Regenerative medicine frontier research targeting mesenchymal cells for the treatment of congenital upper urinary tract abnormalities.

• Project/Area Number: 20K18150
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Jichi Medical University (2021-2022); Wakayama Medical University (2020)
• Principal Investigator: Hyuga Taiju 自治医科大学, 医学部, 講師 (50741279)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 尿路 / 間葉 / 再生医学 / 間葉細胞 / 可視化 / 上部尿路 / 尿管 / ソノポレーション / 平滑筋

Outline of Research at the Start

上部尿路に異常を示す先天性疾患の治療方法の確立に、困難が伴っている。特に上部尿路の低形成に対して、手術治療効果は限定的であり、根本的な間葉層、平滑筋層の再建が求められている。本研究では、尿管の間葉、平滑筋層の分子発生メカニズムの解析に基づき以下の再生医学研究を展開する。
（1）in vivoの尿路系の評価の為、マウス尿路の可視化技術を確立する（2）尿管の未分化間葉細胞を操作し、ソノポレーション法を用いて細胞増殖因子を改変し、胎児を含む尿管の平滑筋層の増殖、修復操作を行う。（3）成体マウスの尿管の異常モデル（結紮モデルなど）で、尿管の修復実験を行う。

Outline of Final Research Achievements

In the field of pediatric urology, we performed various regenerative studies to treat abnormalities of the kidney and urinary tracts (kidney, ureter, bladder, urethra, etc.). Since an assay system for analyzing the condition of the urinary tract is necessary, we established the assay system for the urinary tract in mice for the first time in the world. Utilizing contrast agent and other techniques, we reported on the anatomy of the mouse urethra. Utilizing the assay system, we are now elucidating the pathology that causes inflammatory changes in the epithelium and mesenchyme after urinary extravasation and subsequent fibrosis of the mesenchyme to the ductal organs.

Academic Significance and Societal Importance of the Research Achievements

小児泌尿器科領域において、尿路の異常の基礎的なメカニズムの解明についてはエビデンスが不足している状況であり、未だわかっていないことが多い。それを解明するために動物実験を行い、情報を蓄積していく必要がある。本研究では、今まで不明であったマウスの尿路の解剖、評価系を開発した(Scientific Reports 2020 Hyuga et al、及び投稿中)。加えて、手術後合併症の発症機序としての病態予後の解明を行った。管腔臓器特有の病態としての　尿漏出後の病態について解明を行いつつある。

Research Products

• [Journal Article] Androgen/Wnt/β-catenin signal axis augments cell proliferation of the mouse erectile tissue, corpus cavernosum (2022)
  • Author(s): Mizuki Kajimoto, Kentaro Suzuki, Yuko Ueda, Kota Fujimoto, Toru Takeo, Naomi Nakagata, Taiju Hyuga, Kyoichi Isono, Gen Yamada
  • Journal Title: Congenit Anom Volume: 62(3) Issue: 3 Pages: 123-133
  • DOI: 10.1111/cga.12465
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of mouse line showing inducible priapism‐like phenotypes (2022)
  • Author(s): Hashimoto Daiki、Fujimoto Kota、Morioka Shin、Ayabe Shinya、Kataoka Tomoya、Fukumura Ryutaro、Ueda Yuko、Kajimoto Mizuki、Hyuga Taiju、Suzuki Kentaro、Hara Isao、Asamura Shinichi、Wakana Shigeharu、Yoshiki Atsushi、Gondo Yoichi、Tamura Masaru、Sasaki Takehiko、Yamada Gen
  • Journal Title: Reproductive Medicine and Biology Volume: 21 Issue: 1
  • DOI: 10.1002/rmb2.12472
  • Peer Reviewed / Open Access
• [Journal Article] A visualization system for erectile vascular dynamics (2022)
  • Author(s): Fujimoto Kota、Hashimoto Daiki、Kashimada Kenichi、Kumegawa Shinji、Ueda Yuko、Hyuga Taiju、Hirashima Tsuyoshi、Inoue Norimitsu、Suzuki Kentaro、Hara Isao、Asamura Shinichi、Yamada Gen
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 10
  • DOI: 10.3389/fcell.2022.1000342
  • Peer Reviewed / Open Access
• [Journal Article] Dynamic erectile responses of a novel penile organ model utilizing TPEM. (2021)
  • Author(s): Hashimoto D, Hirashima T, Yamamura H, Kataoka T, Fujimoto K, Hyuga T, Yoshiki A, Kimura K, Kuroki S, Tachibana M, Suzuki K, Yamamoto N, Morioka S, Sasaki T, Yamada G.
  • Journal Title: Biol Reprod. Volume: in press Issue: 4 Pages: 875-886
  • DOI: 10.1093/biolre/ioab011
  • Peer Reviewed / Open Access
• [Journal Article] 3D reconstruction and histopathological analyses on murine corporal body. (2021)
  • Author(s): Hashimoto D, Kajimoto M, Ueda Y, Hyuga T, Fujimoto K, Inoue S, Suzuki K, Kataoka T, Kimura K, Yamada G.
  • Journal Title: Reprod Med Biol. Volume: 20(2) Issue: 2 Pages: 199-207
  • DOI: 10.1002/rmb2.12369
  • Peer Reviewed / Open Access
• [Journal Article] Radiation inducible MafB gene is required for thymic regeneration (2021)
  • Author(s): Daiki Hashimoto, Jose Gabriel R. Colet, Aki Murashima, Kota Fujimoto, Yuko Ueda, Kentaro Suzuki, Taiju Hyuga, Hiroaki Hemmi, Tsuneyasu Kaisho, Satoru Takahashi, Yousuke Takahama and Gen Yamada1
  • Journal Title: Scientific Reports Volume: - Issue: 1 Pages: 10439-10439
  • DOI: 10.1038/s41598-021-89836-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Radiation inducible MafB gene is required for thyme regeneration (2021)
  • Author(s): Hashimoto Daiki, Jose Gabriel R. Colet, Aki Murashima, Kota Fujimoto, Yuko Ueda, Kentaro Suzuki, Taiju Hyuga, Hiroaki Hemmi, Tsuneyasu Kaisho, Satoru Takahashi, Yousuke Takahama, Gen Yamada
  • Journal Title: Scientific Reports Volume: in press
  • Peer Reviewed
• [Journal Article] Evaluation of surgical procedures of mouse urethra by visualization and the formation of fistula (2020)
  • Author(s): Hyuga Taiju、Hashimoto Daiki、Matsumaru Daisuke、Kumegawa Shinji、Asamura Shinichi、Suzuki Kentaro、Katayama Kei-ichi、Nakamura Shigeru、Nakai Hideo、Yamada Gen
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 18251-18251
  • DOI: 10.1038/s41598-020-75184-5
  • Peer Reviewed / Open Access