2002 Fiscal Year Annual Research Report

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

Research Project

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)	田中守慶應義塾大学, 医学部, 専任講師 (20207145) 丸山哲夫慶應義塾大学, 医学部, 専任講師 (10209702) 岡野栄之慶應義塾大学, 医学部, 教授 (60160694) 清水亜紀慶應義塾大学, 医学部, 助手 (60306826) 伊谷有未慶應義塾大学, 医学部, 助手 (50338183)
Keywords	子宮内膜 / 幹細胞
Research Abstract	本年度は、雌性生殖器官組織のなかで、増殖・分化・剥脱という月経周期を延々と反復するユニークな生物学的ポテンシャルを保有する子宮内膜組織における成体幹細胞の同定・分離・培養技術の検討を行った。 (1)子宮内膜幹細胞の同定・分離(1)他の幹細胞に共通なマーカーによる同定・選別:子宮内膜幹細胞の同定のため、既知の他臓器幹細胞マーカー(例えば神経幹細胞に特異的な蛋白質Musashi-1等)に対する抗体を用いて免疫組織染色による位置的・時間的な幹細胞局在の確認を行った。Musashi-1を含めたいくつかの既知幹細胞マーカー陽性細胞は、必ずしも幹細胞が比較的豊富にあると考えられる基底層には局在しておらず、子宮内膜組織構成細胞の多様性を考慮すると、多重染色などによるより詳細な解析が必要であることが明らかとなった。 (2)Side Population(SP)法の応用:Hoechst33342染色によるSide Population分離方法により、高い幹細胞活性を持つことが予想される細胞集団の同定分離を子宮内膜において試みた。内膜組織からのSP細胞分離条件の検討を重ねた結果、安定的にSP細胞を分離する方法を確立した。これにより、内膜組織中において一定の頻度でSP細胞が常に存在することを証明した。また、これらの細胞の各種マーカーによる表面抗原解析によると、必ずしも一つのlineageに特化可能なphenotypeは有しておらず、幹/前駆細胞的性格を強く示唆した。

Research Products

(40 results)

All Other

All Publications (40 results)

