Elucidation of the mechanism for embryo implantation by transcription factor HAND2

• Project/Area Number: 17K11260
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Kansai Medical University
• Principal Investigator: OKADA Hidetaka 関西医科大学, 医学部, 教授 (80330182)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 子宮内膜 / 性ステロイドホルモン

Outline of Final Research Achievements

Progestin is an essential regulator of decidualization and a prerequisite for successful blastocyst implantation. Decidualization of the human endometrium involves a dramatic morphological and functional differentiation of human endometrial stromal cells (ESCs). We have demonstrated that small interfering RNA‐mediated silencing of HAND2 expression in ESCs during progestin‐induced decidualization attenuates both the morphological differentiation and the levels of the decidua‐specific factors. Furthermore, HAND2 regulated the expression of angiogenic factors. These results suggest that the transcription factor HAND2 plays a key role in the regulation of the decidualization and angiogenesis of human ESCs.

Academic Significance and Societal Importance of the Research Achievements

不妊治療において、着床率向上のために黄体ホルモン補充療法が行われている。黄体ホルモンは、胚着床ならびに以後の妊娠維持に必要不可欠な性ステロイドホルモンである。今回の検討により、HAND2という転写因子が、黄体ホルモンによる子宮内膜の機能調整に重要な役割を担っていることが明らかとなった。本研究により見出した新知見は、将来の不妊治療（生殖医療）の発展に寄与すると考える。

