Regeneration of mouse uterus using decellularized uterine matrix transplantation

• Project/Area Number: 16K15700
• 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: Osuga Yutaka 東京大学, 医学部附属病院, 教授 (80260496)
• Co-Investigator(Kenkyū-buntansha): 廣田 泰 東京大学, 医学部附属病院, 講師 (40598653)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 子宮 / 脱細胞化 / 再生 / STAT3 / 着床 / 細胞外基質 / 妊娠 / 組織再生 / マウス / 卵巣ホルモン / 子宮再生 / 月経 / 分娩後 / 再生医学

Outline of Final Research Achievements

The aim of this study is to establish a new therapeutic strategy for implantation failure. We established a method of uterine regeneration through decellularized uterine matrix transplantation in mice. The decellularized uterine matrices obtained after SDS treatment were transplanted into the recipient mouse uteri with artificially induced defects. All the uterine layers were recovered at the sites of decellularized uterine matrix transplantation within a month. In the regenerated uterus, normal implantation and pregnancy maintenance were observed. The tissue regeneration processes were totally impaired in mice with uterine deletion of STAT3, a downstream signaling pathway of LIF, suggesting that STAT3 has a critical role in uterine regeneration as well as implantation. Thus, decellularized uterine matrix is a possible tool for regeneration of the functional uterus.

Research Products

• [Journal Article] ジエノゲストの子宮腺筋症患者における臨床評価 - 多施設共同ランダム化プラセボ対照二重盲検並行群間用量反応比較試験 - (2017)
  • Author(s): 大須賀穣, 渡邉学, 萩野篤司
  • Journal Title: 薬理と治療 Volume: 198 Pages: 4277-4284
  • Peer Reviewed
• [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
  • 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] Enhanced HIF2α expression during human trophoblast differentiation into syncytiotrophoblast suppresses transcription of placental growth factor (2017)
  • Author(s): Fujii Tatsuya、Nagamatsu Takeshi、Morita Kazuki、Schust Danny J.、Iriyama Takayuki、Komatsu Atsushi、Osuga Yutaka、Fujii Tomoyuki
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 12455-12455
  • DOI: 10.1038/s41598-017-12685-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of the efficacy and safety of dienogest in the treatment of painful symptoms in patients with adenomyosis: a randomized, double-blind, multicenter, placebo-controlled study (2017)
  • Author(s): Osuga Yutaka、Fujimoto-Okabe Haruka、Hagino Atsushi
  • Journal Title: Fertil Steril Volume: 108 Issue: 4 Pages: 673-678
  • DOI: 10.1016/j.fertnstert.2017.07.021
  • Peer Reviewed
• [Journal Article] Long-term use of dienogest in the treatment of painful symptoms in adenomyosis (2017)
  • Author(s): Osuga Yutaka、Watanabe Manabu、Hagino Atsushi
  • Journal Title: J Obstet Gynaecol Res Volume: 43 Issue: 9 Pages: 1441-1448
  • DOI: 10.1111/jog.13406
  • Peer Reviewed
• [Journal Article] Development of endometrioma after cervical conization (2017)
  • Author(s): Takahashi Nozomi、Koga Kaori、Arakawa Ichiro、Harada Miyuki、Oda Katsutoshi、Kawana Kei、Fujii Tomoyuki、Osuga Yutaka
  • Journal Title: Gynecol Endocrinol Volume: 34 Issue: 4 Pages: 1-4
  • DOI: 10.1080/09513590.2017.1393660
  • Peer Reviewed
• [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] The Emerging Role of FOXL2 in Regulating the Transcriptional Activation Function of Estrogen Receptor β: An Insight into Ovarian Folliculogenesis (2017)
  • Author(s): Hirano M, Wada-Hiraike O, Fu H, Akino N, Isono W, Sakurabashi A, Fukuda T, Morita Y, Tanikawa M, Miyamoto Y, Nishi Y, Yanase T, Harada M, Oishi H, Yano T, Koga K, Oda K, Kawana K, Fujii T, Osuga Y.
  • Journal Title: Reprod Sci Volume: 24 Issue: 1 Pages: 133
  • DOI: 10.1177/1933719116651150
  • 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] The assessment of myometrium perfusion in patients with uterine fibroid by arterial spin labeling MRI. (2016)
  • Author(s): Takahashi N, Yoshino O, Hiraike O, Maeda E, Nakamura M, Hori M, Harada M, Koga K, Saito S, Fujii T, Osuga Y.
  • Journal Title: Springerplus Volume: 5 Issue: 1 Pages: 1907-1907
  • DOI: 10.1186/s40064-016-3596-0
  • Peer Reviewed / Open Access
• [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] Assisted reproductive technology pregnancy complications are significantly associated with endometriosis severity before conception: a retrospective cohort study. (2016)
  • Author(s): Fujii T, Wada-Hiraike O, Nagamatsu T, Harada M, Hirata T, Koga K, Fujii T, Osuga Y.
  • Journal Title: Reprod Biol Endocrinol Volume: 14 Issue: 1 Pages: 73-73
  • DOI: 10.1186/s12958-016-0209-2
  • Peer Reviewed / Open Access
• [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] 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] 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] Usefulness of T2 star-weighted imaging in ovarian cysts and tumors. (2016)
  • Author(s): Takahashi N, Yoshino O, Maeda E, Naganawa S, Harada M, Koga K, Hiraike O, Nakamura M, Tabuchi T, Hori M, Saito S, Fujii T, Osuga Y.
  • Journal Title: J Obstet Gynaecol Res Volume: 42 Issue: 10 Pages: 1336-1342
  • DOI: 10.1111/jog.13056
  • Peer Reviewed
• [Journal Article] Where are oncofertility and fertility preservation treatments heading in 2016? (2016)
  • Author(s): Harada M, Osuga Y.
  • Journal Title: Future Oncol Volume: 12 Issue: 20 Pages: 2313-2321
  • DOI: 10.2217/fon-2016-0161
  • Peer Reviewed
• [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] Diet and Supplements for Endometriosis (2017)
  • Author(s): Yutaka Osuga
  • Organizer: 6 th Asian Congress of Endometriosis
  • Int'l Joint Research / Invited
• [Presentation] Novel immune mechanism in the development of endometriosis (2017)
  • Author(s): Yutaka Osuga
  • Organizer: 19th World Congress on In Vitro Fertilization in conjunction with VI. Society of Reproductive Medicine and Surgery Congress
  • Int'l Joint Research / Invited
• [Presentation] Novel strategies for ART in patients with endometriosis, adenomyosis, and uterine fibroid. (2017)
  • Author(s): Yutaka Osuga
  • Organizer: The 11th Congress of the Pacific Society for Reproductive Medicine
  • Int'l Joint Research / Invited
• [Presentation] Current problems in infertile women associated with endometriosis. (2017)
  • Author(s): Yutaka Osuga
  • Organizer: 7th Congress of the Asia Pacific Initiative on Reproduction
  • Int'l Joint Research / Invited
• [Presentation] Results from a phase 2 study of Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, VS. placebo in women with endometriosis-associated pain. (2017)
  • Author(s): Yutaka Osuga
  • Organizer: World Congress of Endometriosis 2017
  • Int'l Joint Research / 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