, Mamoru Tanaka
  • Organizer: 13th World Congress on Endometriosis (WCE2017)
  • Int'l Joint Research
• [Presentation] 子宮内膜症の各病態における上皮間葉転換状態の解析と子宮内膜症におけるZEB1の浸潤性マーカーとしての可能性 (2017)
  • Author(s): 升田博隆，古谷正敬，丸山哲夫，内田 浩，内田明花，吉村泰典，佐谷秀行，片渕秀隆，田中 守
  • Organizer: 第35回日本受精着床学会
• [Presentation] Differential status of epithelial-mesenchymal transition in endometriosis and adenomyosis: ZEBI as a potential indicator of endometriotic invasiveness (2017)
  • Author(s): Hirotaka Masuda, Masataka Furuya, Hironori Asada, Tetsuo Maruyama, Hiroshi Uchida, Sayaka Uchida, Yasunori Yoshimura, Hidetaka Katabuchi, Hideyuki Saya, Mamoru Tanaka, Daisuke Aoki
  • Organizer: 第69回日本産科婦人科学会International Session
• [Presentation] Impact of subclinical hypothyroidism on subsequent pregnancy outcome in women with unexplained recurrent pregnancy loss (2017)
  • Author(s): Sayaka Uchida, Tetsuo Maruyama, Maki Kagami, Fumie Miki, Hanako Hihara, Shoko Tomisato, Satomi Katakura, Yushi Yoshimasa, Hirotaka Masuda, Hiroshi Uchida, Mamoru Tanaka, Daisuke Aoki
  • Organizer: 第69回日本産科婦人科学会
• [Remarks] 慶應義塾大学医学部産婦人科学教室ホームページ
  • URL: http://www.obgy.med.keio.ac.jp/research/03rep-endo.php