Elucidation of novel factors contributing to the aquisition of uterine receptivity

• Project/Area Number: 25670695
• 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)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 着床 / 胚受容能 / 子宮 / プロゲステロン / プロゲステロン受容体 / 妊娠 / 細胞増殖 / マウスモデル / 産婦人科学

Outline of Final Research Achievements

The embryo does not normally implant in the cervix but in the uterus. Stromal proliferation and epithelial differentiation, what we here call the proliferation/differentiation switching (PDS), occurs in the receptive uterus. We found that progesterone (P) signaling induces PDS and successful implantation in the receptive uterus, while elevated microRNA-200a leads to the reduction of PR expression and the promotion of P metabolism, and further non-responsiveness of PDS in the cervix. These findings indicate that P signaling deficiency by microRNA-200a confers cervical non-responsiveness to embryo implantation.

Research Products

• [Journal Article] プロテオミクスを用いた妊娠成立・維持機構の研究. (2015)
  • Author(s): 松尾光徳，廣田泰
  • Journal Title: HORMONE FRONTIER IN GYNECOLOGY Volume: 22 Pages: 11-17
• [Journal Article] MicroRNA-200a locally attenuates progesterone signaling in the cervix, preventing embryo implantation. (2014)
  • Author(s): Hirofumi Haraguchi, Tomoko Saito-Fujita, Yasushi Hirota, Mahiro Egashira, Leona Matsumoto, Mitsunori Matsuo, Takehiro Hiraoka, Kaori Koga, Naoko Yamauchi, Masashi Fukayama, Amanda Bartos, Jeeyeon Cha, Sudhansu K. Dey, Tomoyuki Fujii, Yutaka Osuga.
  • Journal Title: Mol Endocrinol. Volume: 28(7) Issue: 7 Pages: 1108-17
  • DOI: 10.1210/me.2014-1097
  • Peer Reviewed
• [Journal Article] Application of detergents or high hydrostatic pressure as decellularization process in uterine tissues and their subsequent effects on in vivo uterine regeneration in murine models (2014)
  • Author(s): E.G.Santoso, K.Yoshida, Y.Hirota, M.Aizawa,O.Yoshino, A.Kishida, Y.Osuga, S.Saito, T.Ushida, K.S.Furukawa,
  • Journal Title: PLoS ONE Volume: 9 Issue: 7 Pages: 1-13
  • DOI: 10.1371/journal.pone.0103201
  • Peer Reviewed / Open Access
• [Journal Article] IL-1β increases expression of tryptophan 2,3-dioxygenase and stimulates tryptophan catabolism in endometrioma stromal cells. (2014)
  • Author(s): Urata Y, Koga K, Hirota Y, Akiyama I, Izumi G, Takamura M, Nagai M, Harada M, Hirata T, Yoshino O, Kawana K, Fujii T, Osuga Y.
  • Journal Title: Am J Reprod Immunol. Volume: 72 Issue: 5 Pages: 496-503
  • DOI: 10.1111/aji.12282
  • Peer Reviewed / Open Access
• [Journal Article] Dienogest reduces proliferation, aromatase expression and angiogenesis, and increases apoptosis in human endometriosis. (2014)
  • Author(s): Miyashita M, Koga K, Takamura M, Izumi G, Nagai M, Harada M, Hirata T, Hirota Y, Fujii T, Osuga Y.
  • Journal Title: Gynecol Endocrinol. Volume: 30 Issue: 9 Pages: 644-648
  • DOI: 10.3109/09513590.2014.911279
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Bone Morphogenetic Protein 6 in Accumulation and Regulation of Neutrophils in the Human Ovary. (2014)
  • Author(s): Akiyama I, Yoshino O, Osuga Y, Shi J, Takamura M, Harada M, Koga K, Hirota Y, Hirata T, Fujii T, Saito S, Kozuma S.
  • Journal Title: Reproductive Sciences Volume: 21 Issue: 6 Pages: 772-777
  • DOI: 10.1177/1933719113518988
  • Peer Reviewed
