成体幹細胞システムを標的にした雌性生殖器官疾患の病因解明とその制御

2008 Fiscal Year Annual Research Report

• Project/Area Number: 20249067
• Research Institution: Keio University
• Principal Investigator: 吉村 泰典 Keio University, 医学部, 教授 (10129736)
• Co-Investigator(Kenkyū-buntansha): 丸山 哲夫 慶應義塾大学, 医学部, 講師 (10209702) ; 内田 浩 慶應義塾大学, 医学部, 助教 (90286534) ; 梶谷 宇 慶應義塾大学, 医学部, 助教 (60407111)
• Keywords: 再生医学 / 移植・再生医療 / 幹細胞 / マイクロアレイ

Research Abstract

本研究では、雌性生殖器官における成体幹細胞システムの基礎的解明をさらに進めていくと同時に、多角的な臨床応用を目指して、成体幹細胞を用いた疾患モデルの構築、およびSP法に拠らない新しい幹細胞分離法の確立を通じて、幹細胞を標的にした雌性生殖器疾患に対する治療法の開発を目的とする。
まず、我々の既報の内膜症モデルマウス(Masuda, et al., PNAS, 2007)を用い、再構築内膜組織における幹細胞の同定をlabel retaining cell (LRC)法と増殖マーカーにより行った。その結果、生体同様、内膜-筋接合部に特に増殖の盛んな細胞が集積していた。しかしLRC細胞は十分に検出されず、BrdU投与の時期や量など検討を要することが判明した。
一方、SP法に拠らない新しい幹細胞分離法として、まず子宮筋幹細胞について検討したところ、子宮筋細胞のなかでLin(CD31, CD45, Glycophrin A)陰性かつCD34陽性/CD49f陽性細胞(Lin-/Double Positive Cells; Lin-/DPC)が幹細胞特性を有することが判明した。具体的には、Lir-/DPCのみがSP分画を含んでおり, in vitroで骨・脂肪・軟骨細胞へ分化した。また、我々の既報(Ono, et al., PNAS, 2007)では、子宮筋幹細胞は低酸素で効率良く増殖したが、Lin-/DPCも同様に低酸素で高い増殖効率を示した。さらに、重度免疫不全マウスへの子宮への移植実験では、in vivoでヒト子宮平滑筋様の組織を構築し得た.このように表面抗原による新しい方法で単離されたLin-/DPCが組織幹細胞特性を有することから、本法を他の雌性生殖器官幹細胞の分離・同定・機能解析に応用することが可能となり、次年度に向けての重要な基盤データが得られた。

