雌性生殖器官における成体幹細胞システムの解明と再生医学への応用

2004 Fiscal Year Annual Research Report

• Project/Area Number: 14207066
• Research Institution: Keio University
• Principal Investigator: 吉村 泰典 慶應義塾大学, 医学部, 教授 (10129736)
• Co-Investigator(Kenkyū-buntansha): 岡野 栄之 慶應義塾大学, 医学部, 教授 (60160694) ; 丸山 哲夫 慶應義塾大学, 医学部, 講師 (10209702) ; 田中 守 慶應義塾大学, 医学部, 助講師 (20207145) ; 松崎 有未 慶應義塾大学, 医学部, 助教授 (50338183) ; 内田 浩 慶應義塾大学, 医学部, 助手 (90286534)
• Keywords: 子宮内膜 / 子宮筋 / 幹細胞 / 免疫不全マウス

Research Abstract

本年度は、これまでの研究成果に基づいて得られたヒト子宮内膜side population(endometrial SP : ESP)細胞の組織幹細胞特性について、細胞分子生物学的アプローチを用いて、より詳細な検討を行った
分離したESPのin vitroでの単独培養は困難であったが、様々な細胞との共培養系ではESPは増殖可能であり、特にOP-9細胞をフィーダーにした場合、安定的な増殖が得られただけでなく、ESPは神経様細胞などの異なる細胞系譜へ分化転換をし得た。
異なるヒト3個体のESPおよびnon-ESPよりRNAを抽出し、GeneChip^<【○!R】>による遺伝子発現プロファイリング解析を行ったところ、non-ESPに比べてESPに強く発現している遺伝子群に、ABCG2やCD34などの一般幹細胞マーカーが含まれていた。
ESPおよびnon-ESPを免疫不全マウスへ移植したところ、ESP移植部位において、プロゲステロン受容体が陽性の腺管構造を有する子宮内膜様組織の再構築が認められた。現時点で24個体に移植を行ったが、内膜組織の各コンポーネント(例えば血管のみ)より成る様々な組織も構築されることが判明し、その多様性はnon-ESPに比べてESPで高かった。
以上、in vitro培養実験、発現遺伝子プロファイル、および移植実験の結果から、ESPが高い幹細胞的特性を有することが明らかとなった。同様のアプローチで雌性生殖器官のひとつである子宮筋よりSPを分離し解析した結果、子宮筋SPも組織幹細胞ポテンシャルを有するというデータを得ている。
このように雌性生殖器の幹細胞は、生殖器由来疾患の発生・進展機構の解明、ならびに各組織に共通する組織再生メカニズムの解明に貢献するのみならず、雌性生殖器の機能不全・欠損に対する再生医療における医療資源になり得る可能性が示された。