• [Journal Article] Bone morphogenetic protein 7 increased vascular endothelial growth factor (VEGF)-a expression in human granulosa cells and VEGF receptor expression in endothelial cells. (2014)
  • Author(s): Akiyama I, Yoshino O et al.
  • Journal Title: Reprod Sci. Volume: 21(4) Issue: 4 Pages: 477-82
  • DOI: 10.1177/1933719113503411
  • Peer Reviewed
• [Journal Article] 着床における黄体ホルモン(プロゲステロン)の作用. (2014)
  • Author(s): 藤田知子，廣田泰
  • Journal Title: 医学のあゆみ Volume: 248 Pages: 914-915
• [Journal Article] 着床期子宮におけるプロゲステロンの作用機構 (2014)
  • Author(s): 廣田泰，藤田知子，大須賀穣，藤井知行
  • Journal Title: 日本生殖免疫学会誌 Volume: 29 Pages: 6-11
  • NAID: 130005111147
• [Journal Article] Endometrial cellular senescence contributes to preterm birth (2014)
  • Author(s): Hirota Y.
  • Journal Title: Inflammation and Regeneration Volume: 34 Issue: 1 Pages: 064-068
  • DOI: 10.2492/inflammregen.34.064
  • NAID: 130004943854
  • ISSN: 1880-8190, 1880-9693
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 着床における黄体ホルモン（プロゲステロン）の作用 (2014)
  • Author(s): 藤田知子、廣田泰
  • Journal Title: 医学のあゆみ Volume: 248 Pages: 914-915
• [Journal Article] Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions. (2013)
  • Author(s): Cha J, Bartos A, Egashira M, Haraguchi H, Saito-Fujita T, Leishman E, Bradshaw H, Dey SK, Hirota Y# (#corresponding author).
  • Journal Title: The Journal of Clinical Investigation Volume: 69 Issue: 9 Pages: 454-462
  • DOI: 10.1172/jci70098
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Uterine receptivity and embryo–uterine interactions in embryo implantation: lessons from mice. (2013)
  • Author(s): Egashira M, Hirota Y#. (#corresponding author)
  • Journal Title: Reproductive Medicine and Biology Volume: 12 Issue: 4 Pages: 127-132
  • DOI: 10.1007/s12522-013-0153-1
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 加齢と炎症―免疫老化と細胞老化による加齢炎症のニッチ形成― (2013)
  • Author(s): 廣田泰
  • Journal Title: 別冊 BIO Clinica 慢性炎症と疾患 Volume: 2 Pages: 40-46
• [Journal Article] Interleukin-4 and prostaglandin E2 synergistically up-regulate 3β-hydroxysteroid dehydrogenase type 2 in endometrioma stromal cells (2013)
  • Author(s): Urata Y, Osuga Y, Akiyama I, Nagai M, Izumi G, Takamura M, Hasegawa A, Harada M, Hirata T, Hirota Y, Yoshino O, Koga K, Kozuma S
  • Journal Title: J Clin Endocrinol Metab Volume: 98(4) Issue: 4 Pages: 1583-90
  • DOI: 10.1210/jc.2012-3475
  • Peer Reviewed
• [Journal Article] Follistatin is induced by IL-1βand TNF-αin stromal cells from endometrioma (2013)
  • Author(s): Akiyama I, Yoshino O, Osuga Y, Izumi G, Urata Y, Hirota Y, Hirata T, Harada M, Koga K, Ogawa K, Kozuma S
  • Journal Title: Reprod Sci Volume: 20(6) Issue: 6 Pages: 675-9
  • DOI: 10.1177/1933719112463253
  • Peer Reviewed
• [Journal Article] Cyclic Stretch Augments Production of Neutrophil Chemokines and Matrix Metalloproteinases-1 (MMP-1) from Human Decidual Cells, and the Production was Reduced by Progesterone. (2013)
  • Author(s): Zhao Y, Koga K, Osuga Y, Izumi G, Takamura M, Harada M, Hirata T, Hirota Y, Yoshino O, Inoue S, Fujii T, Kozuma S
  • Journal Title: Am J Reprod Immunol Volume: 69 Issue: 5 Pages: 454-462
  • DOI: 10.1111/aji.12092
  • Peer Reviewed
• [Presentation] 分娩後子宮に存在する老化細胞の除去機構と次回妊娠への影響 (2014)
  • Author(s): 江頭真宏, 廣田泰, 藤田知子, 原口広史, 松本玲央奈, 松尾光徳, 平岡毅大, 大須賀穣, 藤井知行
  • Organizer: 第29回日本生殖免疫学会
  • Place of Presentation: 東京
  • Year and Date: 2014-12-13
• [Presentation] 黄体ホルモンによる子宮内膜の機能調節と着床 (2014)