Research Products

• [Journal Article] Prenatal diagnosis of retroperitoneal teratoma : a case report and review of the literature. (2009)
  • Author(s): Asai S, Ishimoto H, Kim SH, Higuchi T, Minegishi K, Tanaka M, Hoshino K, Morikawa Y, Yoshimura Y
  • Journal Title: Fetal Diagn Ther 25 Pages: 76-78
  • Peer Reviewed
• [Journal Article] The UDP-glucose receptor P2RY14 triggers innate mucosalimmunity in the female reproductive tract by inducing IL-8. (2009)
  • Author(s): Arase T, Uchida H, Kajitani T, Ono M, Tamaki K, Oda H, Nishikawa S, Kagami M, Nagashima T, Masuda H, Asada H, Yoshimura Y, Maruyama T
  • Journal Title: The Journal of Immunology (In press)
  • Peer Reviewed
• [Journal Article] Ureteral catheter placement for prevention of ureteral injury during laparoscopic hysterectomy. (2008)
  • Author(s): Tanaka Y, Asada H, Kuji N, Yoshimura Y
  • Journal Title: J Obstet Gynaecol Res 34 Pages: 67-72
  • Peer Reviewed
• [Journal Article] Analysis of serum FSH bioactivity in a patient with an FSH-secreting pituitary microadenoma and multicystic ovaries : A Case Report. (2008)
  • Author(s): Kajitani T, Liu S, Maruyama T, Uchida H, Sakurai R, Masuda H, Nagashima T, Ono M, Arase T, Yoshimura Y
  • Journal Title: Hum Reprod 23 Pages: 435-439
  • Peer Reviewed
• [Journal Article] Glycodelin inhibits progression to S phase and cell proliferation : a progesterone-induce regulator for endometrial epithelial cell growth. (2008)
  • Author(s): Ota K, Maruyama T, Uchida H, Ono M, Nagashima T, Arase T, Kajitani T, Kagami M, Morita M, Yoshimura Y
  • Journal Title: Mol Hum Reprod 14 Pages: 17-22
  • Peer Reviewed
• [Journal Article] Activation of SRC kinase and phosphorylation of STAT5 are required for decidual transformation of human endometrial stromal cells. (2008)
  • Author(s): Nagashima T, Maruyama T, Uchida H, Kajitani T, Arase T, Ono M, Oda H, Kagami M, Masuda H, Nishikawa S, Arase H, Yoshimura Y
  • Journal Title: Endocrinology 149 Pages: 1227-1234
  • Peer Reviewed
• [Journal Article] In vivo imaging in humanized mice. (2008)
  • Author(s): Masuda H, Okano HJ, Maruyama T, Yoshimura Y, Okano H, Matsuzaki Y
  • Journal Title: Curr Top Microbiol Immunol 324 Pages: 179-196
  • Peer Reviewed
• [Journal Article] The periphery of the human fetal adrenal gland is a site of angiogenesis : Zonal differential expression and regulation of angiogenic factors. (2008)
  • Author(s): Ishimoto H, Minegishi K, Higuchi T, Furuya M, Asai S, Kim SH, Tanaka M, Yoshimura Y, Jaffe RB
  • Journal Title: J Clin Endocrinol Metab 93 Pages: 2402-2408
  • Peer Reviewed
• [Journal Article] Semiquantitative assessment of MR imaging in prediction of efficacy of gonadotropin-releasing hormone agonist for volume reduction of uterine leiomyoma : Initial experience. (2008)
  • Author(s): Okuda S, Oshio K, Shinmoto H, Tanimoto A, Asada H, Fujii T, Yoshimura Y, Kuibayashi S
  • Journal Title: Radiology 248 Pages: 917-924
  • Peer Reviewed
• [Journal Article] Buoyant density and sedimentation dynamics of HIV-1 in two density-gradient media for semen processing. (2008)
  • Author(s): Kuji N, Yoshii T, Hatnatani T, Hanabusa H, Yoshimura Y, Kato S
  • Journal Title: Fertil Steril 90 Pages: 1983-1987
  • Peer Reviewed
• [Journal Article] Pregnancy outcomes of reciprocal translocation carriers who have a history of repeated pregnancy loss. (2008)
  • Author(s): Ozawa N, Maruyama T, Nagashima T, Ono M, Arase T, Ishimoto H, Yoshimura Y
  • Journal Title: Fertil Steril 90 Pages: 1301-1304
  • Peer Reviewed
• [Journal Article] Occipital hemangioma : prenatal sonographic and magnetic resonanee image. (2008)
  • Author(s): Miyakoshi K, Tanaka M, Matsumoto T, Hattori Y, Minegishi K, Ishimoto H, Yoshimura Y
  • Journal Title: J Obstet Gynaecol Res 34 Pages: 666-669
  • Peer Reviewed
• [Journal Article] Molecular and cellular mechanisms for differentiation and regeneration of the uterine endometrium. (2008)
  • Author(s): Maruyama T, Yoshimura Y
  • Journal Title: Endocr J 55 Pages: 795-810
  • Peer Reviewed
• [Journal Article] Regeneration and adult stem cells in the human female reproductive tract. (2008)
  • Author(s): Ono M, Maruyama T, Yoshimura Y
  • Journal Title: Stem Cells and Cloning Pages: 23-29
  • Peer Reviewed
• [Presentation] The role of uterine smooth muscle stem cells, isolated based on cell surface markers, in myometrial remodeling in the pregnantuterus. (2009)
  • Author(s): Ono M, Maruyama T, Kajitani T, Uchida H, Oda H, Nishikawa S, Kagami M, Arase T, Nagashima T, Masuda H, Morikawa S, Mabuchi Y, Okano H, Matsuzaki Y, Yoshimura Y
  • Organizer: Society for Gynecologic Investigation 56^<th> Annual Meeting
  • Place of Presentation: Glasgow, Scotland
  • Year and Date: 20090317-20090321
• [Presentation] Psychosocial stress and mental health status of Japanese couples with a history of repeated pregnancy. (2008)
  • Author(s): Kagami M, Maruyama T, Kozumi T, Arase T, Uchida H, Yoshimura Y
  • Organizer: ASRM 2008 Annual Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 20081108-20081112
• [Presentation] Isolation and functional analysis of putative human endometrialstem/progenitor cells. (2008)
  • Author(s): Masuda H, Maruyama T, 0no M, Nagashima T, Kajitani T, Okano H, Matsuzaki Y, Yoshimura Y
  • Organizer: Annual Meeting of The European of Human Reproduction and Embryology.
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20080706-20080709
• [Book] Current topics in Microbiology and Immunology Humanized Mice. (2008)
  • Author(s): Masuda H, Okano HJ, Maruyama T, Yoshimura Y, Okano H, Matsuzaki Y
  • Total Pages: 179-196
  • Publisher: Springer