Research Products

• [Journal Article] Histone acetylation in reproductive organs : significance of histone deacetylase inhibitors in gene transcription. (Review) (2005)
  • Author(s): Uchida H, Maruyama T, Arase T, Ono M, Nagashima T, Masuda H, Asada H, Yoshimura Y
  • Journal Title: Reprod Med Biol 4(2)(In press)
• [Journal Article] A reduction in intraovarian arterial blood flow resistance after ovulation is necessary to achieve pregnancy in natural cycle. (2005)
  • Author(s): Nakagawa K, Ozawa N, Takamatsu K, Takahashi Y, Irahara M, Yoshimura Y, Saito H.
  • Journal Title: J Assist Reprod Genet 22 Pages: 9-14
• [Journal Article] Protein kinase α activity and protein phosphorylation during the mouse sperm acrosomal reaction. (2005)
  • Author(s): Kuji N, Tanaka Y, Komatsu S, Yoshimura Y.
  • Journal Title: Arch Androl 51 Pages: 55-64
• [Journal Article] H1FOO Is Coupled to the Initiation of Oocytic Growth. (2005)
  • Author(s): Tanaka, M, Kihara, M, Hennebold, J.D, Eppig, J.J, Viveiros, M.M, Emery, B.R, Carrell, D.T, Kirkman, N.J, Meczekalski, B, Zhou, J, Bondy, C.A, Becker, M., Schultz, R.M, Misteli, T, De La Fuente, R, King, G.J, Adashi, E.Y.
  • Journal Title: Biol Reprod 72 Pages: 135-142
• [Journal Article] Follicle stimulating hormone-secreting pituitary microadenoma with fluctuating levels of ovarian hyperstimulation. (2004)
  • Author(s): Maruyama T, Masuda H, Uchida H, Nagashima T, Yoshimura Y
  • Journal Title: Obstet Gynecol. (In press)
• [Journal Article] Oocyte-specific linker histone. (2004)
  • Author(s): Tanaka M, Teranishi T, Furuya M, Tanaka Y, Minegishi K, Miykoshi K, Ishimoto H, Yoshimura Y.
  • Journal Title: Hum Cell 17 Pages: 157-159
• [Journal Article] Chromation remodeling with oocyte-specific linker histones. (2004)
  • Author(s): Tanaka M, Teranishi T, Furuya M, Tanaka Y, Minegishi K, Miyakoshi K, Ishimoto H, Yoshimura Y
  • Journal Title: J Mamm Ova Res 21 Pages: 82-88
• [Journal Article] Association of male infertility with Pro185Ala polymorphism in the aryl hydrocarbon receptor repressor gene : implication for the susceptibility to dioxins. (2004)
  • Author(s): Watanabe M, Sueoka K, Sasagawa I, Nakabayashi A, Yoshimura Y, Ogata T.
  • Journal Title: Fertil Steril 82 Pages: 1067-1071
• [Journal Article] Absent inner dynein arms in a fetus with familial hydrocephalus-situs abnormality. (2004)
  • Author(s): Kosaki K, Ikeda K, Miyakoshi K, Ueno M, Kosaki R, Takahashi D, Tanaka M, Torikata C, Yoshimura Y, Takahashi T.
  • Journal Title: Am J Med Genet 129A Pages: 308-311
• [Journal Article] Pulmonary hypoplasia : Prediction with use of ratio of MR imaging-measured fetal lung volume to US-estimated fetal body weight. (2004)
  • Author(s): Tanigaki S, Miyakoshi K, Tanaka M, Hattori Y, Matsumoto T, Ueno K, Uehara K, Nishimura O, Minegishi K, Ishimoto H, Shinmoto H, Ikeda K, Yoshimura Y.
  • Journal Title: Radiology 232 Pages: 767-772
• [Journal Article] Hypertensive disorders in Japanese women with gestational glucose intolerance. (2004)
  • Author(s): Miyakoshi K, Tanaka M, Matsumoto T, Hattori Y, Ueno K, Teranishi T, Minegishi K, Ishimoto H, Shimada A, Yoshimura Y.
  • Journal Title: Diabetes Research and Clinical Practice 64 Pages: 201-205
• [Journal Article] Kupffer cells alter organic anion transport via multidrug resistance protein 2 in the post-cold ischemic rat liver. (2004)
  • Author(s): Kudo A, Kashiwagi S, Kajimura M, Yoshimura Y, Uchida K, Arii S, Suematsu M.
  • Journal Title: Hepatology 39 Pages: 1099-1109
• [Journal Article] Preimplantation diagnosis of duchenne muscular dystrophy. (2004)
  • Author(s): Hashiba T, Watanabe H, Maeda T, Tajima H, Kuji N, Sueoka K, Yoshimura Y
  • Journal Title: J Mamm Ova Res 21 Pages: 7-21
• [Journal Article] Rapid replacement of somatic linker histones with the oocyte-specific linker histone H1foo in nuclear transfer. (2004)
  • Author(s): Teranishi T, Tanaka M, Kimoto S, Ono Y, Miyakoshi K, Kono T, Yoshimura Y