[Publications] Sakai N, Maruyama T, Sakurai R, Masuda H, Yamamoto Y, Shimizu A, Kishi I, Asada H, Yamagoe S. Yoshimura Y: "Involvement of histone acetylation in ovarian steroid-induced decidualization of human endometrial stromal cells"J Biol Chem. (in press). (2003)
[Publications] Nakamura Y, Yamamoto M, Oda E, Yamamoto A, Kanemura Y, Hara M, Suzuki A, Yamasaki M, Okano H: "Experession of tubulin beta II in neural stem/progrenitor cells and radial fibers during human fetal brain development"Lab Invest. (in press). (2003)
[Publications] Sasaki T, Kitagawa K, Sugimura S, Omura-Matsuoka E, Tanaka S. Yagita Y, Okano H, Matsumoto M, Hori M: "Implication of Cyclooxygenase-2 on enhanced neurogenesis in the adult hippocampus after ischemia"J. Neurosci. Res. (in press). (2003)
[Publications] Okano H, Ogawa Y, Nakamura M, Kaneko S, Iwanami A, Toyama A: "Transplantation of neural stem cells into the spinal cord after injury"Seminar in Cell & Devlopmental Biol. (in press). (2003)
[Publications] Yoshimura Y: "Insulin-like growth factors and their binding proteins: the potential relevance to reproductive physiology"Reprod Med Biol. 2. 11-34 (2003)
[Publications] Ozawa N, Goda N, Makino N, Yamaguchi T, Yoshimura Y, Suematsu M: "Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ in response to stress"J Clin Invest. 109. 457-467 (2002)
[Publications] Tei C, Maruyama T, Kuji N, Miyazaki T, Mikami M, Yoshimura Y: "Reduced expression of avb3 integrin in the endometrium of unexplained infertility patients with recurrent IVF-ET failures: Improvement by danazol treatment"J Assist Reprod Genet. 20(1). 13-20 (2003)
[Publications] Maruyama T, Farina A, Dey A, Cheong J, Bermudez VP, Tamura T, Sciortino S, Shuman J, Hurwitz J, Ozato K: "A mammalian bromodomain protein Brd4 interacts with the replication factor C and inhibits progression to S phase"Mol Cell Biol. 22(18). 6509-6520 (2002)
[Publications] Yamamoto Y, Maruyama T, Sakai N, Sakurai R, Shimizu A, Hamatani T, Uchida H, Sabe H. Yoshimura Y: "Expression and subcellular distribution of the active form of c-Src tyrosine kinase in differentiating human endometrial stromal cells"Mol Hum Reprod. 8(12). 1117-1124 (2002)
[Publications] Asada H, Kishi I, Kaseda S, Nakagawa H, Maruyama T, Yoshimura Y: "Laparoscopic treatment of polycystic ovaries with the Holmium: YAG laser"Fertil Steril. 4(77). 852-853 (2002)
[Publications] Minegishi K, Tanaka M, Nishimura O, Tanigaki S, Miyakoshi K, Ishimoto H, Yoshimura Y: "Reactive oxygen species mediate leukocyte-endothelium interactions in prostaglandin F 2α -induced luteolysis in rats"Am J Physiol Endocrinol Metad. 283. E1308-E1315 (2002)
[Publications] Shiokawa S, Iwashita M, Akimoto Y, Nagamathu S, Sakai K, Hamashi H, Kabir-Salmani M, Nakamura Y, Uehata M, Yoshimura Y: "Small guanosine triphospatase RhoA and Rho-associated kinase as regulators of trophoblast migration"J Clin Endocrinol Metab. 87. 5808-5816 (2002)
[Publications] Ueno K, Tanaka M, Miyakoshi K, Zhao C, Shinmoto H, Nishimura G, Yoshimura Y: "Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation"Prenat Diagn. 22. 1071-1075 (2002)
[Publications] Kashiwagi S, Kajimura M, Yoshimura Y, Suemathu M: "Nonendothelial source of nitric oxide in arterioles but not in venules. Alternative source revealed in vivo by diaminofluorescein microfluorogrphy"Cir Res. 91. e55-e64 (2002)
[Publications] Tanaka M, Teranishi T, Miyakoshi K, Jiaxue W, Ueno K, Mathumoto T, Hattori Y, Yoshimura Y: "Oocyte-specific linker histone in mammalian species"J Mamm Ova Res. 19. 60-65 (2002)
[Publications] Yoshimura Y: "The role of integrins in the human reproductive process"J Reprod Dev. 48. 215-232 (2002)
[Publications] Maruyama T, Yamamoto Y, Sakai N, Shimizu A, Shimoki A, Masuda H, Yoshimura Y: "Protein tyrosine phosphorylation signaling in the differentiation of human endmetrial stromal cells"Keio J Med. 6(51). 93-99 (2002)
[Publications] Ozawa N, Goda N, Makino N, Yamaguchi T, Yoshimura Y, Suematsu M: "Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ in response to stress"J Clin Invest. 109. 457-467 (2002)