  • Author(s): 廣田泰
  • Organizer: 第29回日本生殖免疫学会
  • Place of Presentation: 東京
  • Year and Date: 2014-12-12
  • Invited
• [Presentation] プロゲステロンによる子宮内膜の機能調節と着床 (2014)
  • Author(s): 廣田泰
  • Organizer: 第59回日本生殖医学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2014-12-05
  • Invited
• [Presentation] Decidual cellular senescence contributes to preterm delivery. (2014)
  • Author(s): 廣田泰
  • Organizer: 46th International Congress on Pathophysiology of Pregnancy / 35th Japan Society for the Study of Hypertension in Pregnancy.
  • Place of Presentation: 東京
  • Year and Date: 2014-09-19
  • Invited
• [Presentation] MicroRNA-200a confers progesterone signaling deficiency making the cervix unfavorable to embryo implantation (2014)
  • Author(s): Hirota Y
  • Organizer: Gordon Research Conference on Mammalian Reproduction
  • Place of Presentation: New London, USA
  • Year and Date: 2014-08-13
  • Invited
• [Presentation] 妊娠成立に関わるプロゲステロン・シグナルの意義とその調節機構 (2014)
  • Author(s): 廣田泰
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-24
  • Invited
• [Presentation] Defective decidualization with cellular senescence and its outcome (2013)
  • Author(s): Hirota Y
  • Organizer: The 9th Conference of the Pacific Rim Society for Fertility and Sterility
  • Place of Presentation: 神戸国際会議場、神戸市
  • Invited
• [Presentation] プロゲステロン・シグナルと着床～マウスモデルから得た新しい知見 (2013)
  • Author(s): 廣田泰
  • Organizer: 第31回日本受精着床学会総会・学術講演会
  • Place of Presentation: 別府国際コンベンションセンター、別府市
  • Invited
• [Presentation] 細胞老化シグナルを介した早産の発生機構に着目した新しい治療アプローチについての提案 (2013)
  • Author(s): 廣田泰
  • Organizer: 第41回日本臨床免疫学会総会
  • Place of Presentation: 海峡メッセ下関、下関市
  • Invited
• [Presentation] プロゲステロンによって誘導されるガレクチン-1は、妊娠の維持に重要である (2013)
  • Author(s): 廣田泰, 原口広史, 大須賀穣, 藤井知行, 上妻志郎
  • Organizer: 第65回日本産科婦人科学会学術講演会
  • Place of Presentation: ロイトン札幌、札幌市
• [Presentation] プロゲステロンによって子宮に誘導されるガレクチン１は妊娠維持に作用する (2013)
  • Author(s): 廣田泰、藤田知子、原口広史、江頭真宏、大須賀穣、藤井知行、上妻志郎、SK Dey
  • Organizer: 第86回日本内分泌学会学術総会
  • Place of Presentation: 仙台国際センター、仙台市
• [Presentation] Macrophages are involved in the clearance of stromal senescent cells in the postpartum uterus (2013)
  • Author(s): 江頭真宏, 廣田泰, 藤田知子, 原口広史, 大須賀穣, 藤井知行
  • Organizer: 第13回東京大学生命科学シンポジウム
  • Place of Presentation: 東京大学伊藤国際学術研究センター、東京都文京区
• [Presentation] IL-1βは子宮内膜上皮細胞由来のIL-8を介して妊娠初期絨毛細胞の細胞遊走と細胞増殖を促す (2013)
  • Author(s): 江頭真宏, 廣田泰, 原口広史, 藤田知子, 甲賀かをり, 大須賀穣, 藤井知行
  • Organizer: 第31回日本受精着床学会総会・学術講演会
  • Place of Presentation: 別府国際コンベンションセンター、別府市
• [Presentation] 着床前の子宮体部内膜の分化・増殖状態の変化は胚受容能を表し、その変化は上皮のプロゲステロン受容体発現によって維持されている (2013)
  • Author(s): 原口広史，廣田泰，藤田知子，江頭真宏，松本玲央奈，松尾光徳, 甲賀かをり，大須賀穣，藤井知行
  • Organizer: 第58回日本生殖医学会学術講演会
  • Place of Presentation: 神戸国際会議場、神戸市
• [Presentation] 分娩後子宮に存在する老化細胞のクリアランス機構 (2013)
  • Author(s): 江頭真宏, 廣田泰, 藤田知子, 原口広史, 松本玲央奈, 松尾光徳, 大須賀穣, 藤井知行
  • Organizer: 第58回日本生殖医学会学術講演会
  • Place of Presentation: 神戸国際会議場、神戸市
• [Presentation] マウス分娩後子宮に存在する老化細胞のクリアランス機構 (2013)
  • Author(s): 江頭真宏, 廣田泰, 藤田知子, 原口広史, 松本玲央奈, 松尾光徳, 大須賀穣, 藤井知行, 今川和彦, 前多敬一郎
  • Organizer: 第106回日本繁殖生物学会
  • Place of Presentation: 東京農工大学農学部府中キャンパス、東京都府中市
• [Book] プリンシプル産科婦人科学１ 婦人科編 (2014)
  • Author(s): 廣田泰．監修：武谷雄二, 上妻志郎, 藤井知行, 大須賀穣
  • Total Pages: 920
  • Publisher: メジカルビュー社
• [Remarks] Researchmap
  • URL: http://researchmap.jp/yhirota-tky/
• [Remarks] さきがけ慢性炎症
  • URL: http://www.inflam.jst.go.jp/research/p_2210hirota/index.html