Research Products

• [Journal Article] Immune Tolerance of the Human Decidua (2021)
  • Author(s): Mutara H, Tanaka S, Okada H
  • Journal Title: Journal of clinical medicine Volume: 10 Issue: 2 Pages: 351-351
  • DOI: 10.3390/jcm10020351
  • Peer Reviewed / Open Access
• [Journal Article] Characterizing the gut microbiota in females with infertility and preliminary results of a water-soluble dietary fiber intervention study (2020)
  • Author(s): Komiya Shinnosuke、Naito Yuji、Okada Hidetaka、Matsuo Yoshiyuki、Hirota Kiichi、Takagi Tomohisa、Mizushima Katsura、Inoue Ryo、Abe Aya、Morimoto Yoshiharu
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 67 Issue: 1 Pages: 105-111
  • DOI: 10.3164/jcbn.20-53
  • NAID: 130007867952
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Glucose transporter 1 is important for the glycolytic metabolism of human endometrial stromal cells in hypoxic environment. (2020)
  • Author(s): Kido T, Murata H, Nishigaki A, Tsubokura H, Komiya S, Kida N, Kakita-Kobayashi M, Hisamatsu Y, Tsuzuki T, Hashimoto Y, Okada H.
  • Journal Title: Heliyon. Volume: 8 Issue: 6 Pages: e03985-e03985
  • DOI: 10.1016/j.heliyon.2020.e03985
  • Peer Reviewed / Open Access
• [Journal Article] The transcription factor HAND2 up-regulates transcription of the IL15 gene in human endometrial stromal cells (2020)
  • Author(s): Murata H, Tanaka S, Tsuzuki-Nakao T, Kido T, Kakita-Kobayashi M, Kida N, Hisamatsu Y, Tsubokura H, Hashimoto Y, Kitada M, Okada H
  • Journal Title: The Journal of Biological Chemistry Volume: 295 Issue: 28 Pages: 9596-9605
  • DOI: 10.1074/jbc.ra120.012753
  • Peer Reviewed / Open Access
• [Journal Article] Thyroid Hormone Facilitates in vitro Decidualization of Human Endometrial Stromal Cells via Thyroid Hormone Receptors (2020)
  • Author(s): Kakita-Kobayashi Maiko、Murata Hiromi、Nishigaki Akemi、Hashimoto Yoshiko、Komiya Shinnosuke、Tsubokura Hiroaki、Kido Takeharu、Kida Naoko、Tsuzuki-Nakao Tomoko、Matsuo Yoshiyuki、Bono Hidemasa、Hirota Kiichi、Okada Hidetaka
  • Journal Title: Endocrinology Volume: 161 Issue: 6
  • DOI: 10.1210/endocr/bqaa049
  • Peer Reviewed
• [Journal Article] Resveratrol protects mitochondrial quantity by activating SIRT1/PGC-1α expression during ovarian hypoxia. (2020)
  • Author(s): Nishigaki A, Kido T, Kida N, Kakita-Kobayashi M, Tsubokura H, Hisamatsu Y, Okada H.
  • Journal Title: Reprod Med Biol. Volume: 19 Issue: 2 Pages: 189-197
  • DOI: 10.1002/rmb2.12323
  • Peer Reviewed
• [Journal Article] Progestin-induced heart and neural crest derivatives-expressed transcript 2 inhibits angiopoietin 2 via fibroblast growth factor 9 in human endometrial stromal cells. (2019)
  • Author(s): Murata H, Tsuzuki T, Kido T, Kakita-Kobayashi M, Kida N, Hisamatsu Y, Okada H.
  • Journal Title: Reprod Biol. Volume: 19 Issue: 1 Pages: 14-21
  • DOI: 10.1016/j.repbio.2019.02.005
  • Peer Reviewed
• [Journal Article] Cytomorphological features of atypical polypoid adenomyoma of the endometrium (2019)
  • Author(s): Arimoto Tomoko、Ishida Mitsuaki、Ebisu Yusuke、Sandoh Kaori、Okano Kimiaki、Mizokami Tomomi、Kita Masato、Okada Hidetaka、Tsuta Koji
  • Journal Title: Cytopathology Volume: 30 Issue: 3 Pages: 323-325