[Publications] Sakakibara S, Nakamura Y, Koike M, Takano H, Uchiyama, Noda T, Okano H: "RNA-binding protein Musashi family, roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation"Proc Natl Acad Sci USA. 99. 15194-15199 (2002)
[Publications] Kuranaga E, Kanuka H, Igaki T, Sawamoto K, Ichijo H, Okano H, Miura M: "Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila"Nature Cell Biol. 4. 705-710 (2002)
[Publications] Kanemura Y, Mon H, Kobayashi S, Islam O, Kodama E, Yamamoto A, Nakanishi Y, Arita N, Yamasaki M, Okano H, Miyake J, Hara M: "Evaluation of in-vitro proliferative activity of human fetal neural stem cell"J Neurosci Res. 69. 869-879 (2002)
[Publications] Johansson CB, Lothian C, Molin M, Okano H, Lendahi U: "Nestin enhancer requirements for expression in normal and injured adult CNS"J. Neurosci Res. 69. 784-794 (2002)
[Publications] Murayama A, Matsuzaki Y, Kawaguti A, Shimazaki T, Okano H: "Flow cytometric analysis of stem cells in the developing and adult mouse brain"J Neurosci Res. 69. 837-847 (2002)
[Publications] Ogawa Y, Sawamoto K, Miyata T, Miyao S, Watanabe M, Toyama Y, Nakamura M, Bregman B.S, Koike M, Uchiyama Y, Okano H: "Transplantation of in vitro expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats"J Neurosci Res. 69. 925-953 (2002)
[Publications] Yagita Y, Kitagawa K, Sasaki T, Miyata T, Okano H, Hori T, Matsumoto M: "Musashi1 and Nestin as useful markers of neuronal progenitor cells in rat hippocampus after forebrain ischemia"J Neurosci Res. 69. 750-756 (2002)
[Publications] Shamloula H.K, Mbogho M.P, Pimentel A.C, Chrzanowska-Lightowlers Z.M.A, Hyatt V, Okano H.Venkatech T.R: "rugose (rg), a Drosophila A kinase Anchor Protein (DAKAP), is required for required for retinal pattern formation and interacts genetically with multiple signaling pathways"Genetics. 161. 693-710 (2002)
[Publications] Cuadrado A, Garcia-Fernandez L.F, Imai T, Okano H, Munoz A: "Neural RNA-binding protein Musashi-1 modulates tau pre-mRNA alternative splicing and is regulated by thyroid hormone in the developing rat brain"Mol Cell Neurosci. 20. 198-210 (2002)
[Publications] Shu H-J, Saito T, Watanabe H, Ito J-I, Takeda H, Okano H, Kawata S: "Expression of the Musashil gene encoding the RNA-binding protein in human hepatoma cell lines"Biochem Biophys Res Com. 293. 150-154 (2002)
[Publications] Shibata M, Yamawaki T, Sasaki T, Hattori H, Hamada J, Fukuuchi Y, Okano H, Miura M: "Upregulation of Akt phosphorylation at the early stage of middle cerebral artery occlusion in mice"Brain Res. 942. 1-10 (2002)
[Publications] Iwai Y, Hirota Y, Ozaki K, Okano H, Takeichi M, Uemura T: "DN-cadherin-dependent synaptogenesis in the Drosophila visual system"Mol Cell Neurosci. 19. 375-388 (2002)
[Publications] Takasawa K.-I, Kitagawa K, Yagita Y, Sasaki T, Tanaka S, Ohtsuki T, Miyata T, Okano H, Hori M, Matsumoto M: "Increased proliferation of neural progenitor cells but reduced survival newborn cells in the contralateral hippocampus after focal cerebral ischemia in rats"J Cereb Blood Flow Metab. 22. 299-307 (2002)
[Publications] Okano H: "Neural stem cells: progression of basic research and perspective for clinical application"Keio J Med. 51. 115-158 (2002)
[Publications] Okano H: "The stem cell biology of the central nervous system"J Neurosci Res. 69. 698-707 (2002)
[Publications] Okano H, Imai T, Okabe M: "Musashi: a translational regulator of cell fates"J Cell Sci. 115. 1355-1359 (2002)
[Publications] Okano H, Yoshizaki I, Shimazaki T, Sawamoto K: "Isolation and transplantation of dopaminergic neurons and neural stem cells"Parkinsonism Relat Disord. 9. 23-28 (2002)
[Publications] Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC, Melton DA.: "" Stemness" : transcriptional profiling of embryonic and adult stem cells"Science. 298(5593). 597-600 (2002)
[Publications] 丸山哲夫, 吉村泰典: "「臨床エビデンス婦人科学」生殖内分泌疾患[総論]ホルモン療法の基本"メジカルビュー(in press). (2003)
[Publications] 鈴森薫, 吉村泰典, 堤治編: "新しい産科学.生殖医療から周産期医療まで"名古屋大学出版会. 286 (2002)
[Publications] 吉村泰典: "生殖医療のあり方を問う"診断と治療社. 156 (2002)
[Publications] 吉村泰典編: "インフォームドコンセントのための図説シリーズ子宮内膜症"医薬ジャーナル社. 44 (2002)