  • Journal Title: Dev Biol 266 Pages: 76-86
• [Journal Article] Spatiotemporal patterns of Musashi1 expression during inner ear development. (2004)
  • Author(s): Sakaguchi H, Yaoi T, Suzuki T, Okano H, Hisa Y, Fushiki N.
  • Journal Title: Neuroreport 15 Pages: 997-1001
• [Journal Article] Mapping spatio-temporal activation of Notch signaling during neurogenesis and gliogenesis in the developing mouse brain. (2004)
  • Author(s): Tokunaga A, Kohyama J, Yoshida T, Nakao K, Sawamoto K, Okano H
  • Journal Title: J Neurochem 90 Pages: 142-154
• [Journal Article] Isolation and transplantation of dopaminergic neurons generated from mouse embryonic stem cells. (2004)
  • Author(s): Yoshizaki T, Inaji M, Kouike H, Shimazaki T, Sawamoto K, Ando K, Date I, Kobayashi K, Suhara T, Uchiyama Y, Okano H
  • Journal Title: Neurosci Lett 363 Pages: 33-37
• [Journal Article] Human Amnion Mesenchyme Cells Express Phenotype of Neuronal Progenitor Cells. (2004)
  • Author(s): Sakuragawa N, Kakinuma K, Hatada S, Kikuchi A, Okano H, Uchida S, Kamo I, Yokoyama Y
  • Journal Title: J Neurosci Res 78 Pages: 208-214
• [Journal Article] Human neuronal stem cells improve sensorimotor and cognitive impairment in Mongolian gerbils after ischemia. (2004)
  • Author(s): Ishibashi S, Sakaguchi, M., Kuroiwa, T., Shimazaki, T., Okano H, Mizusawa, H
  • Journal Title: J Neurosci Res 78 Pages: 215-223
• [Journal Article] Possible origin of the astroblastoma : A novel concept based on experimental findings from clinical material and a review of the literature. (2004)
  • Author(s): Uchida K, Mukai, M., Okano H., Hayashi, T., Kawase, T
  • Journal Title: Neurosurgery 55 Pages: 977-987
• [Journal Article] Characterization of isoforms of MOVO zinc finger protein, a mouse homologue of Drosophila Ovo, as transcription factor. (2004)
  • Author(s): Unezaki, S., Nishikawa, M., Okuda-Ashitaka, E., Masu, Y., Mukai, M., Kobayashi, S., Sawamoto, K., Okano H., Ito, S
  • Journal Title: Gene 336 Pages: 47-58
• [Journal Article] Non-hematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. (2004)
  • Author(s): Kawada H, Fujita J, Kinjo K, Matsuzaki Y, Tsuma M, Miyatake H, Muguruma Y, Itabashi Y, Ikeda Y, Ogawa S, Okano H, Hotta T, Ando K, Fukuda K
  • Journal Title: Blood 104 Pages: 3581-3587
• [Journal Article] Retinoic acid-concentration-dependent acquisition of neural cell identity during in vitro differentiation of mouse embryonic stem cells. (2004)
  • Author(s): Okada Y, Shimazaki T, Sobue G, Okano H
  • Journal Title: Dev Biol 275 Pages: 124-142
• [Journal Article] Differential expression of Pax6 and Ngn2 between pair-generated cortical neurons. (2004)
  • Author(s): Kawaguchi A., Ogawa M., Saito K., Matsuzaki F., Okano H, Miyata T
  • Journal Title: J Neurosci Res 78 Pages: 784-795
• [Journal Article] Deltex induces an accumulation of the vesicular Notch protein and activates Suppressor of hairless-independent Notch signaling in Drosophila. (2004)
  • Author(s): Hori K, Ito M., Fuwa TJ, Okano H., Baron M, Matsuno K
  • Journal Title: Development 131 Pages: 5527-5537
• [Journal Article] Comparison between fetal spinal cord-and forebrain-derived neural stem/progenitor cells as a source of transplantation for spinal cord injury (2004)
  • Author(s): Watanabe K, Nakamura M, Iwanami A, Fujita Y, Kanemura Y, Toyama Y, Okano H
  • Journal Title: Dev Neurosci 26 Pages: 275-287
• [Journal Article] The origin of bone marrow-derived cardiomyocytes is mesenchymal : little contribution of hematopoietic cells. (2004)
  • Author(s): Kawada H., Fujita J., Matsuzaki Y., Tsuma M., Miyatake H., Muguruma Y, Itabashi Y., Okano H., Ogawa S., Hotta T., Ando K., Fukuda K
  • Journal Title: Blood (In press)
• [Journal Article] Hematopoietic and nonhematopoietic potentials of Hoechst(low)/side population cells isolated from adult rat kidney. (2004)
  • Author(s): Iwatani H, Ito T, Imai E, Matsuzaki Y, Suzuki A, Yamato M, Okabe M, Hori M
  • Journal Title: Kidney Int 65 Pages: 1604-1614