  • DOI: 10.1111/cyt.12673
  • Peer Reviewed
• [Journal Article] Motivating Mothers to Recommend Their 20-Year-Old Daughters Receive Cervical Cancer Screening: A Randomized Study (2018)
  • Author(s): Egawa-Takata T, Ueda Y, Morimoto A, Tanaka Y, Yagi A, Terai Y, Ohmichi M, Ichimura T, Sumi T, Murata H, Okada H, Nakai H, Mandai M, Matsuzaki S, Kobayashi E, Yoshino K, Kimura T, Saito J, Hori Y, Morii E, Nakayama T, Asai-Sato M, Miyagi E, Sekine M, Enomoto T, Horikoshi Y, Takagi T, Shimura K
  • Journal Title: Journal of Epidemiology Volume: 28 Issue: 3 Pages: 156-160
  • DOI: 10.2188/jea.JE20160155
  • NAID: 130006434071
  • ISSN: 0917-5040, 1349-9092
  • Peer Reviewed
• [Journal Article] Time-dependent changes of the intention of mothers in Japan to inoculate their daughters with the HPV vaccine after suspension of governmental recommendation. (2018)
  • Author(s): Yagi A, Ueda Y, Tanaka Y, Nakae R, Kakubari R, Morimoto A, Terai Y, Ohmichi M, Ichimura T, Sumi T, Murata H, Okada H, Nakai H, Matsumura N, Yoshino K, Kimura T, Saito J, Ikeda S, Asai-Sato M, Miyagi E, Sekine M, Enomoto T, Hirai K, Horikoshi Y, Takagi T, Shimura K.
  • Journal Title: Hum Vaccin Immunother. Volume: 14 Issue: 10 Pages: 2497-2502
  • DOI: 10.1080/21645515.2018.1480240
  • Peer Reviewed
• [Journal Article] The steroid hormone dydrogesterone inhibits myometrial contraction independently of the progesterone/progesterone receptor pathway. (2018)
  • Author(s): Yasuda K, Sumi GI, Murata H, Kida N, Kido T, Okada H.
  • Journal Title: Life Sci. Volume: 15 Pages: 508-51
  • DOI: 10.1016/j.lfs.2018.07.004
  • Peer Reviewed
• [Journal Article] Decidualization of the human endometrium. (2018)
  • Author(s): Okada H, Tsuzuki T, Murata H.
  • Journal Title: Reprod Med Biol Volume: 17 Issue: 3 Pages: 220-227
  • DOI: 10.1002/rmb2.12088
  • Peer Reviewed
• [Journal Article] Cytological features of atypical polypoid adenomyoma of the endometrium: A case report with literature review. (2017)
  • Author(s): Ebisu Y, Arimoto T, Ishida M, Miyasaka C, Uemura Y, Okada H, Tsuta K.
  • Journal Title: Diagn Cytopathol. Volume: 45 Issue: 4 Pages: 345-349
  • DOI: 10.1002/dc.23665
  • Peer Reviewed
• [Journal Article] 女性不妊における治療薬の基礎と実践：いつ・だれに・どう使うか ②ゴナドトロピン製剤 (2017)
  • Author(s): 都築朋子、木田尚子、小野淑子、岡田英孝
  • Journal Title: 薬局 Volume: 68 Pages: 44-49
• [Journal Article] 不妊症－挙児希望患者の取り扱い－ (2017)
  • Author(s): 岡田英孝
  • Journal Title: 今日の治療指針 Volume: 59 Pages: 1245-46
• [Presentation] Thyroid hormone facilitates in vitro decidualization of human endometrial stromal cells in a thyroid hormone receptors-dependent manner (2020)
  • Author(s): Maiko Kobayashi:1 Hiromi Murata:2, Yoshiko Hashimoto:1, Shinnosuke Komiya:1, Hiroaki Tsubokura:1, Naoko Kida:1, Takeharu Kido:1, Yoji Hisamatsu:1, Toshiko Ono:1, Sonoko Okada:1, Tomoko Nakao:1, Hidetaka Okada:1
  • Organizer: 第72回日本産科婦人科学会学術講演会
• [Presentation] Importance of glucose transporter 1 under hypoxic environment in human endometrium (2020)
  • Author(s): Takeharu Kido:1 Hiromi Murata:1, Hiroaki Tsubokura:1, Naoko Kida:1, Maiko Kobayashi:1, Yoji Hisamatsu:1, Yoshiko Hashimoto:1, Hidetaka Okada:1