2002 Fiscal Year Annual Research Report

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

Principal Investigator

吉村 泰典 慶應義塾大学, 医学部, 教授 (10129736)

Research Products

[Publications] Sakai N, Maruyama T, Sakurai R, Masuda H, Yamamoto Y, Shimizu A, Kishi I, Asada H, Yamagoe S. Yoshimura Y: "Involvement of histone acetylation in ovarian steroid-induced decidualization of human endometrial stromal cells"J Biol Chem. (in press). (2003)

[Publications] Nakamura Y, Yamamoto M, Oda E, Yamamoto A, Kanemura Y, Hara M, Suzuki A, Yamasaki M, Okano H: "Experession of tubulin beta II in neural stem/progrenitor cells and radial fibers during human fetal brain development"Lab Invest. (in press). (2003)

[Publications] Sasaki T, Kitagawa K, Sugimura S, Omura-Matsuoka E, Tanaka S. Yagita Y, Okano H, Matsumoto M, Hori M: "Implication of Cyclooxygenase-2 on enhanced neurogenesis in the adult hippocampus after ischemia"J. Neurosci. Res. (in press). (2003)

[Publications] Okano H, Ogawa Y, Nakamura M, Kaneko S, Iwanami A, Toyama A: "Transplantation of neural stem cells into the spinal cord after injury"Seminar in Cell & Devlopmental Biol. (in press). (2003)

[Publications] Yoshimura Y: "Insulin-like growth factors and their binding proteins: the potential relevance to reproductive physiology"Reprod Med Biol. 2. 11-34 (2003)

[Publications] Ozawa N, Goda N, Makino N, Yamaguchi T, Yoshimura Y, Suematsu M: "Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ in response to stress"J Clin Invest. 109. 457-467 (2002)

[Publications] Tei C, Maruyama T, Kuji N, Miyazaki T, Mikami M, Yoshimura Y: "Reduced expression of avb3 integrin in the endometrium of unexplained infertility patients with recurrent IVF-ET failures: Improvement by danazol treatment"J Assist Reprod Genet. 20(1). 13-20 (2003)

[Publications] Maruyama T, Farina A, Dey A, Cheong J, Bermudez VP, Tamura T, Sciortino S, Shuman J, Hurwitz J, Ozato K: "A mammalian bromodomain protein Brd4 interacts with the replication factor C and inhibits progression to S phase"Mol Cell Biol. 22(18). 6509-6520 (2002)

[Publications] Yamamoto Y, Maruyama T, Sakai N, Sakurai R, Shimizu A, Hamatani T, Uchida H, Sabe H. Yoshimura Y: "Expression and subcellular distribution of the active form of c-Src tyrosine kinase in differentiating human endometrial stromal cells"Mol Hum Reprod. 8(12). 1117-1124 (2002)

[Publications] Asada H, Kishi I, Kaseda S, Nakagawa H, Maruyama T, Yoshimura Y: "Laparoscopic treatment of polycystic ovaries with the Holmium: YAG laser"Fertil Steril. 4(77). 852-853 (2002)

[Publications] Minegishi K, Tanaka M, Nishimura O, Tanigaki S, Miyakoshi K, Ishimoto H, Yoshimura Y: "Reactive oxygen species mediate leukocyte-endothelium interactions in prostaglandin F 2α -induced luteolysis in rats"Am J Physiol Endocrinol Metad. 283. E1308-E1315 (2002)

[Publications] Shiokawa S, Iwashita M, Akimoto Y, Nagamathu S, Sakai K, Hamashi H, Kabir-Salmani M, Nakamura Y, Uehata M, Yoshimura Y: "Small guanosine triphospatase RhoA and Rho-associated kinase as regulators of trophoblast migration"J Clin Endocrinol Metab. 87. 5808-5816 (2002)

[Publications] Ueno K, Tanaka M, Miyakoshi K, Zhao C, Shinmoto H, Nishimura G, Yoshimura Y: "Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation"Prenat Diagn. 22. 1071-1075 (2002)

[Publications] Kashiwagi S, Kajimura M, Yoshimura Y, Suemathu M: "Nonendothelial source of nitric oxide in arterioles but not in venules. Alternative source revealed in vivo by diaminofluorescein microfluorogrphy"Cir Res. 91. e55-e64 (2002)

[Publications] Tanaka M, Teranishi T, Miyakoshi K, Jiaxue W, Ueno K, Mathumoto T, Hattori Y, Yoshimura Y: "Oocyte-specific linker histone in mammalian species"J Mamm Ova Res. 19. 60-65 (2002)

[Publications] Yoshimura Y: "The role of integrins in the human reproductive process"J Reprod Dev. 48. 215-232 (2002)

[Publications] Maruyama T, Yamamoto Y, Sakai N, Shimizu A, Shimoki A, Masuda H, Yoshimura Y: "Protein tyrosine phosphorylation signaling in the differentiation of human endmetrial stromal cells"Keio J Med. 6(51). 93-99 (2002)

[Publications] Ozawa N, Goda N, Makino N, Yamaguchi T, Yoshimura Y, Suematsu M: "Leydig cell-derived heme oxygenase-1 regulates apoptosis of premeiotic germ in response to stress"J Clin Invest. 109. 457-467 (2002)

[Publications] Sakakibara S, Nakamura Y, Koike M, Takano H, Uchiyama, Noda T, Okano H: "RNA-binding protein Musashi family, roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation"Proc Natl Acad Sci USA. 99. 15194-15199 (2002)