  • Organizer: 第72回日本産科婦人科学会学術講演会
• [Presentation] 脱落膜化で誘導されるIL15遺伝子の新規HAND２結合配列の同定 (2020)
  • Author(s): 村田紘未、田中進、中尾朋子、木田尚子、橋本佳子、辻 祥子、小野淑子、岡田園子、岡田英孝
  • Organizer: 第65回日本生殖医学会学術講演会
• [Presentation] Novel function of thyroid hormone during decidualization in human endometrial stromal cells and its molecular mechanism (2019)
  • Author(s): Kobayashi Maiko, Tsubokura Hiroaki, Kido Takeharu, Kida Naoko, Hisamatsu Yoji, Murata Hiromi, Ono Toshiko, Okada Sonoko, Nakao Tomoko, Okada Hidetaka
  • Organizer: 第71回日本産科婦人科学会学術講演会
• [Presentation] Heart and neural crest derivatives-expressed transcript 2 involves in vascular maturation during decidualization of human endometrial stromal cells via fibroblast growth factor (2019)
  • Author(s): Murata Hiromi, Nakao Tomoko, Kido Takeharu, Kida Naoko, Kobayashi Maiko, Hisamatsu Yoji, Tsubokura Hiroaki, Okada Hidetaka
  • Organizer: 第71回日本産科婦人科学会学術講演会
• [Presentation] Metabolic pathway of human endometrial stromal cell under hypoxic condition (2019)
  • Author(s): Kido Takeharu, Murata Hiromi, Tsubokura Hiroaki, Kida Naoko, Kobayashi Maiko, Hisamatsu Yoji, Nakao Tomoko, Okada Hidetaka
  • Organizer: 第71回日本産科婦人科学会学術講演会
• [Presentation] PROGESTIN ENHANCES INTERLEUKIN‐15 VIA A TRANSCRIPTION FACTOR HAND2 IN HUMAN ENDOMETRIUM (2019)
  • Author(s): Hidetaka Okada, Hiromi Murata, Naoko Kida, Maiko Kobayashi, Takeharu Kido, Hiroaki Tsubokura, Yoji Hisamatsu, Tomoko Nakao
  • Organizer: ASPIRE2019
  • Int'l Joint Research
• [Presentation] The influence of hypoxia on angiogenesis and metabolism in human endometrial stromal cells (2019)
  • Author(s): Hidetaka Okada, Takeharu Kido
  • Organizer: 75th ASRM Scientific Congress & Expo
  • Int'l Joint Research
• [Presentation] 地域で診る子宮内膜症 (2018)
  • Author(s): 木戸 健陽, 溝上 友美, 北 正人, 岡田 英孝
  • Organizer: 第39回日本エンドメトリオーシス学会
• [Presentation] 大阪がん・生殖医療ネットワーク設立に向けてのアンケート調査 (2018)
  • Author(s): 大八木 知史, 筒井 建紀, 井上 朋子, 都築 朋子, 岡田 英孝
  • Organizer: 第70回日本産科婦人科学会学術講演会
• [Presentation] 子宮内膜症性嚢胞管理の妥当性 後向き研究(Validity of management against the endometriotic cyst: a retrospective study) (2018)
  • Author(s): Kido Takeharu, Tsuzuki Tomoko, Kida Naoko, Kobayashi Maiko, Hisamatsu Yoji, Murata Hiromi, Mizokami Tomomi, Kita Masato, Okada Hidetaka
  • Organizer: 第70回日本産科婦人科学会学術講演会
• [Presentation] HAND2はプロゲステロン誘導性脱落膜化においてヒト子宮内膜のIL-15を調節する (2018)
  • Author(s): Murata Hiromi, Kida Naoko, Kido Takeharu, Kobayashi Maiko, Hisamatsu Yoji, Ono Toshiko, Okada Sonoko, Tsuzuki Tomoko, Okada Hidetaka
  • Organizer: 第70回日本産科婦人科学会学術講演会
• [Presentation] ヒト子宮内膜においてプロゲスチンにより誘導されるHand2はIL-15を制御する (2017)
  • Author(s): 村田 紘未, 木田 尚子, 小林 真以子, 木戸 健陽, 小野 淑子, 岡田 園子, 都築 朋子, 岡田 英孝
  • Organizer: 第69回日本産科婦人科学会学術講演会
• [Presentation] 転写因子HAND2によるヒト子宮内膜機能調節機構の解明 (2017)
  • Author(s): 村田 紘未, 小林 真以子, 木戸 健陽, 木田 尚子, 松本 みお, 岡野 友美, 吉田 彩, 久松 洋司, 小野 淑子, 岡田 園子, 都築 朋子, 岡田 英孝
  • Organizer: 第62回日本生殖医学会
• [Presentation] 凍結融解胚移植のホルモン補充周期における黄体ホルモン製剤の種類による臨床成績に及ぼす影響 (2017)
  • Author(s): 木田 尚子, 都築 朋子, 木戸 健陽, 小林 真以子, 岡野 友美, 村田 紘未, 久松 洋司, 小野 淑子, 岡田 園子, 岡田 英孝
  • Organizer: 第62回日本生殖医学会
• [Remarks] 関西医科大学産婦人科
  • URL: http://www7.kmu.ac.jp/obgyn/
• [Remarks]
  • URL: http://www.kmu.ac.jp/faculty/medical/category3/unit19.html