[Publications] Kuranaga E, Kanuka H, Igaki T, Sawamoto K, Ichijo H, Okano H, Miura M: "Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila"Nature Cell Biol. 4. 705-710 (2002)

[Publications] Kanemura Y, Mon H, Kobayashi S, Islam O, Kodama E, Yamamoto A, Nakanishi Y, Arita N, Yamasaki M, Okano H, Miyake J, Hara M: "Evaluation of in-vitro proliferative activity of human fetal neural stem cell"J Neurosci Res. 69. 869-879 (2002)

[Publications] Johansson CB, Lothian C, Molin M, Okano H, Lendahi U: "Nestin enhancer requirements for expression in normal and injured adult CNS"J. Neurosci Res. 69. 784-794 (2002)

[Publications] Murayama A, Matsuzaki Y, Kawaguti A, Shimazaki T, Okano H: "Flow cytometric analysis of stem cells in the developing and adult mouse brain"J Neurosci Res. 69. 837-847 (2002)

[Publications] Yagita Y, Kitagawa K, Sasaki T, Miyata T, Okano H, Hori T, Matsumoto M: "Musashi1 and Nestin as useful markers of neuronal progenitor cells in rat hippocampus after forebrain ischemia"J Neurosci Res. 69. 750-756 (2002)

[Publications] Cuadrado A, Garcia-Fernandez L.F, Imai T, Okano H, Munoz A: "Neural RNA-binding protein Musashi-1 modulates tau pre-mRNA alternative splicing and is regulated by thyroid hormone in the developing rat brain"Mol Cell Neurosci. 20. 198-210 (2002)

[Publications] Shu H-J, Saito T, Watanabe H, Ito J-I, Takeda H, Okano H, Kawata S: "Expression of the Musashil gene encoding the RNA-binding protein in human hepatoma cell lines"Biochem Biophys Res Com. 293. 150-154 (2002)

[Publications] Shibata M, Yamawaki T, Sasaki T, Hattori H, Hamada J, Fukuuchi Y, Okano H, Miura M: "Upregulation of Akt phosphorylation at the early stage of middle cerebral artery occlusion in mice"Brain Res. 942. 1-10 (2002)

[Publications] Iwai Y, Hirota Y, Ozaki K, Okano H, Takeichi M, Uemura T: "DN-cadherin-dependent synaptogenesis in the Drosophila visual system"Mol Cell Neurosci. 19. 375-388 (2002)

[Publications] Okano H: "Neural stem cells: progression of basic research and perspective for clinical application"Keio J Med. 51. 115-158 (2002)

[Publications] Okano H: "The stem cell biology of the central nervous system"J Neurosci Res. 69. 698-707 (2002)

[Publications] Okano H, Imai T, Okabe M: "Musashi: a translational regulator of cell fates"J Cell Sci. 115. 1355-1359 (2002)

[Publications] Okano H, Yoshizaki I, Shimazaki T, Sawamoto K: "Isolation and transplantation of dopaminergic neurons and neural stem cells"Parkinsonism Relat Disord. 9. 23-28 (2002)

[Publications] Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC, Melton DA.: "" Stemness" : transcriptional profiling of embryonic and adult stem cells"Science. 298(5593). 597-600 (2002)

[Publications] 丸山哲夫, 吉村泰典: "「臨床エビデンス婦人科学」生殖内分泌疾患[総論]ホルモン療法の基本"メジカルビュー(in press). (2003)

[Publications] 鈴森 薫, 吉村 泰典, 堤 治 編: "新しい産科学.生殖医療から周産期医療まで"名古屋大学出版会. 286 (2002)

[Publications] 吉村 泰典: "生殖医療のあり方を問う"診断と治療社. 156 (2002)

[Publications] 吉村 泰典 編: "インフォームドコンセントのための図説シリーズ子宮内膜症"医薬ジャーナル社. 44 (2002)

吉村泰典慶應義塾大学, 医学部, 教授 (10129736)

[Publications] 鈴森薫, 吉村泰典, 堤治編: "新しい産科学.生殖医療から周産期医療まで"名古屋大学出版会. 286 (2002)

[Publications] 吉村泰典: "生殖医療のあり方を問う"診断と治療社. 156 (2002)

[Publications] 吉村泰典編: "インフォームドコンセントのための図説シリーズ子宮内膜症"医薬ジャーナル社. 44 (2002)